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Genetic and epidemiologic aspects of multiple sclerosis in British Columbia Sadovnick, Adele D. 1979

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GENETIC AND EPIDEMIOLOGIC ASPECTS OF MULTIPLE SCLEROSIS IN BRITISH COLUMBIA by ADELE D. SADOVNICK B.Sc, McGill University, 1972 M.Sc, McGill University, 1974 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Medical Genetics) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November 1979 Adele D. Sadovnick^ .1.979 In presenting th is thesis in par t ia l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the Library sha l l make i t f ree ly avai lab le for reference and study. I further agree that permission for extensive copying of th is thesis for scholar ly purposes may be granted by the Head of my Department or by his representat ives. I t i s understood that copying or publ icat ion of th is thesis for f inanc ia l gain shal l not be allowed without my written permission. ^ M e d i c a l G e n e t i c s Department of _ The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date A p r i l 23, 1980 1-6 B P 75-5 ! ! E ABSTRACT The e t i o l o g y of m u l t i p l e s c l e r o s i s (MS) remains unknown d e s p i t e much r e s e a r c h . The c o n t r o v e r s y about a g e n e t i c com-ponent to MS has been going on f o r n e a r l y a c e n t u r y . Using v a r i o u s sources, the two main ones being the B r i t i s h Columbia (B.C.) Health S u r v e i l l a n c e R e g i s t r y and the B.C. D i v i s i o n of the MS S o c i e t y of Canada, 983 persons, rep o r t e d to have MS and l i v i n g i n B.C. on A p r i l 30, 1976, were a s c e r t a i n e d . These data g i v e a prevalence r a t e f o r the p r o v i n c e of 39.9 per 100,000 p o p u l a t i o n and a femalermale sex r a t i o of 1.9:1. These f i n d i n g s are what i s expected f o r a n o r t h e r n , temperate region such as B.C. Genetic and medical h i s t o r i e s were obtained f o r 416 of the a s c e r t a i n e d p a t i e n t s . Empiric f a m i l i a l r e c u r r e n c e r i s k s , needed f o r g e n e t i c coun-s e l l i n g , were d e r i v e d f o r f i r s t , second, and t h i r d degree r e l a -t i v e s of p a t i e n t s . The f a m i l y data were t e s t e d f o r " g o o d n e s s - o f - f i t " to the m u l t i f a c t o r i a l two-threshold model of i n h e r i t a n c e . T h i s model was r e j e c t e d on the b a s i s t h a t "too many" f a m i l i e s with at l e a s t two a f f e c t e d s i b l i n g s were observed than can be expected under the model. T h i s i s evidence f o r e i t h e r (a) a g e n e t i c model with a higher recurrence r i s k than the m u l t i f a c t o r i a l model or (b) g e n e t i c h e t e r o g e n e i t y . - i i i -There i s evidence f o r phenotypic h e t e r o g e n e i t y i n MS. P a t i e n t s with a f a m i l y h i s t o r y of the d i s e a s e tend to develop MS at an e a r l i e r age than do those with no f a m i l y h i s t o r y . Pregnancy i n c r e a s e s the r i s k of an e x a c e r b a t i o n during a "pregnancy year", p a r t i c u l a r l y d u r i n g the three months p o s t -partum. However, pregnancy does not appear to a f f e c t the l o n g -term prognosis f o r MS. In summary, the r e s u l t s from t h i s study c o n f i r m the f i n d -ings of others t h a t a g e n e t i c f a c t o r (or f a c t o r s ) i s a s s o c i a t e d with the m a n i f e s t a t i o n of MS and t h a t there i s an i n c r e a s e d frequency of the d i s e a s e among r e l a t i v e s of p a t i e n t s compared with the g e n e r a l p o p u l a t i o n . While the p r e c i s e g e n e t i c model i s u n c l e a r , r e c u r r e n c e r i s k estimates have been d e r i v e d f o r the f i r s t time. Hence g e n e t i c c o u n s e l l i n g i s recommended f o r a l l MS p a t i e n t s and t h e i r f a m i l i e s . - i v -TABLE OF CONTENTS PAGE ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i i LIST OF FIGURES x ACKNOWLEDGEMENTS x i CHAPTER 1: INTRODUCTION 1 CHAPTER 2: BACKGROUND 2.1. What i s M u l t i p l e S c l e r o s i s ? 2.1.1. G e n e r a l D e s c r i p t i o n 4 2.1.2. E t i o l o g y 8 2.1.3. G e n e t i c s 11 2.1.4. P r e v a l e n c e 20 CHAPTER 3: MATERIALS AND METHODS 3.1. Data 3.1.1. A s c e r t a i n m e n t Sources 22 3.1.2. P r o c e d u r e s f o r C o n t a c t i n g P o t e n t i a l S u b j e c t s 25 3.1.3. Data C o l l e c t i o n 26 3.1.4. C o n f i r m a t i o n o f D i a g n o s i s 26 3.2. Data A n a l y s i s 3.2.1. "PGOODFIT" A n a l y s i s 27 3.2.2. P h e n o t y p i c H e t e r o g e n e i t y 37 - v -PAGE 3.2.3. Grading the D i s a b i l i t y i n P a t i e n t s 37 3.2.4. Chi-Square (X 2) S t a t i s t i c 38 3.2.5. One-Way A n a l y s i s of Variance 39 3.2.6.. Confidence L i m i t s 39 CHAPTER 4: RESULTS 4.1. Su b j e c t s 4.1.1. Attempts to Contact P o t e n t i a l S u b j e c t s ... 40 4.1.2. Data C o l l e c t i o n 42 4.1.3. General D e s c r i p t i o n of the Subjects 42 4.2. Empiric F a m i l i a l Recurrence R i s k s 46 4.3. "PGQODFIT" A n a l y s i s 52 4.4. Phenotypic Heterogeneity 4.4.1. Age of Onset 52 4.4.2. F i r s t Symptoms 57 4.4.3. S e v e r i t y ' 61 4.5. Pregnancy 63 4.6. Epidemiology 4.6.1. Prevalence Rates 72 4.6.2. Sex R a t i o s 72 CHAPTER 5: DISCUSSION 5.1. Subjects 5.1.1. Data C o l l e c t i o n 76 5.1.2. General D e s c r i p t i o n of the Subjects 77 5.2. Empiric F a m i l i a l Recurrence Risks 78 - v i -PAGE 5 . 3 . Genetics of MS 84 5 . 4 . Phenotypic Heterogeneity 92 5 . 5 . Pregnancy 93 5 . 6 . Epidemiology 5 . 6 . 1 . Prevalence Rates 96 5 . 6 . 2 . Sex Ratios 98 CHAPTER 6 : CONCLUSIONS 99 FOOTNOTES ' 1 0 1 BIBLIOGRAPHY 102 APPENDICES APPENDIX A: Letter Describing the Intended Study to Potential Subjects 113 APPENDIX B: Form on Which Potential Subjects Indicated their Willingness to Participate 114 APPENDIX C: Questionnaire Used for Obtaining Data 115 APPENDIX D: Description of Cases of "Possible" MS among Relatives of Probands 125 APPENDIX E: "PGOODFIT" Programme 129 APPENDIX F: Calculation of " r " and "h 2" by MULFAC 130 APPENDIX G: Empiric F a m i l i a l Recurrence Risks 134 APPENDIX H: Pregnancy and MS 137 - v i i -LIST OF TABLES TABLE NUMBER TITLE PAGE I F a m i l i a l Incidence of MS: Survey of the Literature 13 II HLA Antigens Reported to be Associated with MS 18 III Preliminary Sources of Ascertainment of Cases in Study 23 IV Coding of the Nuclear Families of Probands According to Family Structure ... 30 V Components of Variance 3 3 VI Results of Attempts to Contact Potential Subjects 41 VII Frequency of Use for Each Method of Data Col l e c t i o n 43 VIII Description of the Probands with Respect to Sex, Age of Onset of MS, Age at the Time of Study, and Duration of MS 44 IX Description of the Five Probands Who Died after P a r t i c i p a t i o n 45 X Proportion of Probands with a Family History of MS 47 XI Empiric Recurrence Risks for MS 49 XII Frequency of MS among Relatives of the Probands (by Degree of the Relationship) . 50 XIII Prevalence of MS among Relatives of the Probands Compared with Rates for the General Population 51 XIV Computed "PRG" Values for MS 53 XV Computed "PRL" Values for MS 54 - v i i i -TABLE NUMBER TITLE PAGE XVI P r o p o r t i o n of Males and Females Report-ing Each of S i x Fr e q u e n t l y Reported F i r s t Symptoms of MS 59 XVII P r o p o r t i o n s of Probands with and without a Family H i s t o r y of MS Reporting Each of Six F r e q u e n t l y Reported F i r s t Symptoms of MS 60 XVIII P r o p o r t i o n of Males and Females i n Each of Three D i s a b i l i t y C a t e g o r i e s f o r MS .... 62 XIX P r o p o r t i o n of Probands with and without a Family H i s t o r y of MS i n Each of Three D i s a b i l i t y C a t e g o r i e s 64 XX P r o p o r t i o n of Probands with and without a Family H i s t o r y of MS i n Each of the Six D i s a b i l i t y Grades 65 XXI Pregnancy H i s t o r i e s f o r 278 Females with MS 66 XXII Comparison of the Relapse (Exacerbation) Rates f o r Women with and without a H i s t o r y of Pregnancies. Comparison of These Rates with t h a t f o r Women du r i n g a Pregnancy Year 68 XXIII Comparison of the P r o p o r t i o n of Females with and without Pregnancies i n Each of the Three D i s a b i l i t y C a t e g o r i e s f o r MS ... 70 XXIV E f f e c t of Pregnancy on MS i n A s s o c i a t i o n with the Presence or Absence of a Family H i s t o r y of " D e f i n i t e " or " C l i n i c a l l y D e f i n i t e " MS 71 XXV Age and S e x - S p e c i f i c Prevalence Rates f o r B r i t i s h Columbia 73 XXVI The Sex R a t i o s f o r MS P a t i e n t s i n B r i t i s h Columbia, Winnipeg, and Saskatoon 75 XXVII Increased Risk of MS to R e l a t i v e s of Pro-bands Compared with the General P o p u l a t i o n 79 - ix -TABLE NUMBER TITLE PAGE XXVIII G o o d n e s s - o f - f i t of Empi r i c Risks f o r S i b l i n g s of Probands to the Autosomal Dominant and Autosomal Recessive Models of I n h e r i t a n c e 85 XXIX Comparison of H e r i t a b i l i t y Estimates from Var i o u s S t u d i e s ... 91 XXX Prevalence Rates i n Canada 97 XXXI R e s u l t s of MULFAC A n a l y s i s on Data 133 XXXII Empi r i c Recurrence Risks f o r " D e f i n i t e " and " C l i n i c a l l y D e f i n i t e " MS 134 XXXIII Empiric Recurrence Risks f o r " P o s s i b l e " MS 135 XXXIV Empiric Recurrence Risks f o r " D e f i n i t e " , " C l i n i c a l l y D e f i n i t e " and " P o s s i b l e " MS ... 136 - x -LIST OF FIGURES FIGURE NUMBER TITLE PAGE 1 Schematic G e n e t i c Map o f Human HLA Region 15 2 The I n h e r i t a n c e o f HLA H a p l o t y p e s 16 3 Graph: C o r r e l a t i o n i n L i a b i l i t y (r) between R e l a t i v e s as a F u n c t i o n o f the P r e v a l e n c e i n the P o p u l a t i o n (Kp) and the P r e v a l e n c e i n R e l a t i v e s of A f f e c t e d I n d i v i d u a l s (K R) 34 4 Two-Threshold Model f o r D i s o r d e r s w i t h D i f f e r e n t P r e v a l e n c e Rates f o r Males and Females 36 5 Graph: Age o f Onset D i s t r i b u t i o n s i n A s s o c i a t i o n w i t h the Sex o f the Proband . 56 6 Graph: Age of Onset D i s t r i b u t i o n s i n A s s o c i a t i o n w i t h the Presence or Absence of a F a m i l y H i s t o r y of MS 58 7a E m p i r i c Recurrence R i s k s f o r F i r s t Degree R e l a t i v e s of Female Probands 81 7b E m p i r i c R ecurrence R i s k s f o r F i r s t Degree R e l a t i v e s o f Male Probands 81 8 E m p i r i c R ecurrence R i s k s f o r F i r s t Degree R e l a t i v e s o f Probands 82 9 E m p i r i c Recurrence R i s k s f o r F i r s t , Second, and T h i r d Degree R e l a t i v e s o f Probands 83 - x i ACKNOWLEDGEMENTS The subject matter of this thesis was inspired by a very courageous lady, Evelyn G. Opal, who stimulated my interest in multiple s c l e r o s i s by showing that a person a f f l i c t e d with the disease can s t i l l a c t i v e l y contribute to society. I wish to thank the members of my advisory committee for their continuous assistance throughout the duration of this study, in p a r t i c u l a r , Dr. James R. M i l l e r , chairman. I would l i k e to acknowledge the assistance of the late Benjamin K. Trimble in the formulation of this research plan. Special appreciation goes to Dr. Anne Spence, Division of Medical Genetics, University of C a l i f o r n i a at Los Angeles, without whom the "PGOODFIT" analysis would not have been possible. The Multiple Sclerosis Society of Canada provided finan-c i a l support for the duration of this study. Additional sup-port for the "PGOODFIT" analysis was provided by the Division of Medical Genetics, University of C a l i f o r n i a at Los Angeles through PHS grants MCH-927, HD-04612, HD-00345, and HD-05615. This study was part of a collaborative programme involving the V i t a l S t a t i s t i c s Division of the B r i t i s h Columbia Ministry of Health and the Department of Medical Genetics at the Univer-s i t y of B r i t i s h Columbia. Permission to use the p r o v i n c i a l v i t a l and health records was conditional upon the s t r i c t - x i i -observation of the oath of-secrecy respecting the non-statis-t i c a l information contained in the records. The assistance of the B.C. Division of the Multiple Scler-osis Society of Canada i s g r a t e f u l l y acknowledged. I wish to thank Dr. P a t r i c i a Baird, Department of Medical Genetics, University of B r i t i s h Columbia, and Dr. Nancy Mendell, Division of Microbiology and Immunology, Duke University, for their useful c r i t i c i s m s and suggestions. F i n a l l y , I would l i k e to thank Arnie, Jodi, and Joshua for their patience and encouragement. I trust that they think i t was a l l worthwhile. - 1 -CHAPTER I INTRODUCTION M u l t i p l e s c l e r o s i s (MS) i s a d i s e a s e of the c e n t r a l ner-vous system c h a r a c t e r i z e d , p a t h o l o g i c a l l y , by d emyelination and the formation of g l i o t i c l e s i o n s c a l l e d "plaques". The d i s e a s e shows g r e a t v a r i a b i l i t y i n the age of onset and i n the degree of d i s a b i l i t y i n a s s o c i a t i o n with the dura-t i o n of the i l l n e s s . There i s no d i a g n o s t i c t e s t s p e c i f i c f o r MS and the d i a g n o s i s can be d e f i n i t e l y confirmed only at autopsy. A l l these f a c t o r s make MS a d i f f i c u l t d i s e a s e to diagnose and t r e a t . The e t i o l o g y of MS i s unknown. The occurrence of f a m i l i a l aggregates and the r e s u l t s from HLA s t u d i e s suggest t h a t there i s a g e n e t i c component. E p i d e m i o l o g i c surveys have shown that the prevalence of the d i s e a s e v a r i e s with the geographic r e -g i o n . The prevalence r a t e decreases towards the equator. The most favoured e t i o l o g i c h ypothesis f o r MS i s a slow a c t i n g v i r u s . There i s c o n t r o v e r s y as to whether g e n e t i c f a c t o r s i n f l u e n c e a person's s u s c e p t i b i l i t y to t h i s v i r u s . Although there have been s e v e r a l p o p u l a t i o n s t u d i e s of MS in v a r i o u s regions of the world, no such survey has been done in B r i t i s h Columbia (B.C.), Canada. B . C i s i n a temperate zone with most of i t l y i n g between the 49° and 60° northern - 2 -l a t i t u d e s . C o a s t a l regions have a m i l d , wet c l i m a t e with the average temperature i n J u l y being 23°C and i n January, 0°C. A province-wide survey of MS was f e a s i b l e f o r s e v e r a l reasons: (a) R e s u l t s from v a r i o u s e p i d e m i o l o g i c surveys i n d i c a t e that n o r t h e r n , temperate regions are "high r i s k zones" f o r MS. By d e f i n i t i o n , a "high r i s k zone" f o r MS i s one with more than 40 a f f e c t e d persons per 100,000 p o p u l a t i o n (Kurtzke, 1977; McAlpine e t a l . , 1972). Since B.C. i s g e o g r a p h i c a l l y s i t u a t e d i n such a r e g i o n , i t was probable t h a t a s u f f i c i e n t number of p a t i e n t s would be a s c e r t a i n e d to make the study s t a t i s t i c a l l y m eaningful. (b) B.C. has a "Health S u r v e i l l a n c e R e g i s t r y " which r e g i s t e r s persons with handicapping and/or g e n e t i c c o n d i t i o n s . The e x i s -tence of t h i s " R e g i s t r y " g r e a t l y eased the task of a s c e r t a i n i n g MS p a t i e n t s throughout the p r o v i n c e . The main aim of the r e s e a r c h was to i n v e s t i g a t e g e n e t i c aspects of MS. I t was hoped t h a t e m p i r i c f a m i l i a l r ecurrence r i s k s important, f o r g e n e t i c c o u n s e l l i n g , c o u l d be d e r i v e d . In a d d i t i o n , i n s i g h t i n t o the e t i o l o g y of MS co u l d be gained by t e s t i n g the " g o o d n e s s - o f - f i t " of the data t o the m u l t i f a c t o r i a l model of i n h e r i t a n c e . MS data has never been f o r m a l l y t e s t e d f o r " g o o d n e s s - o f - f i t " to any model of i n h e r i t a n c e . The study was a l s o designed to assess whether there i s evidence that the n a t u r a l h i s t o r y of MS d i f f e r s depending on the sex of the - 3 -proband and the presence or absence of a family history for MS. C l i n i c a l features investigated in th i s regard were age of onset, f i r s t reported symptoms, and severity. Although not a main aim of the study, i t was possible to derive minimal prevalence rates for B.C. - 4 -CHAPTER 2 BACKGROUND 2.1. WHAT IS MULTIPLE SCLEROSIS? 2.1.1. General D e s c r i p t i o n MS i s one of the most common causes of n e u r o l o g i c a l d i s -a b i l i t y i n a d u l t s . Females are the more f r e q u e n t l y a f f e c t e d sex (Acheson, 1977). MS i s p r i m a r i l y a dis e a s e of Caucasians although i t has been r e p o r t e d i n other races ( A l t e r & Harshe, 1975; M i l l a r & A l l i s o n , 1971; Beebe e t a l . , 1967). Any s p e c i f i c symptom of the d i s e a s e i s r e l a t e d to one or more areas of dem y e l i n a t i o n i n the b r a i n or s p i n a l cord ( S i l -berberg, 1978). Although the d i s t r i b u t i o n of the l e s i o n s i n the white matter appears t o be random, some symptoms occur more f r e q u e n t l y than o t h e r s . Motor symptoms, i n c l u d i n g weakness or lack of c o o r d i n a t i o n i n one or more limbs, i n t e n t i o n tremor, s p a s t i c i t y , and i n v o l u n t a r y f l e x o r spasms are the most common ( S i l b e r b e r g , 1978; McAlpine e t a l . , 1972). The course of the d i s e a s e i s v a r i a b l e . The most common course i s one of ex a c e r b a t i o n s f o l l o w e d by r e m i s s i o n s . A f t e r the i n i t i a l a t t a c k , symptoms o f t e n disappear e n t i r e l y or improve s i g n i f i c a n t l y w i t h i n days or weeks. Most p a t i e n t s , a f t e r f o l -lowing a r e m i s s i o n / e x a c e r b a t i o n c y c l e f o r s e v e r a l y e a r s , begin to experience p r o g r e s s i v e d e t e r i o r a t i o n . However, not a l l - 5 -p a t i e n t s i n i t i a l l y have t h i s c y c l e i n the e a r l y stages of t h e i r i l l n e s s . The d i s e a s e can be p r o g r e s s i v e from the onset; t h i s i s common i n persons who experience t h e i r f i r s t symptom at a r e l -a t i v e l y " o l d e r " age, 35 and above (Cazzulo e t a l . , 1978; Rose, 1974) . There have been r e p o r t s of autopsy-confirmed cases of MS i n which death occurred s i x to twelve weeks a f t e r a sudden onset (McAlpine e t a l . , 1972). O c c a s i o n a l l y , the d i a g n o s i s of MS i s made at autopsy i n persons who had been symptom-free throughout a long and a c t i v e l i f e (McAlpine e t a l . , 1972). Persons with MS show, p a t h o l o g i c a l l y , d i s s o l u t i o n of the myelin i n the c e n t r a l nervous system, but there does not appear to be any damage t o e i t h e r the axons or neurons them-s e l v e s . The myelin-producing o l i g o d r e n d r o g l i a disappear from the r e g i o n s of demyelination and are r e p l a c e d by p r o l i f e r a t i n g a s t o c y t e s . T h i s a s t o c y t i c s c a r r i n g i s r e s p o n s i b l e f o r the name " M u l t i p l e S c l e r o s i s " . The g l i o t i c l e s i o n s (plaques) are f i r m to the touch and vary i n diameter from 1 or 2 mm to s e v e r a l c e n t i m e t e r s . These plaques are of d i f f e r e n t ages and are g r o s s l y v i s i b l e . F r e q u e n t l y , at autopsy, more plaques are observed than would be expected based on the d i s a b i l i t y of the p a t i e n t ( S i l b e r b e r g , 1978; McAlpine et a l . , 1972). A p r e c i s e d i a g n o s i s of MS i s important i n any r e s e a r c h on t h i s d i s o r d e r so t h a t the study group can be a c c u r a t e l y i d e n -t i f i e d . Although there i s no completely accurate d i a g n o s t i c t e s t , other than autopsy (Rawson, 1978), r e c e n t advances towards the development of one are pr o m i s i n g . Since the 1940's, - 6 -cerebrospinal f l u i d (CSF) has been studied as a tool for the diagnosis of MS (Christensen et a l . , 1978; Silberberg, 1978; Delmotte & Gonsette, 1977; Johnson & Nelson, 1977). CSF can be examined for c e l l count, protein l e v e l s , and IgG leve l s but the most accurate diagnostic test (95% accuracy) is the i d e n t i -f i c a t i o n of o l i g o c l o n a l bands in f l u i d from MS patients. Upon electrophoresis, antibodies s p e c i f i c to MS patients appear in s u f f i c i e n t quantity to form a band of their own, the o l i g o c l o n a l band. A diagnosis of MS i s usually based on the results from tests on CSF and from c l i n i c a l examination. For studies of patients with MS, both the National Multiple Sclerosis Society (U.S.A.) and the Multiple S c l e r o s i s Society of Canada agree that the diagnostic c r i t e r i a outlined by Schumacher et a l . (1965) are the best to date in allowing accu-rate i d e n t i f i c a t i o n of the study group. These c r i t e r i a are: a) There must be objective abnormalities on neuro-l o g i c a l examination attributable to dysfunction of the central nervous system. Symptoms alone, no matter how suggestive, cannot be accepted as diagnostic of multiple s c l e r o s i s . b) On neurological examination or by history, there must be evidence of involvement of two or more separate parts of the central nervous system. (In determining m u l t i p l i c i t y of lesions, c e r t a i n signs or combination of them require cautious inte r p r e t a t i o n . For example, paleness of the temporal half of the optic disc is pathologic only i f beyond the average range and i f supported by evidence of impairment of v i s u a l acuity and/or f i e l d or by a history suggesting a previous at-tack of retrobulbar neuropathy. It must also be kept in mind that " m u l t i p l i c i t y of s t r u c t u r a l i n -volvement" may occur in other central nervous system disease without f u l f i l l i n g the requirements of "separateness", " m u l t i p l i c i t y " , or "dissemination" - 7 -of l e s i o n s . Thus, i f the involvement of s e v e r a l s t r u c t u r e s can be a t t r i b u t e d t o a s i n g l e l e s i o n a t one l o c u s , as i s the case, f o r example, i n tumor or i n f a r c t of the brainstem or compression of the s p i n a l c o r d , such involvement cannot be c o n s i d e r e d as f u l f i l l i n g the c r i t e r i o n of " m u l t i p l i c i t y " . F u r t h e r , evidence r e f l e c t i n g the simultaneous and symmetric involvement of the l a t e r a l and p o s t e r i o r columns of the s p i n a l c o r d , found commonly i n d i s e a s e of the c e n t r a l nervous system other than m u l t i p l e s c l e r o s i s , cannot be i n t e r p r e t e d as caused by m u l t i p l e s c l e r o s i s i n absence of a d d i t i o n a l s i t e s of involvement.) c) The o b j e c t i v e n e u r o l o g i c evidence of c e n t r a l nervous system d i s e a s e must r e f l e c t predominantly white matter involvement, i . e . , f i b e r t r a c t damage. Thus, s i g n s must c o n s i s t mainly of o p t i c nerve, c e r e b r a l s u b c o r t i c a l , c o r t i c o b u l b a r , c o r t i c o s p i n a l , medial l o n g i t u d i n a l f a s c i c u l u s , c e r e b e l l a r sub-c o r t i c a l , s p i n o c e r e b e l l a r and long sensory t r a c t ( e s p e c i a l l y p o s t e r i o r column) d y s f u n c t i o n . More than a minor p r o p o r t i o n of s i g n s of lower motor neurone (brainstem, s p i n a l n u c l e a r gray matter, or p e r i p h e r a l nerve) d y s f u n c t i o n w i l l d i s q u a l i f y a s u b j e c t as having m u l t i p l e s c l e r o s i s f o r the pur-poses of an experimental t r i a l of therapy. d) The involvement of the n e u r a x i s must have oc-c u r r e d t emporally i n one or the other of the f o l l o w -ing p a t t e r n s : (1) In two or more episodes of worsening, separated by a p e r i o d of one month or more, each episode l a s t i n g at l e a s t 24 hours. (2) Slow or step-wise p r o g r e s s i o n of s i g n s or symp-toms over a p e r i o d of at l e a s t 6 months. These a r b i t r a r y t i m e - l i m i t s are necessary to exclude: (1) f l u c t u a t i n g or t r a n s i t o r y n e u r o l o g i c impairment due to other causes (e.g. v a s c u l a r ) ; and (2) acute disseminated n e u r o l o g i c d i s e a s e which i s s h o r t - l i v e d and n o n - r e c u r r e n t (such as encephalo-m y e l i t i s ) . e) The ages of the p a t i e n t at the onset of the d i s e a s e must f a l l w i t h i n the range of 10 to 50 y e a r s , i n c l u s i v e . f) The p a t i e n t ' s s i g n s and symptoms cannot be ex-p l a i n e d b e t t e r by some other d i s e a s e p r o c e s s , a d e c i s i o n which must be made by a p h y s i c i a n competent in c l i n i c a l neurology. - 8 -There i s no s p e c i f i c treatment for MS and, since the course is so variable, the e f f e c t s of various treatments are d i f f i c u l t to assess. Some of the most commonly used treatments include diets (Liversedge, 1977; Olson, 1976; Klenner , 1973; Swank, 1970); physiotherapy (Liversedge, 1977); ACTH and other c o r t i -costeroids, used to shorten exacerbations (Silberberg, 1978); baclofen to reduce s p a s t i c i t y (Silberberg, 1978; Basmajian, 1975); various drugs and catheters for bladder problems (Silber-berg, 1978 ; Liversedge, 1977); and psychotherapeutic. treatments for the psychological problems frequently associated with MS (Paulley, 1977; Hartings et a l . , 1976). 2.1.2. Etiology The l i t e r a t u r e on research on the etiology of MS i s volum-inous. Charcot (1868) i n i t i a l l y hypothesized that MS could be due to exposure to cold and dampness, physical injury, or emo-tio n a l stress. It was a student of Charcot's who f i r s t proposed that MS could have an "infectious" etiology (Marie, 1884). Since then, many e t i o l o g i c theories have been proposed. The current favoured hypothesis i s that MS i s an infec-tious, possibly v i r a l , disease with a genetic component for s u s c e p t i b i l i t y . Results from epidemiologic surveys suggest a v i r a l etiology (Nathanson & M i l l e r , 1978). • 1* The main elements of the v i r a l theory are as follows: 1. MS i s caused by virus X or several viruses X...Z. * See footnotes, page 101 - 9 -2. Virus X may be either a well-known virus (e.g. measles) or a presently unknown agent. 3. Infection with virus X i s r e l a t i v e l y common and MS i s a rare consequence (case/infection r a t i o i s low). 4. Infections r e s u l t i n g in MS are i n i t i a l l y s i l e n t or resemble other benign v i r a l i nfections. 5. Incubation from infection to onset of MS i s long (years). It i s believed that the virus leading to MS c h a r a c t e r i s t i -c a l l y has a long incubation period and slow i n f e c t i o n . These features have been observed in conditions with known v i r a l etiology such as rabies, serum he p a t i t i s i n f e c t i o n , and Creutzfeldt-Jacob disease. As noted, the most common course in MS involves remission/ exacerbation. This i s compatible with a v i r a l etiology as two diseases with a slow v i r a l etiology, subacute sclerosing panen-c e p h a l i t i s and progressive multifocal leukoencephalopathy, occasionally show a remiss ion/exacerbation course. At autopsy, MS i s characterized by destruction of the mye-l i n sheath with preservation of the axon. Selective myelin destruction has been seen in v i r a l disease of man and animals. Therefore, although the evidence i s i n d i r e c t , the findings in MS appear to be compatible with a v i r a l etiology, although by an, as yet, unidentified v i r u s . Two recent studies have suggested that MS may be a trans-missible disease. The observation of an increased frequency of lymphocytotoxic antibodies in MS patients and their close r e l a -tives led to the hypothesis that there i s a transmissible agent - 10 -(virus?) in MS (Schocket& Weiner, 1978). A study in the Faroes concluded that MS was brought to the area by B r i t i s h troops in World War II and that, at least in the Faroe Islands, MS is a transmissible, probably infectious disease although only one per 500 exposed show the MS phenotype (Kurtzke & Hyllested, 1979). There i s some evidence that the responsible virus could be the measles virus and that MS i s a rare consequence of infec-tion by this agent. Evidence to support this is that some MS patients have increased serum antibody t i t r e s to measles, an increased frequency of cerebrospinal f l u i d antibody to measles, and evidence of measles virus antigen in the jejunal mucosa (Rastogi et a l . , 1978; Houff et a l . , 1977; Pertschuk et a l . , 1977) . The measles virus can act as a slow virus with a long latent period, an hypothesized c h a r a c t e r i s t i c of the "MS v i r u s " (Millar & A l l i s o n , 1971). MS and measles could be associated in several ways. MS could be an immunologic response to p e r s i s -tent measles infection (Field, 1973), an age-dependent host response to measles (Alter, 1976), or associated with the a c t i -vation of latent measles (Fraser, 1977). Some investigators have concluded that MS patients own more housepets,especially dogs, than do controls and therefore pos-tulate that MS could be due to the transfer of an infectious agent, possibly the canine distemper virus (Cook et a l . , 1979; - 11 -Burridge, 1978) from the dog to the human host (Kurland & Brian, 1978; Chan, 1977; Cook & Dowling, 1977). However, recent work has f a i l e d to find an increase of pet ownership among MS patients (Bunnell et a l . , 1979). Carp et a l . (1972) described a factor, later to be c a l l e d - "Multiple Sclerosis Associated Agent" or "MSAA", in MS brain homogenates which, when injected into mice, r e s u l t in a de-pression in the percentage of polymorphonuclear neutrophils (PMNs) in mouse peripheral blood. Attempts to repeat Carp's findings were i n i t i a l l y unsuccessful and later successful (Brown & Gajdusek, 1974; McNeil et a l . , 1974). This led to Carp's work being labelled a "milestone" in MS ( E d i t o r i a l , 1976). However, recent work has again f a i l e d to confirm Carp's results (Madden et a l . , 1978). 2.1.3. Genetics The controversy as to whether or not there i s a genetic component to MS has been going on for nearly a century. Gowers (1893) stated that a f a m i l i a l incidence of MS was "quite excep-t i o n a l " whereas Eichhorst (1896), who published the f i r s t report of f a m i l i a l MS, lab e l l e d the disease as "inherited, trans-missible . " Evidence suggesting a genetic contribution to the e t i o l -ogy, of MS. came i n i t i a l l y from general population and twin studies and, within the l a s t decade, from HLA studies. - 12 -Although never formally tested, MS does not appear to show a clear-cut Mendelian segregation pattern in families although f a m i l i a l aggregates are usually observed in population studies. TABLE I l i s t s the f a m i l i a l incidence of MS found in several studies from 1933 to date. The v a r i a b i l i t y of these results may be due to several factors including the aim and structure of the studies, the population being investigated, and the accuracy of the MS diagnosis. Genetic hypotheses of autosomal recessive or dominant inheritance with greatly reduced penetrance as well as multi-f a c t o r i a l inheritance have been postulated (Tiwari et a l . , 1980) . Autosomal recessive inheritance with reduced penetrance has been hypothesized based on the results from twin studies (Mackay & Myrianthopoulos, 1966) and general population studies (Castaigne et a l . , 1970; Poskanzer et a l . , 1965). However, other investigations of twins (Bobowick et a l . , 1978; Cendrowski, 1968; Pratt, 1951) have concluded that environmental factors are very important. The results from several population sur-veys have f a i l e d to find evidence in favour of an autosomal recessive mode of inheritance (Gilbert, 1971; Cendrowski, 1968). The occurrence of MS in three successive generations has raised the p o s s i b i l i t y of autosomal dominant inheritance (Bird, 1975). Visscher et a l . (1979) postulated autosomal dominant inheritance with 5% penetrance based on HLA studies, the results of which gave evidence for the presence of a "MS s u s c e p t i b i l i t y gene". - -13 -TABLE I: FAMILIAL INCIDENCE OF MS: SURVEY OF THE LITERATURE AUTHOR & YEAR Curtius, 1933 Pratt, Compston, & McAlpine, 1951 Muller, 1953 Hadley, 1954 M i l l a r & A l l i s o n , Sutherland, 1956 . Abb & Schaltenbrand, LOCATION OF THE STUDY Bonn & Heidelberg, Germany London, England PERCENTAGE OF PATIENTS WITH FAMILY HISTORY OF MULTIPLE SCLEROSIS Sweden Scotland 1954 Northern Ireland Northern Scotland Germany 1956 Hyllested, 1956 Mackay & Myriantho-poulos, 1966 White & Wheelan, 19,59 Alter et a l 1962 Fog & Hyllested, 19 6 3 Schapira, Poskanzer, & M i l l e r , 1963 Stazio et a l . , Verdes et a l . , Hader, 1978 This thesis i' 1964 1978 Denmark U.S.A. & Canada Kingston, Ontario, Canada Israel Orkney & Shetland Island Faroes Durham & Northumberland, England Winnipeg, Manitoba, Canada Bucharest, Rumania Saskatoon, Saskatchewan, Canada Vancouver, B r i t i s h Columbia, Canada 9, 6, 3 3. 6 4 5 6 3 6* 11.0* 6.5 2.6 22.0* 0.0 11.6* 12.5* 5.8 3.8 1.8 19.4* 22.6* (twin study) *Stated by the author to include cases of "possible" MS as well as " d e f i n i t e " and " c l i n i c a l l y d e f i n i t e " . - 14 -When evaluating the claims of these d i f f e r e n t modes of inheritance, i t must be remembered that, with the concept of reduced penetrance, any genetic model can be made to f i t the data (Edwards, 1960) . An important advance in genetics has been the i d e n t i f i c a -tion of the major histocompatibility complex (HLA) in man. The HLA region is located on the short arm of chromosome 6 and is composed of l o c i that control the synthesis of transplantation antigens and function in the immune process (Rosenberg & Kidd, 1977; Kidd, 1976). Each locus has a number of a l l e l e s , a l l of which have not yet been i d e n t i f i e d . The set of HLA genes on one chromosome i s a haplotype (Thompson & Thompson, 1980). Each person, therefore, has two haplotypes. Genes of a haplotype move as a unit (except for recombinants due to crossing over) and there i s therefore a 25% chance that two s i b l i n g s w i l l have i d e n t i c a l HLA antigens. FIGURE 1 is a schematic representation of the HLA region. FIGURE 2 i l l u s t r a t e s the inheritance of HLA haplotypes. Association between s p e c i f i c HLA antigens and s p e c i f i c diseases has been observed. Such associations could be ex-plained in several ways (Rosenberg & Kidd, 1977): (a) the association could be by chance; (b) disease s u s c e p t i b i l -i t y could be d i r e c t l y related to the presence (or absence) of s p e c i f i c antigens; (c) MS could be more common-in a subgroup of people and this group could have a d i f f e r e n t d i s t r i b u t i o n D(R) B C A human HLA 0 . 7 HH>2 0.6 The l e t t e r s above the line indicate l o c i . The numbers under the line are approximate percentage recombination fracti o n s . FIGURE 1: SCHEMATIC GENETIC MAP OF HUMAN HLA REGIONS (FROM BODMER, 19 78) l I A l B8 CW1 DW6 A l B8 CW1 DW6 A2 B7 CW2 DW5 A9 A l B5 B8 CW5 CW1 DW1 DW6 A9 B5 :3Wl A3 B12 CW4 DW2 A3 B12 CW4 DW2 A2 B7 CW2 DW5 A9 A2 B5 B7 CW5 CW2 DW1 DW5 A3 A l B12 B8 CW4 CW1 DW2 DW6 A3 B12 CW4 DW2 o FEMALE MALE i—1 FIGURE 2: THE INHERITANCE OF HLA HAPLOTYPES (FROM THOMPSON & THOMPSON, 198 0) - 17 -of haplotypes; (d) linkage disequilibrium could exist between the a l l e l e s for the antigen (s) and disease s u s c e p t i b i l i t y . Linkage disequilibrium is the tendency, in a population, for some a l l e l e s in the haplotype to occur together more frequently than expected by chance. Studies on the association between HLA and disease are based on either general population or family data. If an association of a par t i c u l a r haplotype or HLA antigen i s observed in a population of unrelated patients with a given disease, family data can provide more information. Using these data, i t i s possible to test the n u l l hypothesis (HQ) of independent segregation between the disease and HLA marker a l l e l e s . Rejec-tion of the H Q suggests linkage disequilibrium between the a l l e l e s for the antigen(s) and disease s u s c e p t i b i l i t y . The p o s s i b i l i t y of an association between HLA types and MS was raised as such an association has been reported for other diseases that resemble MS in that there i s f a m i l i a l clustering with no clear Mendelian pattern and a v i r a l e t i o l o g y has been postulated (Rosenberg & Kidd, 1977; Kidd, 1976). In general population studies, i t has been observed that various HLA a n t i -gens occur more or less frequently in MS patients when compared with controls (TABLE I I ) . These findings, however, are not universal and depend on the population being studied (Brautbar et a l . , 1977; Z i b e t t i et a l . , 1977; Saito et a l . , 1976). As a result of these population studies, research began on the - 18 -TABLE II: HLA ANTIGENS REPORTED TO BE ASSOCIATED WITH MULTIPLE.SCLEROSIS ANTIGENS FOUND ANTIGENS FOUND MORE FREQUENTLY* v LESS FREQUENTLY* IN MS PATIENTS IN_MS PATIENTS THAN; IN CONTROLS THAN IN CONTROLS - A l ( J e r s i l d , 1977) HLA - A2 ( J e r s i l d , 1977) - A3 . (Naito et al.", 1972) - A28 ( J e r s i l d , 1977) - B7 (Paty et a l . , 1977) - B12 (Paty et a l . , 1977) - B8 ( J e r s i l d , 1977) - Bwl5 ( J e r s i l d , 1977) - B18 (Paty et a l . , 1977) - Bwl7 ( J e r s i l d , 1977) - Cw2 (Bertrams, 1977) - Bw22 (J e r s i l d , 1977) - Cw4 (Bertrams, 1977) - Bw4 0 ( J e r s i l d , 1977) - Dw2 (Paty et a l . , 1977) - Dw5 (Batchelo r et a l . , 1978) - Dw3 (Grosse-Wilde et a l . , 1977) - DRw2 (Moerloose et a l . , 1979) - DRw3 (Moerloose et a l . , 1979) * 5% l e v e l of significance - 19 -segregation of HLA a l l e l e s within "multiplex" f a m i l i e s , i . e . families with at least two MS patients. I n i t i a l results were c o n f l i c t i n g with some indicating a s i g n i f i c a n t segregation of MS-associated haplotypes (Hens & Carlton, 1978; Drachman et a l . , 1976; Olsson et a l . , 1976; Bird, 1975) and others showing no such association (Eldridge, et a l . , 1978). Visscher et a l . (1979) investigated 12 multiplex families and a l l MS cases in each family shared at least one chromosome (the p r o b a b i l i t y of this occurring without genetic linkage is 0.001). These results suggest the presence of a MS determinant (MS susceptible gene?) in or near the HLA region of chromosome 6. As some unaffected r e l a t i v e s also had the same haplotypes as MS patients, additional factors (genetic and/or environmental) must be involved in the manifestation of c l i n i c a l MS, i . e . a given haplotype may be a necessary but not s u f f i c i e n t cause. Tiwari et a l . (1980) did linkage analysis on family data from 72 multiplex f a m i l i e s . Although the results provide f u r -ther evidence for linkage between the hypothetical MS gene and HLA, the authors caution that the analysis required the assump-tion of single gene inheritance with reduced penetrance and the v a l i d i t y of this assumption is unknown. They also stress that the analysis was done for both dominant inheritance with 5% penetrance (Visscher et a l . , 1979) and autosomal recessive inheritance with 43% penetrance (Mackay & Myrianthopoulos, 1966) and both models supported the hypothesis of linkage. This could indicate that, as has been suggested for juvenile diabetes - 20 -(Suarez et a l . , 1979), MS possibly results from an interaction between two or more l o c i , only one of which i s near or in the HLA region. In summary, the current opinion in the l i t e r a t u r e i s that MS has an infectious, probable v i r a l , etiology with both envi-ronmental and genetic factors influencing the expression of the disease. 2.1.4. Prevalence It was Charcot (1877) who f i r s t commented on the fact that MS was more prevalent in some countries than in others but epidemiologic studies on the disease began in earnest only in the early 1950's. In the northern hemisphere, the prevalence of MS gradu-a l l y decreases towards the equator and, although fewer studies have been done, this trend appears to hold for the southern hemisphere as well (Acheson, 1977; Kurtzke, 1977; Alter & Morariu, 1973; M i l l a r & A l l i s o n , 1971; Alter & Kurtzke, 1968; Beebe et a l . , 1967). Areas of high prevalence (greater than 40 per 100,000) are Europe (between the 45° and 65° north l a t i -tudes) ; northern USA; southern Canada; New Zealand; and southern Au s t r a l i a (McAlpine et a l . , 1972). Areas of low prevalence (less than 19 per 100,000) are portions of Latin America, Asia, and A f r i c a near the equator (Kurtzke, 1977). In general, MS is more prevalent in the temperate zones than in the tropics and subtropics (Kurland, 1968). - 21 -The e f f e c t of m i g r a t i o n on the p r e v a l e n c e of MS has been the s u b j e c t of many i n v e s t i g a t i o n s . The r e s u l t s from a l a r g e s u r v e y o f immigrants t o I s r a e l i n d i c a t e t h a t people m a i n t a i n the p r e v a l e n c e r a t e s of t h e i r c o u n t r y o f o r i g i n ( L e i b o w i t z & A l t e r , 1973). Other s t u d i e s ( D e t e l s e t a l . , 1978; A l t e r e t a l . , 1978; K u r t z k e , 1977) have c o n c l u d e d t h a t the age a t the time of m i g r a t i o n i s an i m p o r t a n t f a c t o r . The " c r i t i c a l age" f o r m i g r a -t i o n has been s a i d t o be 15 y e a r s but a r e c e n t s t u d y ( A l t e r e t a l . , 1978) has i n d i c a t e d t h a t i t c o u l d be as low as f i v e y e a r s of age . Most m i g r a t i o n s t u d i e s i n v o l v e p ersons moving from a r e a s of " h i g h r i s k " t o r e g i o n s of "low r i s k " . T h e r e are i n d i c a t i o n s t h a t the p o p u l a t i o n r i s k i s somewhat lowered w i t h the move (Acheson, 1977). A r e c e n t s t u d y ( D e t e l s e t a l . , 1978; V i s s c h e r e t a l . , 1977) s u g g e s t s t h a t moving from a "low r i s k " t o a " h i g h r i s k " a r e a i n c r e a s e s the r i s k . Age s p e c i f i c s t u d i e s suggest t h a t a m i g r a n t p o p u l a t i o n adopts a r i s k i n t e r m e d i a t e between t h a t o f the c o u n t r y o f o r i g i n and the new home (Acheson, 1977). - 22 -CHAPTER 3 MATERIALS & METHODS 3.1. DATA 3.1.1. Ascertainment Sources On prevalence date, A p r i l 30, 1976, 983 persons presumed to have MS and to f i t the c r i t e r i a for inclusion in this study were ascertained. These c r i t e r i a were that the person currently was l i v i n g in B.C., was the proband for his/her family, and was diagnosed as having " c l i n i c a l l y d e f i n i t e " MS. TABLE III l i s t s the f i r s t source of ascertainment for these individuals, i . e . the preliminary source. 75.5% of these persons were f i r s t ascertained through the B.C. Health Surveillance Registry which is part of the Division of V i t a l S t a t i s t i c s within the Ministry of Health of B r i t i s h Columbia (Health Surveillance Registry Annual Report #3, 1977). The B.C. Health Surveillance Registry was established in 1952 as the "Crippled Children's Registry". Its i n i t i a l function was to follow children with disabling conditions to insure that they received proper treatment and r e h a b i l i t a t i o n . To be e l i -gible for r e g i s t r a t i o n , a person had to be under 21 years of age and have a d i s a b i l i t y "severe enough to interfere with normal l i v i n g , obtaining an education and later earning a TABLE I I I : PRELIMINARY SOURCES OF ASCERTAINMENT OF CASES IN STUDY FEMALES MALES TOTAL PERCENTAGE B.C. Health S u r v e i l l a n c e R e g i s t r y 517 225 742 75 .5 B.C. D i v i s i o n o f the MS S o c i e t y of Canada 85 91 176 17 .9 G.F. Strong R e h a b i l i t a t i o n Center 13 7 20 2 .0 Extended Care F a c i l i t i e s 4 5 9 0 .9 P e r s o n a l R e f e r r a l s 6 2 8 0 .8 L o c a l MS Groups: 19 9 28 2 .9 Whip(Vancouver Island) (6) (4) (10) Vernon Chapter (MS S o c i e t y ) (2) (3) ( ,5) V i c t o r i a Chapter (MS S o c i e t y ) (4) (2) ( 6) Kelowna Chapter (MS S o c i e t y ) (5) - ( 5) P e n t i c t o n Chapter (MS So c i e t y ) (2) ( 2) TOTAL 644 339 983 100 .0 - 24 -l i v e l i h o o d " . In 1960, the age l i m i t of 21 was e l i m i n a t e d , the name changed to the " R e g i s t r y f o r Handicapped C h i l d r e n and A d u l t s " , and the c r i t e r i a f o r r e g i s t r a t i o n were expanded to inc l u d e persons with a "long-term p h y s i c a l , mental and/or emo-t i o n a l problem which i s l i k e l y t o be permanently d i s a b l i n g , i n t e r f e r e with h i s edu c a t i o n , or prevent f u l l and open employ-ment". In 1962, the r e g i s t r a t i o n c r i t e r i a were again expanded to i n c l u d e i n d i v i d u a l s with a " f a m i l i a l c o n d i t i o n or c o n g e n i t a l malformation which i s not d i s a b l i n g " . By 1975, i t was evident t h a t the f u n c t i o n of the R e g i s t r y had expanded to i n c l u d e r e s e a r c h and the establishment of b a s e - l i n e s t a t i s t i c s as w e l l as the follow-up of handicapped persons. The name was t h e r e -f o r e changed to the present one (Lowry e t a l . , 1975). Although r e g i s t r a t i o n i s not compulsory, the B.C. Health S u r v e i l l a n c e R e g i s t r y has v a r i o u s sources of ascertainment such as p u b l i c h e a l t h u n i t s ; c e r t a i n v i t a l and h o s p i t a l r e c o r d s ; s p e c i a l t r e a t -ment c e n t e r s such as the Canadian N a t i o n a l I n s t i t u t e f o r the B l i n d , the G.F. Strong R e h a b i l i t a t i o n Centre, the Canadian A r t h r i t i s and Rheumatism S o c i e t y ; a s s o c i a t i o n s for the handi-capped; and p r i v a t e p h y s i c i a n s . The B.C. Health S u r v e i l l a n c e R e g i s t r y assures the p r i v a c y o f a l l r e g i s t e r e d persons and t h e r e f o r e the author could not co n t a c t d i r e c t l y any r e g i s t e r e d MS p a t i e n t t o ask f o r h i s / h e r p a r t i c i p a t i o n i n t h i s study. T h i s had to be done by c o n t a c t i n g the r e g i s t e r i n g source which, i n t u r n , approached the p a t i e n t on the author's b e h a l f . - 25 -In addition to the B.C. Health Surveillance Registry, MS patients were ascertained through the B.C. Division of the MS Society of Canada; the G.F. Strong Rehabilitation Centre; extended care f a c i l i t i e s located throughout the province; per-sonal r e f e r r a l s from other subjects in the study; private physicians; branches of the MS Society located in Kelowna, Penticton, Vernon, and V i c t o r i a ; and an independent MS group "With Help, Individuals Progress" (WHIP) located on Vancouver Island. 3.1.2. Procedures for Contacting Potential Subjects Most of the 983 persons ascertained were known to more than one source, e.g. the B.C. Health Surveillance Registry and the B.C. Division of the MS Society of Canada. Since each agency has i t s own procedure which the author had to follow in order to ask patients to participate in the study, i t was decided that i f a person was known to more than one agency, contact would be made through the source requiring the simplest procedure. Therefore the agency through which potential sub-jects were contacted was not necessarily the preliminary source of ascertainment. For reasons of c o n f i d e n t i a l i t y , the B.C. Health Surveillance Registry required the most complex proce-dure for contacting patients, allowing no d i r e c t contact between the author and patients. Therefore only those persons known solely to the Registry were contacted through this agency. - 26 -Most potential subjects were contacted through the B.C. Division of the MS Society of Canada. The Society sent a l e t t e r from the author (APPENDIX A) to a l l i t s members describing the proposed study. Persons were asked to f i l l out a form (APPENDIX B) to be d i r e c t l y returned to the author. On th i s form, they i n d i -cated whether or not they wished to p a r t i c i p a t e . P a r t i c i p a t i o n was voluntary and subjects were free to withdraw at any time. A l l participants were assured that the information was s t r i c t l y c o n f i d e n t i a l . The research proposal and a l l l e t t e r s and forms used in th i s study were approved by the appropriate University Committee. 3.1.3. Data Co l l e c t i o n Genetic and medical h i s t o r i e s were obtained for each sub-j e c t . This information was gathered by the author either interviewing the subject in person or over the telephone or by the subject completing a detailed questionnaire (APPENDIX C). The same basic information was obtained regardless of the method used. 3.1.4. Confirmation of Diagnosis As previously discussed in section 2.1.2, MS can be diag-nosed r e l i a b l y only at autopsy. In l i v i n g patients, diagnosis is made only after long-term follow-up by a physician and the results of various c l i n i c a l and laboratory examinations. There-fore, three categories of MS are referred to throughout this - 27 -thesis. These are " d e f i n i t e " MS where the diagnosis was con-firmed at autopsy; " c l i n i c a l l y d e f i n i t e " MS where the patient's physician (neurologist whenever possible) reported d i r e c t l y to the author that, after long-term follow-up, he/she had no doubts about the diagnosis of MS in a p a r t i c u l a r i n d i v i d u a l ; and "possible" MS, a heterogeneous category including suspected cases and persons for whom a physician could not be contacted for confirmation of a diagnosis. APPENDIX D describes a l l cases of "possible" MS. 3.2. DATA ANALYSIS 3.2.1. "PGOODFIT" Analysis This programme was developed by Gladstien et a l . (1978) to test the goodness-of-fit of family data to a two-threshold model for disorders with d i f f e r e n t prevalence rates for males and females. As w i l l be discussed in part ( i i i ) of t h i s section, th i s two-threshold model was developed to explain the occurrence of disorders showing no clear Mendelian patterns and having d i f -ferent prevalence rates for the two sexes (Kidd & Spence, 1976; Kidd et a l . , 1973). "PGOODFIT" compares the observed number of nuclear families (the proband, his parents and siblings) having at least two s i b l i n g s affected with a p a r t i c u l a r d i s -order with the t h e o r e t i c a l d i s t r i b u t i o n for such families under the model. Parameters of the analysis include ascertainment - 28 -p r o b a b i l i t y (II) , h e r i t a b i l i t y e s t i m a t e s (h^) , and f a m i l y 2 s t r u c t u r e . For each c o m b i n a t i o n of n and h , two p r o b a b i l i t i e s are c a l c u l a t e d . "PRG" i s the p r o b a b i l i t y , under the model, of ha v i n g the observed number or more f a m i l i e s w i t h a t l e a s t two a f f e c t e d s i b l i n g s and "PRL" i s the p r o b a b i l i t y of h a v i n g the observed number o f f a m i l i e s or l e s s w i t h m u l t i p l e a f f e c t e d s i b s h i p s . The model i s r e j e c t e d i f s i g n i f i c a n t l y (5% l e v e l ) too many or t o o few f a m i l i e s a re observed f o r p l a u s i b l e v a l u e s of h and II. To det e r m i n e the t h e o r e t i c a l d i s t r i b u t i o n f o r the number of f a m i l i e s w i t h a t l e a s t two a f f e c t e d s i b l i n g s , the c o n d i t i o n a l p r o b a b i l i t y (p^) i s computed f o r the i t h f a m i l y . P arameters i n v o l v e d i n the c o m p u t a t i o n o f p^ i n c l u d e p a r e n t a l s t a t u s ( a f f e c t e d or u n a f f e c t e d ) , the number of sons i n the f a m i l y , the number of d a u g h t e r s i n the f a m i l y , and whether the f a m i l y was a s c e r t a i n e d by a son or a d a u g h t e r . APPENDIX E shows the co m p u t a t i o n s done by the "PGOODFIT" programme. T h i s programme as w e l l as the "MULFAC" programme ( p a r t i i i of t h i s s e c t i o n ) were run f o r these d a t a by Dr. M. Anne Spence and A s s o c i a t e s , D i v i s i o n of M e d i c a l G e n e t i c s , U n i v e r s i t y of C a l i f o r n i a a t Los A n g e l e s . ( i ) Coding of the Data S i n c e "PRG" and "PRL" v a l u e s are based on the p r o b a b i l i t y of o b s e r v i n g a t l e a s t two a f f e c t e d s i b l i n g s per f a m i l y , f a m i l i e s i n which the proband was an o n l y c h i l d c o u l d n ot be used i n the a n a l y s i s . In a d d i t i o n , probands who were adopted were e x c l u d e d - 29 -from the analysis as there was no accurate information on the natural nuclear families of these individuals. As w i l l be d i s -cussed in section 4.1.1, 416 of the i n i t i a l 983 ascertained MS patients participated in this study. Of these 416, a t o t a l of 364 probands and their families (87.5%) were suitable for inclusion in the "PGOODFIT" analysis. The families were coded according to family structure, i . e . the number of sons and daughters; the disease status of the parents; and whether the family was ascertained through an affected son or daughter. TABLE I V l i s t s the family structure for the 364 f a m i l i e s . The number of affected s i b l i n g s per family and the category of MS in r e l a t i v e s of the proband were also coded. ( i i ) Ascertainment Probab i l i t y (n) II i s defined as the pr o b a b i l i t y that an affected individual be independently ascertained for study (Gladstien et a l . , 1978). As n -* 0, there i s only one ascertained person (proband) per family regardless of the t o t a l number of affected i n d i v i d u a l s . II = 1 indicates that a l l affected persons in a given population have been independently ascertained. The design of this study i s such that there i s only one proband per family. There were, however, a few instances when a r e l a t i v e of the proband, not necessarily a s i b l i n g , was independently ascertained. The n value of 0.001 was chosen as - 30- -TABLE IV: CODING OF THE NUCLEAR FAMILIES OF PROBANDS ACCORDING TO FAMILY STRUCTURE NUMBER OF FAMILIES , ASCERTAINED: MOTHER FATHER # SONS # DAUGHTERS BY SONS BY DAUGHTERS possible normal 1 normal affected 0 affected normal 2 normal normal 0 normal. normal 2 normal normal 1 normal possible 1 affected normal 1 affected normal 0 normal normal 3 normal normal 2 normal normal 1 normal normal 0 possible normal 3 affected normal 2 normal normal 3 normal normal 2 normal normal 1 normal normal 0 normal affected 1 normal normal 4 normal normal 3 normal normal 2 normal normal 1 normal normal 0 normal affected 4 possible normal 2 normal normal 5 normal normal 4 normal normal 3 normal normal 2 normal normal 1 normal normal 0 normal normal 1 normal possible 1 normal normal 6 normal normal 5 normal normal 4 normal normal 3 normal normal 2 normal normal 1 1 0 1 2 0 2 0 1 0 2 0 34 0 14 0 1 14 30 2 0 1 2 1 1 3 0 1 0 6 0 1 13'• 15: 2 6 20 3 0 13 1 1 0 2 0 1 1 9 2 2 4 14 3 2 14 4 0 5 4 0 1 1 7 2 2 10 5 3 6 7 4 2 4 5 0 4 2 1 0 4 0 1 1 1 ' 1 2 3 2 3 2 2 4 1 7 5 0 2 6 0 1 5 0 0 6 1 0 1 2 1 2 4 4 3 2 4 4 1 7 5 0 2 6 0 5 (continued) TABLE IV: FAMILY STRUCTURE (continued) NUMBER OF FAMILIES ASCERTAINED: MOTHER FATHER # SONS # DAUGHTERS BY SONS BY.DAUGHTERS normal normal 5 3 2 1 normal normal 3 5 2 0 normal normal 6 2 0 1 normal normal 4 4 0 2 normal normal 2 6 0 3 normal normal 4 5 1 4 normal normal 6 3 0 1 normal normal 5 4 0 1 normal normal 2 7 0 1 normal normal 7 3 1 0 normal normal 5 5 1 1 normal normal 4 6 0 2 normal normal 5 6 1 0 normal normal 3 8 0 1 normal possible 4 8 1 0 normal normal 6 6 1 0 normal normal 7 5 0 1 normal normal 2 10 0 1 normal normal 8 5 1 0 normal normal 6 7 0 1 normal normal 5 8 0 1 normal normal 7 8 0 1 TOTAL 125 239 - 32 -being s u f f i c i e n t l y close to zero. A few higher values for n (0.1; 0.2; 0.5) were also analyzed in case the II •> 0 r e s t r i c -tion was too stringent. 2 ( m ) H e r i t a b i l i t y (h ) Estimates Genetic variance i s composed of additive and non-additive components. Additive genetic variance (V^) refers to the aver-age e f f e c t s of ind i v i d u a l genes on the t r a i t or disease. It refers to the genes as transmitted by the gametes. Non-additive genetic variance refers to the genes in the d i p l o i d state. V-j-and V D are the components of non-additive genetic variance. V D refers to the interaction of genes at one locus whereas Vj refers to the interaction of genes at d i f f e r e n t l o c i . TABLE V l i s t s the various components of variance. H e r i t a b i l i t y i s the additive genetic variance expressed as a proportion of the 2 t o t a l phenotypic variance, i . e . h = V^/Vp. Using the concepts of threshold and l i a b i l i t y for disorders showing no clear Mendelian pattern, Falconer (1965) derived a 2 method for estimating h from the prevalence of a disorder in the general population and among r e l a t i v e s of affected i n d i v i -duals. Using this information, i t i s possible to calculate the cor r e l a t i o n in l i a b i l i t y between r e l a t i v e s ( r ) . The r e l a t i o n between r and the prevalence rates for the general population and r e l a t i v e s of affected individuals i s i l l u s t r a t e d by 2 FIGURE 3. h = r / c o e f f l c i e n t of the relationship (Falconer, 1965). Falconer's method was adapted (Reich et a l . , 1972) - 33 -TABLE V: COMPONENTS OF VARIANCE (Falconer, 1967) VARIANCE COMPONENT SYMBOL Phenotypic V p Genotypic V Q Additive* Vft Dominance** V Q Interaction** Vj. Environmental V £ VG = V A + VD + V I v = v + V = V + v + v + v P G E A D I E 2, HERITABILITY (h ) = V A/V p * Additive genetic variance refers to the average e f f e c t of indiv i d u a l genes on the t r a i t (or disease) ** VD and Vj are the components of non-additive genetic vari-ance. VQ refers to the interaction of genes at one locus, Vj refers to the interaction of genes at d i f f e r e n t l o c i . - 34 -0 FIGURE 3: GRAPH: CORRELATION IN LIABILITY (r) BETWEEN RELATIVES AS A FUNCTION OF PREVALENCE IN THE POPULATION (K ) AND PREVALENCE IN RELATIVES P OF AFFECTED INDIVIDUALS (K R) (FROM REICH ET AL., 1972) - 35 -to a two-threshold model for disorders that c l i n i c a l l y show two forms, severe and mild. The position of the two thresholds i s a function of the population prevalence for the two forms of the disorder. The narrower (n) form, i . e . the less common form, is e n t i r e l y within the wider (w) or more common form. Kidd et a l . (1973) further adapted the two-threshold model to disorders for which males and females have d i f f e r e n t prevalence rates. FIGURE 4 i l l u s t r a t e s the two-threshold model as proposed by Reich et a l . and adapted by Kidd et a l . Combining the work of Falconer (1965), Reich et a l . (1972), and Kidd et a l . (1973), a computer programme "MULFAC" was de-2 veloped to calculate r and h . (The actual calculations done by MULFAC are summarized in APPENDIX F.) 2 Two h values obtained from MULFAC were 0.73, i f eases of "possible" MS were considered "affected" and 0.584 i f cases of "possible" MS were considered "normal". These two values were 2 "bracketed" by three additional h estimates - a value (0.8) s l i g h t l y greater than 0.73, another (0.5) s l i g h t l y less than 0.58, and f i n a l l y one (0.65) intermediate between the two estimates from MULFAC. (iv) Sex-Specific Prevalence Rates The prevalence rates used in the analysis were 0.00028:'for males and 0.00052 for females. Since the aim of this study was not to determine prevalence rates, additional analyses using prevalence rates derived from a large Los Angeles-Seattle study -* n = males w = females FIGURE 4: TWO-THRESHOLD MODEL FOR DISORDERS WITH DIFFERENT PREVALENCE RATES FOR MALES AND FEMALES (KIDD ET AL". , 1973), ADAPTED FROM REICH ET AL. (1972) - 37 -0.00038 f o r males and 0.00090 f o r females - ( D e t e l s e t a l . , 1978) were a l s o done. The r e s u l t s d i d n o t d i f f e r s i g n i f i c a n t l y . 3.2.2. P h e n o t y p i c H e t e r o g e n e i t y The d a t a were a n a l y z e d f o r e v i d e n c e o f p h e n o t y p i c h e t e r o -g e n e i t y . P h e n o t y p i c f e a t u r e s examined were age of o n s e t , f i r s t symptom o f MS r e p o r t e d by the proband, and s e v e r i t y of the d i s e a s e . P h e n o t y p i c h e t e r o g e n e i t y was examined i n terms of the sex of the proband ( s i n c e females are more f r e q u e n t l y a f f e c t e d than are males) and the presence o r absence o f a f a m i l y h i s t o r y o f " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS. Probands w i t h a f a m i l y h i s t o r y o f " p o s s i b l e " MS were e x c l u d e d from the a n a l y s e s s i n c e the d e f i n i t i o n o f " p o s s i b l e " MS i n t h i s t h e s i s i s heterogeneous. 3.2.3. G r a d i n g the D i s a b i l i t y i n the Probands V a r i o u s methods f o r g r a d i n g the degree o f d i s a b i l i t y i n MS p a t i e n t s have been d e v e l o p e d ( K u r t z k e , 1961; M c A l p i n e & Compston, 1952; A l e x a n d e r , 1951). The one most s u i t a b l e f o r the p r e s e n t s t u d y was d e r i v e d by H y l l e s t e d (1956) and i s a q u a n t i t a t i v e e s t i m a t e of d i s a b i l i t y based on the d i s t a n c e t h a t a p a t i e n t can walk. D i s a b i l i t i e s due t o v i s u a l p roblems, l o s s of b l a d d e r con-t r o l , and i m p a i r e d use o f arms a r e not d i r e c t l y measured but these f a c t o r s are i n d i r e c t l y e v a l u a t e d s i n c e , i f s e v e r e , they - 38 -would a f f e c t a person's m o b i l i t y . The f o l l o w i n g i s a d e s c r i p -t i o n of the s i x d i s a b i l i t y grades d e s c r i b e d by H y l l e s t e d (1956). GRADE 1: Able t o manage i n every r e s p e c t . Walk unaided out of doors and i n d o o r s . Handwriting almost unchanged. GRADE 2: S l i g h t l y d i s a b l e d . D i f f i c u l t y i n walking, r e q u i r e s a s t i c k out of doors but walks p r a c t i c a l l y unaided indoors, Perhaps m i l d d i s t u r b a n c e s of upper limbs and d i f f i.culty i n w r i t i n g . GRADE 3: Moderately d i s a b l e d with p a r t i c u l a r d i f f i c u l t i e s i n walking. P r e f e r a b l y two s t i c k s out of doors or aided by h e l p e r s . Leans on f u r -n i t u r e when walking i n d o o r s . Requires a s s i s t a n c e f o r c e r t a i n simple d u t i e s such as e a t i n g . GRADE 4: F a i r l y s e v e r e l y d i s a b l e d . Can only walk a few steps indoors; out of doors, o n l y a car or whee l c h a i r . Needs h e l p f o r s e v e r a l simple d u t i e s but can be l e f t to h i m s e l f without r i s k . GRADE 5: S e v e r e l y d i s a b l e d . Can only s i t i n a c h a i r but i s out of bed most of the day. Needs h e l p f o r e v e r y t h i n g and constant s u p e r v i s i o n . GRADE 6: E n t i r e l y i n c a p a c i t a t e d . Bedridden, i n c o n t i n e n t , completely h e l p l e s s . Grades 1 and 2 can be c a t e g o r i z e d i n t o a "mild" d i s a b i l i t y c a t e g o r y . Grades 3 and 4 repr e s e n t a "moderate" d i s a b i l i t y and grades 5 and 6 re p r e s e n t a "severe" d i s a b i l i t y . 3.2.4. Chi Square (X ) S t a t i s t i c The X s t a t i s t i c was used to i n v e s t i g a t e agreement between sample p r o p o r t i o n s , using 2 x k contingency t a b l e s with k - 1 degrees of freedom (Snedecor & Cochran, 1978). Unless o t h e r -wise s t a t e d , k '= 2 i n t h i s t h e s i s . T e s t s were compared to a * See f o o t n o t e s , page 101 - 39 -c r i t i c a l value of p = 0.05. values were not s i g n i f i c a n t u n l e s s otherwise s t a t e d . 3.2.5. One-Way A n a l y s i s of Variance A one-way a n a l y s i s of v a r i a n c e (Snedecor & Cochran, 1978) was used f o r t e s t i n g the d i f f e r e n c e s between the p o p u l a t i o n means of k groups, where each group i ( i = l,2,..k) c o n s i s t s of n^ o b s e r v a t i o n s x ^ j (j = l , 2 , . . n ^ ) . The F s t a t i s t i c was used and t e s t s were compared to a c r i t i c a l value of p = 0.05. The two degrees of freedom used were DF^ (treatment degrees of f r e e -dom, i . e . k - 1) and DF2 (error degrees of freedom, i . e . i l l " i " k>. 3.2.6. Confidence L i m i t s 95% confidence l i m i t s are s t a t e d wherever r e l e v a n t . These were c a l c u l a t e d a c c o r d i n g to the formula p ± 1.96/pq/n' where p = p r o p o r t i o n a f f e c t e d ; q = 1 - p; n = number of cases (Sne-decor & Cochran, 1978). Confidence l i m i t s f o r percentages were c a l c u l a t e d a c c o r d i n g to the formula p ± Q l . 96/pq/n)' x 100] . - 40 -CHAPTER 4 RESULTS 4.1. SUBJECTS 4.1.1. R e s u l t s of Attempts to Contact P o t e n t i a l Subjects TABLE VI summarizes these r e s u l t s . On prevalence date, 983 persons, s a i d to have MS, were a s c e r t a i n e d . These f e l l i n t o the f o l l o w i n g groups based on the r e s u l t s of attempts to have them p a r t i c i p a t e i n t h i s study, (a) For 310, i t was impossible to o b t a i n any i n f o r m a t i o n other than name, age, sex, and the f a c t t h at they were b e l i e v e d t o have MS. (b) One hundred twenty-six persons agreed to p a r t i c i -pate by q u e s t i o n n a i r e . E i g h t y - s i x of these (68.3%) d u l y com-p l e t e d and ret u r n e d the q u e s t i o n n a i r e . The r e s t were never r e t u r n e d , d e s p i t e f o l l o w - u p e i t h e r by l e t t e r or telephone, (c) Three hundred t h i r t y persons agreed t o p a r t i c i p a t e by e i t h e r a p e r s o n a l or telephone i n t e r v i e w . (d) Eighteen persons d i e d a f t e r the prevalence date without p a r t i c i p a t i n g . (e) One hundred two persons r e f u s e d to p a r t i c i p a t e . Seventeen of these s a i d t h a t they were "too i l l " and the remaining 85 gave no reason f o r r e f u s i n g . (f) Twenty-eight i n d i v i d u a l s , a f t e r i n i -t i a l ascertainment, were r u l e d " i n e l i g i b l e " as they f a i l e d to f i t the c r i t e r i a f o r s u b j e c t s as o u t l i n e d i n s e c t i o n 3.1.1. - 4,1 -TABLE VI.: RESULTS OF ATTEMPTS TO CONTACT POTENTIAL SUBJECTS FEMALES Participated & included in study 278 Failed to return questionnaire 23 Unattainable after agreeing to take part 50 Refused to participate 65 I n e l i g i b l e - no confirma-tion of diagnosis 5 I n e l i g i b l e - not proband 6 In e l i g i b l e - not in B.C. 3 No contact 2022 Died after A p r i l 30f 1976 without p a r t i c i p a t i n g 12 TOTAL. 64 4 MALES TOTAL PERCENTAGE 138 416 47.3 17 40 4.1 19 69 7.0 37 102 10.5 3 8 0.8 8 14 1.4 3 6 0.6 108 310 31.5 6 18 1.8 339 983 100.0 - 42 -(g) S i x t y - n i n e persons i n i t i a l l y agreed to p a r t i c i p a t e but subsequent attempts t o arrange an i n t e r v i e w proved f u t i l e . Thus, of the 983 cases a s c e r t a i n e d , 416 p a r t i c i p a t e d i n the study. 4.1.2. Data C o l l e c t i o n As d e s c r i b e d i n s e c t i o n 3.1.3f g e n e t i c and medical h i s t o r -i e s were obtained from each s u b j e c t e i t h e r by p e r s o n a l i n t e r -views (310), by the telephone (20), or by the s u b j e c t completing a d e t a i l e d q u e s t i o n n a i r e (86). TABLE VII l i s t s the frequency with which each of these methods f o r data c o l l e c t i o n was used. 4.1.3. General D e s c r i p t i o n of the 416 Subjects TABLE V I I I l i s t s the mean age of onset of the MS, the mean age of the s u b j e c t s at the time of p a r t i c i p a t i o n i n the study, and the mean d u r a t i o n of the MS f o r the probands, by sex of the proband. F i v e s u b j e c t s (two females; three males) d i e d a f t e r par-t i c i p a t i n g i n the study. An autopsy was performed on one of these and the d i a g n o s i s of MS was confirmed. Four of the deaths were a t t r i b u t e d to p r o g r e s s i v e d e t e r i o r a t i o n due to MS and one was a s u i c i d e . TABLE IX g i v e s i n f o r m a t i o n about these f i v e persons. - -4,3' _ TABLE VII: FREQUENCY OF USE FOR EACH METHOD OF DATA COLLECTION NUMBER OF SUBJECTS PERCENTAGE Pe r s o n a l i n t e r v i e w s 310 74 .5 Telephone i n t e r v i e w s 20 4.8 Q u e s t i o n n a i r e s 86 20 .7 TOTAL 416 100.0 - 44 " TABLE V I I I : DESCRIPTION OF THE PROBANDS WITH RESPECT TO SEX, AGE OF ONSET OF MS, AGE AT THE TIME OF THE STUDY, AND DURATION OF MS MEAN AGE ONSET OF THE MS MEAN AGE AT THE TIME OF PARTICIPATION MEAN DURATION OF THE MS UNTIL THE TIME OF PARTICIPATION ? Probands Probands A l l Probands 30.4 ± 10.6* 32.7 ± 13.7 31.2 ± 11.8 48.6 ± 11.7 48.6 ± 11.9 48.6 ± 11.9 18.7 ± 11.8 18.8 ± 15.6 18.8 ± 13.2 * Mean value (years) ± standard d e v i a t i o n of the mean TABLE IX: DESCRIPTION OF THE FIVE PROBANDS WHO DIED AFTER PARTICIPATING AGE AT AGE AT DURATION CODE* SEX ONSET DEATH OF MS A-5 F 15 48 33 B-10 M 30 45 15 L - l M 26 39 13 R-17 M 19 29 10 S-24 F 16 69 53 * - Code refers to subject's i d e n t i f i c a t i o n DISABILITY CAUSE FAMILY GRADE OF DEATH HISTORY 6 MS Negative 6 MS Negative 5 Suicide Negative 6 MS Aunt with MS 5 MS Sister with code - 46 -4.2. EMPIRIC FAMILIAL RECURRENCE RISKS Data were a v a i l a b l e on 7,945 r e l a t i v e s of 416 probands as f o l l o w s : 413 mothers (3 probands were adopted); 413 f a t h e r s (3 probands were adopted); 349 sons, 318 daughters, 575 b r o t h -e r s ; 604 s i s t e r s , 676 aunts; 738 u n c l e s ; 889 n i e c e s ; 764 neph-ews; 1,097 female f i r s t c o u s i n s ; and 1,027 male f i r s t c o u s i n s . Although i n f o r m a t i o n was o c c a s i o n a l l y a v a i l a b l e on grand-parents and second c o u s i n s of probands, these data were ex-cluded from the study s i n c e i t would be d i f f i c u l t to c o n f i r m any diagnoses on grandparents and few probands were f a m i l i a r with these r e l a t i v e s . Therefore any c o n c l u s i o n s drawn about the frequency of MS among them would have a l a r g e degree of e r r o r due to the s m a l l sample s i z e . (i) F a m i l i e s with at l e a s t 2 A f f e c t e d Members TABLE X l i s t s the p r o p o r t i o n of probands with " f a m i l i a l " MS, i . e . at l e a s t one other f a m i l y member suspected of having MS . T h i r t e e n out of 73 probands (17.8%) with a f a m i l y h i s t o r y of " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS had a t l e a s t two r e l a t i v e s diagnosed as having MS. An a d d i t i o n a l four probands had at l e a s t one r e l a t i v e with diagnosed MS and at l e a s t one r e l a t i v e suspected of having MS, i . e , " p o s s i b l e " MS. T h e r e f o r e , a t o t a l of 17/73 probands (23.3%) had at l e a s t two r e l a t i v e s with e i t h e r confirmed and/or suspected MS. TABLE X ^ PROPORTION OF PROBANDS WITH A FAMILY HISTORY OF•MS FAMILY HISTORY OF TOTAL - FAMILY HISTORY OF DEFINITE OR CLINICALLY FAMILY HISTORY DEFINITE MS OR CLINICALLY DEFINITE MS OF POSSIBLE MS DEFINITE MS OR POSSIBLE MS # o "o # o "5 i g, ~o probands (278) 50 18 .0 18 6.5 68 24 .5 <? probands (138) 23 16 .7 3 2.2 26 18 .8 A l l probands (416) 73 17.5 21 5.0 94 22.6 (±3.7)* (±2.1)* (±4.0)* I * 95% confidence l i m i t s - 48 -Three out of 21 probands (14.3%) with a family history of "possible" MS had at least two r e l a t i v e s suspected of having the disease. ( i i ) Frequency of MS Among Relatives of the Probands TABLES XI and XII summarize the frequency of " d e f i n i t e " , " c l i n i c a l l y d e f i n i t e " , and "possible" MS among r e l a t i v e s of the probands. In TABLE XI, r e l a t i v e s are categorized according to the exact r e l a t i o n s h i p . In TABLE XII, r e l a t i v e s are cate-gorized according to the degree of the relationship to the proband. More detailed tables of empiric recurrence r i s k s are given in APPENDIX G. ( i i i ) Prevalence Rates for MS Among Relatives of the Probands From this study the estimated prevalence rate for B.C., a low estimate for reasons discussed in section 5.6.1, i s approx-imately 40 per 100,000 population. A study in Saskatoon (Hader, 1978) estimated a prevalence rate of 110 per 100,000, a very high figure considering the geographic location of Saskatoon. TABLE XIII compares the increase in prevalence rates among re l a t i v e s of the probands as compared with the general popu-l a t i o n using the figures from t h i s thesis and from the Saska-toon study. - 49 -TABLE XI: EMPIRIC RECURRENCE RATES FOR MS NUMBER AND PERCENTAGE WITH "DEFINITE/ CLINICALLY DEFINITE" MS NUMBER AND PERCENTAGE WITH "POSSIBLE" MS TOTAL Parents (826) C h i l d r e n (667) S i b l i n g s (1179) Others (5273) 11 27 48 1.3 0.4 2.3 0.9 11 1.0 19 0.6 0.5 33 0.2. 59 2.3 (±1.0) 1.0 (±0.8) 2.8 (±0.9) 1.1 (±0.3) TOTAL (7945) 89 1.1 29 (±0.2)* 0.4 118 (±0.1) * 1.5 (±0.3) * 95% confi d e n c e l i m i t s - 5 0, -TABLE X I I : FREQUENCY OF MS AMONG RELATIVES OF PROBANDS ' (BY DEGREE OF THE RELATIONSHIP). "DEFINITE/ CLINICALLY DEFINITE" MS "POSSIBLE" MS TOTAL 1st degree (parents; s i b l i n g s ; children) (2672) 41 1.5 1 18 0.7 59 2.2 (±0.6) * 2nd degree (aunts; uncles; nieces; nephews; grandchildren) (3149) 24 0.8 0.2 30 1.0 (±0.3)* 3rd degree (cousins) (2124) 24 1.1 0.2 29 1.4 (±0.5)* TOTAL 89 29 118 * 95% confidence l i m i t s TABLE X I I I : PREVALENCE OF MS AMONG RELATIVES OF THE PROBANDS COMPARED WITH RATES FOR THE GENERAL POPULATION TOTAL STUDIED NUMBER WITH "DEFINITE" OR "CLINICALLY DEFINITE" MS NUMBER WITH "POSSIBLE" MS INCREASED RATES FOR RELATIVES OF PROBANDS EXPRESSED AS MULTIPLES OF THE POPULATION PREVALENCE **@40/100,000 **@110/100,000 Parents 826 11 8 33.0-57.5* 12.1-20.9 C h i l d r e n S i b l i n g s Others TOTAL 667 1179 5273 7945 3 27 48 89 4 6 11 29 11.2-26.2 54 .0-66 .0 22.8-28.0 28.0-37.1 4.1-9.5 20.8-25.4 8.3-10.2 10.2-13.5 * The f i r s t f i g u r e i s f o r " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS; the second f i g u r e i s fo r " d e f i n i t e " , " c l i n i c a l l y d e f i n i t e " , or " p o s s i b l e " MS ** 40/100,000 - low estimate based on data from t h i s t h e s i s 110/100,000 - high estimate based on survey i n Saskatoon (Hader, 1978) - 52 -4.3. "PGOODFIT" PROGRAMME A t o t a l of 23 ("possible" = "normal") or 2,7 ("possible" = " a f f e c t e d " ) f a m i l i e s of the 364 s i b s h i p s c o ntained a t l e a s t two a f f e c t e d i n d i v i d u a l s . TABLE XIV l i s t s the p r o b a b i l i t y of o b s erving t h i s many or more f a m i l i e s with m u l t i p l e a f f e c t e d s i b s h i p s under the model being t e s t e d f o r s e l e c t e d values of 2 II and h and TABLE XV l i s t s the p r o b a b i l i t y of o b serving t h i s many or fewer f a m i l i e s . When the h e r i t a b i l i t y value of 0.65 i s used, the m u l t i f a c -t o r i a l model i s r e j e c t e d f o r a l l values of II i r r e s p e c t i v e of the c l i n i c a l d e f i n i t i o n of " p o s s i b l e " c a ses. A l l lower va l u e s f o r 2 h e r i t a b i l i t y are l i k e w i s e r e j e c t e d . When h =0.8, the model can o n l y be r e j e c t e d f o r n = 0.5 when " p o s s i b l e " cases are con-2 s i d e r e d a f f e c t e d . For the intermediate value of h , r e j e c t i o n of the model depends on the II value and the coding of " p o s s i b l e " oases. 4.4. PHENOTYPIC HETEROGENEITY 4.4.1. Age of Onset For the purpose of t h i s study, age of onset i s d e f i n e d as the age at which the proband, r e t r o s p e c t i v e l y , f i r s t experienced symptoms of MS. At the time of f i r s t e x p e r i e n c i n g these symp-toms, the proband, of course, d i d not r e a l i z e t h a t they were i n d i c a t i v e of MS. The d i a g n o s t i c c r i t e r i a of Schumacher e t a l . TABLE XIV: COMPUTED "PRG" VALUES FOR MS (WHERE "PRG" IS THE PROBABILITY OF HAVING THE OBSERVED NUMBER OF FAMILIES OR MORE WITH AT LEAST TWO AFFECTED SIB-LINGS UNDER THE MODEL BEING TESTED) VALUES ASCERTAINMENT PROBABILITY (II) 0.001 0.1 0.2 0.5 P o s s i b l e 0.80 0.73 0 .65 0.50 = A f f e c t e d (n=27) 0.36 0.09 0.01* 0.00* 0.27 0.06 0.00* 0 .00* 0 .19 0.03* 0.00* 0.00* 0.04* 0.00* 0.00* 0.00* P o s s i b l e 0.80 0.73 0.65 0.58 = Normal (n=23) 0.59 0.24 0 .04* 0.00* 0.49 0 .17 0.01* 0 .02* 0 .39 0.12 0.01* 0.00* 0.14 0.03* 0.00* 0 .00* * s t a t i s t i c a l l y s i g n i f i c a n t - 54 -TABLE XV: COMPUTED "PRL" VALUES FOR MS (WHERE "PRL" IS THE PROBABILITY OF HAVING THE OBSERVED NUMBER OF FAMILIES OR LESS WITH AT LEAST TWO AFFECTED SIB-LINGS UNDER THE MODEL BEING TESTED) ASCERTAINMENT PROBABILITY (II) h VALUES 0.001 0.1 0.2 0.5 P o s s i b l e = A f f e c t e d (n=27) 0.80 0.71 0.80 0.86 0.98 0.73 0.94 0.96 0 .98 0.99 0.65 0 .98 0.98 0.99 0.99 0.50 0.99 0.99 0.99 0.99 P o s s i b l e = Normal (n=23) 0.80 0.50 0.60 0 .69 0.91 0.73 0 .91 0 .90 0.98 0.99 0 .65 0.86 0.90 0.99 0 .99 0.58 0.99 0 .99 0.99 0.99 - 55 -(1965) s t a t e t h a t age of on s e t s h o u l d be w i t h i n the ages of 10 t o 50 y e a r s , i n c l u s i v e . There a r e , however, r a r e r e p o r t s of MS i n c h i l d r e n under 10 y e a r s o f age (Schneider e t a l . , 1969; Low & C a r t e r , 1 9 5 6 ) . ( i ) Sex of the Proband The mean age o f on s e t f o r females (30.0 y e a r s ) d i d not d i f f e r s i g n i f i c a n t l y ( f ^ Q = 1«4) from t h a t f o r males (31.3 y e a r s ) . FIGURE 5 i l l u s t r a t e s the age of onset d i s t r i b u t i o n s f o r males and females as w e l l as f o r a l l the probands r e g a r d l e s s of sex. A l l t h r e e d i s t r i b u t i o n s appear s l i g h t l y skewed. In such a s i t u a t i o n , the median, the p o i n t which h a l f the v a l u e s i n a p o p u l a t i o n exceed and h a l f f a l l s h o r t o f , can o f t e n g i v e a d d i -t i o n a l i n s i g h t i n t o the d i s t r i b u t i o n (Snedecor & Cochran, 1978 ) . The median f o r female probands f a l l s i n age c a t e g o r y 25-29 as does t h a t f o r a l l the probands, r e g a r d l e s s o f sex. However, the median f o r males i s i n age c a t e g o r y 3 0 - 3 4 . The d i s t r i b u -t i o n f o r males a l s o d i f f e r s from the o t h e r two i n t h a t i t appears t o be bimod a l w i t h the two peaks b e i n g i n age c a t e g o r i e s 25-29 and 3 5 - 3 9 . In a d d i t i o n , no male had the on s e t o f the d i s e a s e p r i o r t o age 15 whereas t h r e e females d i d . ( i i ) P r e s e n c e or Absence o f a F a m i l y H i s t o r y o f MS The mean age o f onset f o r probands w i t h a f a m i l y h i s t o r y of " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS (27.3 y e a r s ) was - 56 ~ 90 80 70 60 >i u c % 50 cu fc 40 30 20 10 1 If/ ' / 1 1 i r 1- r — i 1 r -0-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Age c a t e g o r i e s —X Male Probands Female Probands .0 A l l Probands FIGURE 5: GRAPH: AGE OF ONSET DISTRIBUTION IN ASSOCIATION WITH THE SEX OF THE PROBAND - 57 -s i g n i f i c a n t l y younger ( F 3 3 g = 8.2) than t h a t f o r the probands having no f a m i l y h i s t o r y (30.9 y e a r s ) . FIGURE 6 i l l u s t r a t e s the age of onset d i s t r i b u t i o n s f o r these two groups. The median f o r those with a f a m i l y h i s t o r y f a l l s i n t o age category 25-29 whereas t h a t f o r probands without a f a m i l y h i s t o r y i s i n the 30-34 age c a tegory. The d i s t r i b u t i o n for the l a t t e r group appears to be bimodal with the two peaks being i n age c a t e g o r i e s 25-29 and 35-39. 4.4.2. F i r s t Reported Symptoms of MS The f i r s t symptoms of MS most f r e q u e n t l y r e p o r t e d by MS p a t i e n t s are (McAlpine e t a l . , 1972): motor weakness i n one or more limbs; o p t i c n e u r i t i s ; p a r a e s t h e s i a e , the two main types being p i n s and needles or a t i n g l i n g s e n s a t i o n and numbness or a dead f e e l i n g ; double v i s i o n ; v e r t i g o / v o m i t i n g ; d i s t u r b a n c e of m i c t u r i t i o n . Other symptoms l e s s f r e q u e n t l y r e p o r t e d i n -clude hemiplegia, t r i g e m i n a l n e u r a l g i a , and f a c i a l p a l s y . (i) Sex of the Proband TABLE XVI compares the p r o p o r t i o n of males and females r e p o r t i n g each of the above-mentioned f i r s t symptoms of MS. For no symptom d i d the p r o p o r t i o n of males d i f f e r from the p o r p o r t i o n of females. ( i i ) Presence or Absence of a Family H i s t o r y of MS TABLE XVII compares the p r o p o r t i o n of probands with and without a f a m i l y h i s t o r y of MS r e p o r t i n g each of the a b o v e - l i s t e d - 58 -f - i — - — r — — T — « 0-14 15fl9 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 AGE CATEGORIES FIGURE 6: GRAPH: AGE OF ONSET'DISTRIBUTION IN ASSOCIATION WITH THE PRESENCE OR ABSENCE OF A FAMILY HISTORY - 59 -TABLE XVI: PROPORTION OF MALES AND FEMALES REPORTING EACH OF SIX FREQUENTLY REPORTED FIRST SYMPTOMS OF MS FEMALE MALE PROBANDS .. PROBANDS (N = 278) (N = 138) X 2 FIRST SYMPTOMS _ % £ ' % Motor weakness . 59 21.2 28 20.3 0.05 O p t i c n e u r i t i s 49 17.6 20. 14.5 0.71 Pa r a e s t h e s i a e 98 35.3 44 31.9 0.46 Double v i s i o n 21 7.6 13 9.4 0.30 Ve r t i g o / V o m i t i n g 37 13.3 28 20.3 3.36 Disturbance of m i c t u r i t i o n 5 1.8 4 2.9 0.59 Others 9 3.2 1 0.7 - 60 -TABLE XVII: PROPORTION OF PROBANDS WITH AND WITHOUT A FAMILY HISTORY OF MULTIPLE SCLEROSIS REPORTING EACH OF SIX FREQUENTLY REPORTED FIRST SYMPTOMS OF MS PROBANDS PROBANDS WITH WITHOUT A FAMILY HISTORY A FAMILY HISTORY (N = 73) (N = 322) X 2 FIRST SYMPTOMS i % £ % Motor weakness 18 24.7 66 20.5 0.62 O p t i c n e u r i t i s 13 17.8 54 16.8 0.03 Pa r a e s t h e s i a e 22 30.1 112 34.8 0.58 Double v i s i o n 9 12.3 22 6.7 2.53 V e r t i g o / V o m i t i n g 9 12.3 53 16.5 0.78 Disturbance of mictur i t i o n 1 1.4 8 2.5 0.37 Others 1 1.4 7 2.2 - 61 -f i r s t symptoms. For no symptom d i d the p r o p o r t i o n of those with a f a m i l y h i s t o r y d i f f e r from the p r o p o r t i o n of those without a f a m i l y h i s t o r y . 4.4.3. S e v e r i t y S e v e r i t y was graded as d e s c r i b e d i n s e c t i o n 3.2.3. Age of onset and d u r a t i o n of the d i s e a s e must be c o n s i d e r e d when examining s e v e r i t y . The i n i t i a l course of the d i s e a s e can be e i t h e r p r o g r e s s i v e or f o l l o w a r e m i s s i o n / e x a c e r b a t i o n course. The o l d e r the age of onset, the g r e a t e r the chance t h a t the course of the d i s e a s e w i l l be p r o g r e s s i v e d e t e r i o r a t i o n ( C a z z u l l o e t a l . , 1978; Rose, 1974). T h e r e f o r e , as a group, those with an o l d e r mean age of onset would tend to be more s e v e r e l y a f f e c t e d f o r a given dura-t i o n than would those with a younger mean age of onset. Although the course of MS i s v a r i a b l e , the longer the dura-t i o n of the i l l n e s s , the more severe the symptoms. With time, the r e m i s s i o n / e x a c e r b a t i o n c y c l e u s u a l l y becomes one of pro-g r e s s i v e d e t e r i o r a t i o n . (i) Sex of the Proband TABLE XVIII compares the p r o p o r t i o n of males and females i n each of the three d i s a b i l i t y c a t e g o r i e s , i . e . m i l d ; moderate; severe. In none of the c a t e g o r i e s do the p r o p o r t i o n s d i f f e r s i g n i f i c a n t l y . (The mean age of onset does not d i f f e r f o r the sexes. The mean d u r a t i o n f o r males (17.1 years) does not d i f f e r s i g n i f i c a n t l y ( F ^ 1 n = 1.3) from t h a t f o r females (18.4 y e a r s ) . ) - 62 -TABLE XVIII: PROPORTION OF MALES AND FEMALES IN EACH OF THREE DISABILITY CATEGORIES FOR MS FEMALE MALE PROBANDS PROBANDS (N = 278) (N = 138) X 2 DISABILITY CATEGORY f i l l M i l d 88 31.7 32 23.2 3.20 Moderate 124 44.6 67 48.6 0.56 Severe 66 23.7 39 28.2 1.01 - 6 3 -( i i ) Presence or Absence of a Family History of MS TABLE XIX compares the proportion of probands, with and without a family history in each of the three d i s a b i l i t y cate-gories. A s i g n i f i c a n t l y greater proportion of those with a family history are in the mild d i s a b i l i t y category. The cate-gories were broken down into the six d i s a b i l i t y grades of Hyllested (1956) and the difference was in d i s a b i l i t y grade 2 (TABLE XX):. The mean age of onset was s i g n i f i c a n t l y younger for those with a family history of the disease and the mean duration of MS for probands with a family history (19.3 years) does not d i f f e r s i g n i f i c a n t l y (F3go,= 1«1) from that for probands without a family history (17.8 years). Therefore, as expected, the mean age at the time of p a r t i c i p a t i o n in this study was s i g -n i f i c a n t l y younger ( F3g3 = 5.0) for probands with a family h i s -tory when compared with that for those having no family history. 4.5. PREGNANCY Of the 278 women who participated in this study, 226 (81.3%) had been pregnant at least once. TABLE XXI summarizes the "pregnancy h i s t o r i e s " for the women in this study. Eighteen women had the onset of their MS during a pregnancy year (nine months gestation plus three months post-par turn). The remaining 101 women developed symptoms of the disease after a l l pregnancy years had been completed. - 64 -TABLE XIX: PROPORTION OF PROBANDS WITH AND WITHOUT A FAMILY HISTORY OF MS IN EACH OF THE THREE DISABILITY CATEGORIES DISABILITY CATEGORY PROBANDS WITH A FAMILY HISTORY (N = 73) # PROBANDS WITHOUT A FAMILY HISTORY (N = 322) # X' M i l d Moderate Severe 28 38.4 84 26.1 27 37.0 156 48.4 18 24.6 82 25.5 4 .39* 3.13 0.01 * p < 0.05 - 65 -TABLE XX: PROPORTION OF PROBANDS WITH AND WITHOUT A FAMILY HISTORY OF MS IN EACH OF THE SIX DISABILITY GRADES DISABILITY GRADE 1 2 3 4 5 6 PROBANDS WITH A FAMILY HISTORY (N = 73) £ 2 26 20 17 14 4 2.7 35 .6 14 .7 23.3 19 .2 5.5 PROBANDS WITHOUT A FAMILY HISTORY (N = 322) i i 12 3.7 72 22.3 64 19.9 92 28.6 64 19.9 18 5.6 X' 0.47 5 .63* 1.51 0.81 0.01 0 .00 * p < 0.025 - 66 -TABLE XXI: PREGNANCY HISTORIES FOR 278 FEMALES WITH MS NUMBER PREGNANCY HISTORIES OF WOMEN PERCENTAGE Onset of MS i n a pregnancy year 18 6.4 Exacerbation i n a pregnancy year 30 10.8 Pregnancy had no e f f e c t on e x i s t i n g MS 75 27.0 Onset a t l e a s t 4 months post-partum and no subsequent pregnancies 101 36.3 No pregnancies 52 18.7 I n s u f f i c i e n t data 2 0.8 TOTAL 278 100.0 - 67 -One hundred f i v e women had a t o t a l of 192 pregnancies after the onset of MS. Thirty of these women (18.6%) experi-enced an exacerbation of symptoms during at least one pregnancy year. These 30 women had a t o t a l of 43 pregnancy years during which such relapses occurred. The remaining 75 women reported no change in the status of their MS during pregnancy. M i l l a r et a l . (1959) calculated relapse rates for women during the reproductive period, up to age 45, by dividing the to t a l number of relapses by the t o t a l years of exposure to MS (years of exposure being years from the onset to age 45 or the age at the time of pa r t i c i p a t i o n in the study i f i t i s less than 45). His relapse rate for both "married" and "unmarried" women was 0.104 whereas the relapse rate for women during a pregnancy year (0.265) was s i g n i f i c a n t l y higher. Using the method described by M i l l a r et a l . (1959), relapse rates were calculated (APPENDIX H) for the female probands in this study. The rates for "never pregnant" women and women who had been pregnant at least once were 0.14 and 0.11 respectively. These rates were not s i g n i f i c a n t l y d i f f e r e n t . The relapse rate for women during a pregnancy year (0.22) was s i g n i f i c a n t l y higher than that for women who had never been pregnant and that for women who had been pregnant at least once. TABLE XXII summarizes these r e s u l t s , which support the observation by others that pregnancy increases the ri s k of exacerbation during a pregnancy year. The data in this table - 68 -TABLE XXII COMPARISON OF THE RELAPSE (EXACERBATION) RATES FOR WOMEN WITH AND WITHOUT A HISTORY OF PREGNANCIES. COMPARISON OF THESE RATES WITH THAT FOR WOMEN DURING A PREGNANCY YEAR. GROUPS OF WOMEN BEING COMPARED RELAPSE RATES X "Never pregnant" women/women with at l e a s t one pregnancy Women with at l e a s t one pregnancy/women d u r i n g a pregnancy year* "Never pregnant" women/women du r i n g a pregnancy year 0.14/0.11 0.11/0.22 0.14/0.22 2.2 15 .8*** 5.7** * Pregnancy year = nine months g e s t a t i o n + three months post-par turn ** p < 0.025 *** p < 0.005 - 69 -are based on 2 3 3 women. Forty-five female probands were excluded from this particular analysis. In 24 of these women, the onset of MS occurred after age 4 5 , i . e . past the reproductive period as defined by M i l l a r et a l . ( 1 9 5 9 ) . Eighteen other women experi-enced the f i r s t symptoms of the disease during a pregnancy year. The data were i n s u f f i c i e n t for three additional women. The e f f e c t of pregnancy on the long-term severity of MS was also examined. The proportions of "never pregnant" females and females with at least one pregnancy were compared for each of the three d i s a b i l i t y categories for MS. In no case did these proportions d i f f e r s i g n i f i c a n t l y (TABLE XXIII). The mean age of onset for the two groups of women did not d i f f e r s i g n i f i c a n t l y ^ 2 7 4 = 2 . 3 ) nor did the mean duration of the disease (F^^= 2 . 7 ) . The e f f e c t of pregnancy in association with the presence or absence of a family history of " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS was examined for 2 1 0 women (TABLE XXIV). (The analysis excluded 5 2 women who were never pregnant and 1 8 with a family history of "possible" MS.) When compared with females having no family history, a greater proportion of those with f a m i l i a l MS had the onset of the disease during a pregnancy year and a lesser proportion had the onset of the disease after a l l pregnancies were completed. Although the mean duration of the MS was similar for the two groups (F^QQ- 0 . 0 7 ) , the age of onset in women with f a m i l i a l MS was s i g n i f i c a n t l y lower ( F ^ n Q = 7 . 5 ) than that for women having no family history. TABLE XXIII: COMPARISON OF THE PROPORTION OF FEMALES WITH AND WITHOUT A PREGNANCY HISTORY IN EACH OF THE THREE DISABILITY CATEGORIES FOR MULTIPLE SCLEROSIS DISABILITY CATEGORY M i l d Moderate Severe FEMALES WITH AT LEAST ONE PREGNANCY* # 73 102 48 32.7 45 .7 21.6 NEVER PREGNANT FEMALES** # 14 23 16 25.9 43.4 30.2 0.79 0.09 1.79 TOTAL 223 53 * mean age of onset = 28.1 years mean d u r a t i o n of MS = 17.5 years ** mean age of onset = 30.7 years mean d u r a t i o n of MS = 18.4 years - 71 -TABLE XXIV: EFFECT OF PREGNANCY ON MS IN ASSOCIATION WITH THE PRESENCE OR ABSENCE OF A FAMILY HISTORY OF DEFINITE OR CLINICALLY DEFINITE MS PREGNANCY HISTORY PROBANDS WITHOUT A FAMILY HISTORY* % # PROBANDS WITH A FAMILY HISTORY** # X Onset of MS i n a pregnancy year 11 6.5 Relapse i n a pregnancy year 20 11.9 Onset a f t e r a l l preg-nancies completed 84 50.0 Pregnancy had no e f f e c t 53 31.6 7 16.7 8 19.0 11 26.2 16 38.1 4 .39*** 1.49 7.69**** 0 .65 TOTAL 168 42 * mean age of onset = 31.1 years mean d u r a t i o n of MS = 19.9 years ** mean age of onset = 26.9 years mean d u r a t i o n of MS = 19.1 years *** p<'0.05 **** p < 0.01 - 72 -This l a t t e r observation has also been made when comparing a l l probands, regardless of sex, for age of onset in association with the presence or absence of a family history for MS. 4.6. EPIDEMIOLOGY 4.6.1. Prevalence Rate Prevalence i s the number of individuals with a s p e c i f i c disorder or t r a i t l i v i n g in a s p e c i f i c area at a given point in time, the prevalence date. For this study, the prevalence date was A p r i l 30, 1976. A prevalence rate i s defined as the number of affected persons per 100,000 population (Percy et a l . , 1971; Schapira et a l . , 1963). Population figures for B.C. are taken from the July 1, 1976 Census of Canada. On prevalence date, the ascertained 983 cases gave a province-wide prevalence rate of 39.9 per 100,000 popula-tio n . TABLE XXV l i s t s the age and sex-dependent prevalence rates. 4.6.2. Sex Ratios A t o t a l of 983 reported cases of MS were ascertained on prevalence date. This sample consisted of 644 females and 339 males giving a female:male sex r a t i o of 1.9:1. The sex r a t i o for the 416 subjects (278 females, 138 males) was 2:1. The proportion of males and females in the two samples did not d i f -. . 2 fer s i g n i f i c a n t l y (X = 0.21). TABLE XXV: AGE & SEX-SPECIFIC PREVALENCE RATES FOR BRITISH COLUMBIA (BASED ON 98 3 ASCERTAINED CASES) MALES: FEMALES: BOTH SEXES: AGE B.C. # ASCER- PREVALENCE # ASCER- PREV. # ASCER-• PREV. IN POPULATION TAINED RATE POP. IN TAINED RATE/ POP.IN TAINED RATE/ 1976 IN 1000'S CASES PER 100,000 1000 •s CASES 100,000 1000 'S CASES 100,000 0-14 304 .0 - - 291 .2 - - 595.1 - -15-24 231.3 7 3.0 228 .1 9 3.9 459.4 16 3.5 25-34 200.8 32 15.9 194 .9 54 27.7 395.7 86 21.7 , 35-44 144 .8 51 35.2 135 .1 101 74 .8 279.9 15.2 54.3 £ 45-54 134 .4 89 66.2 134 .3 186 138 .6 268 .7 275 102.4 ' 55-64 107.3 87 81.1 118 .4 153 129 .2 225.8 240 106.3 65 + 109 .9 32 29.2 132 .2 59 44.6 242 .1 91 37.6 Age unknown 41 - - 82 - - 123 -TOTAL 1232.5 339 27.5 1234 .1 644 52.2 2466 .6 983 39.9 - 74 -TABLE XXVI compares the p r o p o r t i o n of males and females among MS p a t i e n t s i n B.C., Winnipeg, Manitoba ( S t a z i o e t a l . , 1964) and Saskatoon, Saskatchewan (Hader, 1978). The sex p r o p o r t i o n s f o r the Winnipeg and Saskatoon p o p u l a t i o n s do not 2 d i f f e r s i g n i f i c a n t l y from B.C. (B.C./Winnipeg: X = 0.66; 2 B.C./Saskatoon: X = 0.07). - 75 " TABLE XXVI: THE SEX RATIOS FOR MS PATIENTS IN BRITISH COLUMBIA, WINNIPEG, AND SASKATOON NUMBER OF NUMBER OF FEMALES MALES R A T I Q B. C. 644 339 1.90:1 Winnipeg 104 63 1.65:1 Saskatoon 92 46 2.00:1 - 76 -CHAPTER 5 DISCUSSION 5.1. SUBJECTS 5.1.1. Data Collection A t o t a l of 983 cases of MS were ascertained and of these, 416 (42.3%) participated in this study. Three hundred ten personal interviews were conducted. This method of data c o l l e c t i o n proved to be the most favourable as the subject was usually eager and well-prepared. It was rarely necessary to contact the subject a second time except i f addi-t i o n a l information was needed concerning a r e l a t i v e . Personal interviews were conducted mainly with individuals l i v i n g in Vancouver and the neighbouring mu n i c i p a l i t i e s , the Fraser Val-ley, the Okanagan Valley, and Vancouver Island. Eighty-six persons completed and returned a detailed ques-tionnaire, 68.3% of those who had i n i t i a l l y agreed to do so. Most of these individuals l i v e d in remote regions of B r i t i s h Columbia. Problems were encountered with this method of c o l -lecting data. There was usually a delay in returning the ques-tionnaires and reminders were often necessary. In addition, the subjects frequently f a i l e d to answer a l l the questions adequately and therefore follow-up was necessary. However, one d e f i n i t e - 77 -advantage to the questionnaires, other than the opportunity to include an additional 86 subjects in this study, was that r e l a -tives and physicians often assisted in the completion of the form and therefore much of the information was given in great d e t a i l . Telephone interviews were the least s a t i s f a c t o r y method for data c o l l e c t i o n . Twenty such interviews were conducted and, in most cases, the subject was i n i t i a l l y telephoned for the purpose of arranging a meeting. This proved to be impossible for various reasons but the individuals offered to answer any questions at the time of this i n i t i a l c a l l . These interviews were therefore spontaneous and follow-up was frequently required. It was f e l t , however, that a telephone interview was:preferable to omitting the subject from the study. Despite various problems, the three methods of data c o l l e c -tion provided the same basic information and i t was therefore feasible to include a l l 416 persons in the study. 5.1.2. General Description of the Subjects The mean duration of the MS at the time of p a r t i c i p a t i n g in the study (TABLE VIII) was the same for females and males. This i s important since any differences observed, such as severity, between females and males cannot, therefore, be attributed to differences in the duration of the disease and the effects of sex can therefore be examined. - 78 -5.2. EMPIRIC FAMILIAL RECURRENCE RISKS The f a m i l i a l recurrence risks discussed in t h i s thesis are "empiric" r i s k s , i . e . r i s k s based on observed data rather than t h e o r e t i c a l models (Kidd, 1976). The data from this study support the observations of others that MS shows " f a m i l i a l aggregates" (McAlpine et a l . , 1972). However, the finding that second and t h i r d degree r e l a t i v e s of the probands have an increased prevalence of MS when compared with the general population (TABLE XXVII) tends to disprove the hypothesis that r e l a t i v e s of patients develop the disease due to a "common shared environment" (McAlpine et a l . , 1972). While f i r s t degree r e l a t i v e s (parents, children, siblings) may l i v e together for long periods hence sharing the same environ-ment, this i s generally not the case with second degree r e l a -tives (aunts, uncles, nieces, nephews, grandchildren) and t h i r d degree r e l a t i v e s ( f i r s t cousins). A t o t a l of 22.6 + 4.0% of the probands had a family history of either " d e f i n i t e " / " c l i n i c a l l y d e f i n i t e " MS (17.5 ± 3.7%) or "possible" MS (5.0 ± 2.1%). While these figures are high when compared with most early studies (TABLE I ) , they are compatible with the recent observations for Saskatoon (Hader, 1978). As emphasized in sections 3.1.1 and 3.1.2, care was taken to avoid some bias by using multiple sources of ascertainment and by describing the aims of the study to potential subjects in such a way as to avoid attracting only those persons with " f a m i l i a l " TABLE XXVII: INCREASED RISK TO RELATIVES OF PROBANDS COMPARED WITH THE GENERAL POPULATION DEGREE OF RELATIONSHIP TO PROBAND NUMBER STUDIED NUMBER WITH "DEFINITE" OR "CLINICALLY DEFINITE" MS NUMBER WITH "POSSIBLE" MS TIMES POPULATION PREVALENCE* @4o/ioo,ooo e i i o / i o o . 0 0 0 1st degree 2672 41 18 38.4-55.2** 14.9-20.1 2nd degree 3149 24 19.1-23.8 6.9-8.7 3rd degree 2124 24 28.2-34.1 10 .3-13 .3 * 40/100,000 - low estimate based on data from t h i s t h e s i s 110/100,000 - high estimate based on Saskatoon survey (Hader, 1978) ** The f i r s t f i g u r e i s f o r " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS; the second f i g u r e i s f o r "definite", " c l i n i c a l l y d e f i n i t e " , or " p o s s i b l e " MS . - 80 -MS. As d i s c u s s e d i n s e c t i o n 3.1.4, persons were not c a t e g o r i z e d as having " d e f i n i t e " / " c l i n i c a l l y d e f i n i t e " MS based on "hearsay" evidence. T h e r e f o r e , i t i s b e l i e v e d that the f i g u r e s c i t e d f o r " f a m i l i a l " MS based on t h i s work are as accurate as p r a c t i c a l and may ;represent a low estimate s i n c e the probands would not be aware of r e l a t i v e s i n the e a r l y stages of the d i s e a s e , es-p e c i a l l y i f the degree of the r e l a t i o n s h i p i s d i s t a n t . I t i s recognized that the o v e r a l l r i s k to f i r s t degree r e l a t i v e s of the proband i s low, namely 2.2 ± 0.6%. However, as w i l l be d i s c u s s e d i n s e c t i o n 5.3, these r i s k f i g u r e s are comparable with those p r e d i c t e d by the m u l t i f a c t o r i a l model of inher i t a n c e . The s i g n i f i c a n c e of empiric date for g e n e t i c c o u n s e l l i n g i s based on the assumption t h a t the average frequency "with which a d i s o r d e r has occurred i n the past i s the best estimate that i t w i l l occur i n the f u t u r e " (Kidd, 1976). Since there are recognized problems i n d i a g n o s i n g MS because of the l a c k of a s p e c i f i c d i a g n o s t i c t e s t , e m p i r i c r i s k f i g u r e s must be recog-n i z e d as low estimates of the r i s k f o r the f u t u r e . So t h a t these r i s k f i g u r e s can be more e a s i l y comprehended and used f o r c o u n s e l l i n g , h y p o t h e t i c a l pedigrees have been p r e -pared. F i g u r e s 7 and 8 g i v e empiric recurrence r i s k s (with 95% confidence i n t e r v a l s ) : f o r f i r s t degree r e l a t i v e s of the p r o-bands. F i g u r e 9 l i s t s these r i s k s f o r f i r s t , second, and t h i r d degree r e l a t i v e s of the probands. 02.2±1.6%*| [2.9±2.0% (6/276) 1 j(8/276) (b) /~^2.9±2.8% V J ( 4 / 1 3 7 ) 0.7±1.4% (1/137) 3.4±1.7% (14/408) 1.9±1.4i (7/363) f ) 0 . 9 ± 1 . 2 % (2/231) 1.6+1.5% (4/254) 1.5±1.7% (3/196) 4.2±2.6% (9/212) l^Jl.l±2.1% (1/87) oo 0% (0/95) / - PROBAND FIGURE 7: EMPIRIC RECURRENCE RISKS FOR RELATIVES OF FEMALE AND MALE PROBANDS o -MALE FEMALE - 82 -2.4±1.3% (10/413) 2.2±1.3% (9/413) 2 .8±1.3% (17/604) 2.8±1.4% (16/575) 0 .9±1.0 (3/318) • 6 1.1±1.0% (4/349) - PROBAND MALES AND FEMALES - MALES - FEMALES FIGURE 8: EMPIRIC RECURRENCE RISKS FOR FIRST DEGREE RELATIVES OF PROBANDS - 83 -2.3±1.0% (19/826) 1.8±0 .7% (26/1414) 2.8±0.9% (33/1179) 0.2±0.2% (4/1653) 1.4±0 .5% (29/2124) 1.0±0 .5% (7/667) 1 IL TSL - DEGREE OF THE RELATIONSHIP TO PROBAND - MALES AND FEMALES - PROBAND FIGURE 9: EMPIRIC RECURRENCE RISKS FOR FIRST, SECOND, AND THIRD DEGREE RELATIVES OF THE PROBANDS - 84 -5.3. GENETICS The o b s e r v a t i o n t h a t the prevalence of MS among r e l a t i v e s of p a t i e n t s i s i n c r e a s e d compared with t h a t f o r the g e n e r a l p o p u l a t i o n r e s u l t e d i n the hypothesis t h a t g e n e t i c f a c t o r s are i n v o l v e d i n the e t i o l o g y of the d i s e a s e . Although i t could be argued t h a t "common environmental f a c t o r s " are r e s p o n s i b l e f o r t h i s o b s e r v a t i o n among f i r s t degree r e l a t i v e s of p a t i e n t s , t h i s would not s a t i s f a c t o r i l y e x p l a i n the i n c r e a s e d prevalence among second and t h i r d degree r e l a t i v e s . Recent work with HLA antigens (Tiwari e t a l . , 1980; V i s s c h e r e t a l . , 1979) supports the con-cept of an "MS" gene or genes. (i) S i n g l e Gene I n h e r i t a n c e Both autosomal dominant and autosomal r e c e s s i v e models of i n h e r i t a n c e r e q u i r e t h a t the frequency of a d i s o r d e r among s i b -l i n g s of p a t i e n t s exceed t h a t f o r the g e n e r a l p o p u l a t i o n by a given f a c t o r . T h i s f a c t o r i s d e f i n e d as 0.5/p f o r autosomal dominant i n h e r i t a n c e and 0.25/p f o r autosomal r e c e s s i v e i n h e r i -tance where "p" i s the p r o p o r t i o n of the g e n e r a l p o p u l a t i o n a f f e c t e d with the d i s o r d e r , i . e . the prevalence r a t e (Edwards, 1960). As shown by TABLE XXVIII, t h i s f a c t o r f o r MS data does not approach the expected value f o r e i t h e r autosomal dominant or autosomal r e c e s s i v e i n h e r i t a n c e . The above o b s e r v a t i o n s c o u l d be e x p l a i n e d by the concept of reduced penetrance and both autosomal dominant and autosomal TABLE XXVIII GOODNESS-OF-FIT OF EMPIRIC RISKS FOR SIBLINGS OF PROBANDS TO THE AUTOSOMAL DOMINANT AND AUTOSOMAL RECESSIVE MODES OF INHERITANCE POPULATION PREVALENCE (P), OBSERVED FREQUENCY OF MS AMONG SIBLINGS OF PROBANDS EXPECTED FREQUENCY BASED ON PREVALENCE RATE "FACTOR" BY WHICH OBSERVED FREQUENCY EXCEEDS EXPECTED PREDICTED FACTOR UNDER THE AUTOSOMAL DOMINANT MODEL* PREDICTED FACTOR UNDER THE AUTOSOMAL RECESSIVE MODEL** 40/100,000 ( t h i s study) 27/1179 0.5/1179 54 1250 625 110/100,000 (Hader, 1978) 27/1179 1.3/1179 20.8 455 227 * Expected f a c t o r under the autosomal dominant model = 0.5/p ** Expected f a c t o r under the autosomal r e c e s s i v e model = 0.25/p - 86 -r e c e s s i v e models of i n h e r i t a n c e with g r e a t l y reduced penetrance have been proposed f o r MS (Visscher e t a l . , 1979; Mackay & Myrianthopoulos, 1966). However, the v a l i d i t y of a s i n g l e gene model of i n h e r i t a n c e with reduced penetrance i s qu e s t i o n a b l e as, using t h i s concept, pedigree data can be made to f i t any model (Edwards, 1960). ( i i ) M u l t i f a c t o r i a l Model The m u l t i f a c t o r i a l model i m p l i e s t h a t both environmental and g e n e t i c f a c t o r s are i n v o l v e d i n the m a n i f e s t a t i o n of a dis e a s e or t r a i t . S e v e r a l authors have proposed t h i s mode of i n h e r i t a n c e f o r MS (Tiwari e t a l . , 1980; Ba t c h e l o r e t a l . , 1978; A l t e r , 1977; Zanussi & Scorza-Smeraldi, 1977). A b r i e f d e s c r i p -t i o n of t h i s model i s warranted. M u l t i f a c t o r i a l i n h e r i t a n c e assumes t h a t the t r a i t (or disease) i s due to many g e n e t i c and environmental f a c t o r s . The term was o r i g i n a l l y used to e x p l a i n the d i v e r s i t y of continuous t r a i t s such as hei g h t and weight. To overcome the r e s t r i c t i o n t h a t m u l t i f a c t o r i a l c o n d i t i o n s had to be continuous, i . e . not a l l - o r - n o n e , the assumption was made that there was an u n d e r l y i n g g r a d i e n t of some a t t r i b u t e immediately r e l a t e d to the c a u s a t i o n of the di s e a s e (Falconer, 1965). Measurement of t h i s a t t r i b u t e would give a graded s c a l e of degree of " a f f e c t e d e n e s s " or "n o r m a l i t y " . Persons above a c e r t a i n value show the phenotype; those below do not. The con-cept of an u n d e r l y i n g v a r i a b l e was proposed by C a r t e r (1961). - 87 -The h y p o t h e t i c a l graded a t t r i b u t e i s r e f e r r e d to as an i n d i -v i d u a l ' s " l i a b i l i t y " . L i a b i l i t y i s meant not o n l y to r e f e r to a person's s u s c e p t i b i l i t y (innate tendency t o develop a d i s e a s e ) but a l s o the whole combination of e x t e r n a l f a c t o r s that make a person more or l e s s l i k e l y to develop the d i s e a s e (Falconer, 1965). The p o i n t on the " l i a b i l i t y s c a l e " above which a l l i n d i v i d u a l s are a f f e c t e d and below which a l l are u n a f f e c t e d i s the " t h r e s h o l d " (Falconer, 1965). L i a b i l i t y i s assumed to be normally d i s t r i b u t e d and "standard d e v i a t i o n " i s the u n i t f o r e x p r e s s i o n of the degree of l i a b i l i t y (Falconer, 1965). As d i s -cussed i n s e c t i o n 3.2.1, the concept of " t h r e s h o l d " has been a p p l i e d i n accounting f o r d i s e a s e s , such as MS, where males and females have d i f f e r e n t prevalence r a t e s . Since l i a b i l i t y i s m u l t i f a c t o r i a l , an i n d i v i d u a l ' s t o t a l l i a b i l i t y (L) i s assumed to be equal to the g e n e t i c l i a b i l i t y (G) and the environmental l i a b i l i t y (E), i . e . L = G + E (Mendell & Spence, 1979). "G" i s composed of many genes with s m a l l , e q u a l , and a d d i t i v e e f f e c t s . "E" i s a l s o composed of many en-vironmental f a c t o r s with s m a l l , e q u a l , and a d d i t i v e e f f e c t s . In terms of genes, e q u a l i t y means t h a t no g e n e t i c l o c u s i s more important than any other with r e s p e c t to i t s c o n t r i b u t i o n to "G" and a d d i t i v i t y i m p l i e s t h a t genes at two l o c i c o n t r i b u t e independently to "G", i . e . no e p s i s t a s i s (Mendell & Spence, 1979). Apart from the f a i l u r e of MS data to show c l e a r Mendelian s e g r e g a t i o n , evidence for the m u l t i f a c t o r i a l model i n c l u d e s the f o l l o w i n g : - 88 -(a) There i s an unequal sex r a t i o among the a f f e c t e d . (b) There are f a m i l i a l aggregates. (c) The frequency of MS among s i b l i n g s of the probands i s com-p a t i b l e with the p r e d i c t i o n s of the m u l t i f a c t o r i a l model, i . e . that the frequency be /p where "p" i s the p o p u l a t i o n prevalence (Edwards, 1960). For these d a t a , 27 out of 1179 s i b l i n g s of probands had e i t h e r " d e f i n i t e " or " c l i n i c a l l y d e f i n i t e " MS, g i v i n g a r a t e of 0.02. I f "p" i s 40/100,000, then /p i s 0.02. I f "p" i s 110/100,000 (Hader, 1978), then /p i s 0.03. The observed r a t e of 0.02 i s t h e r e f o r e compatible with the pre -d i c t e d r a t e under the m u l t i f a c t o r i a l model. (d) Under the m u l t i f a c t o r i a l model, the f a c t o r by which the frequency of the d i s e a s e among s i b l i n g s of p a t i e n t s exceeds that for the g e n e r a l p o p u l a t i o n i s d e f i n e d as l / / p (Edwards, 1960.) If "p" i s 40/100,000, then l / / p equals 50. For these data, t h i s f a c t o r i s 54. S i m i l a r l y , i f "p" equals 110/100,000 popu-l a t i o n , the p r e d i c t e d f a c t o r , i . e . l//p, i s 33 and the a c t u a l f a c t o r i s 20.8. These f i n d i n g s are compatible with p r e d i c t i o n s of the m u l t i f a c t o r i a l model. (e) The prevalence rate f o r MS v a r i e s with the l a t i t u d e (en-vironmental e f f e c t ) y e t m i g r a t i o n does not d r a m a t i c a l l y a l t e r a person's r i s k to the d i s e a s e (genetic e f f e c t ) . The data d i f f e r from what i s g e n e r a l l y observed f o r m u l t i -f a c t o r i a l d i s o r d e r s as f o l l o w s : (a) For the m u l t i f a c t o r i a l two-threshold model, r e l a t i v e s of p a t i e n t s of the l e a s t f r e q u e n t l y a f f e c t e d sex, i . e . males i n - 89 -MS, are more f r e q u e n t l y a f f e c t e d than are r e l a t i v e s of p a t i e n t s o f the more f r e q u e n t l y a f f e c t e d sex, i . e . females i n MS (Car-t e r , 1973). The theory behind these o b s e r v a t i o n s i s that per-sons of the l e a s t f r e q u e n t l y a f f e c t e d sex repr e s e n t a more extreme d e v i a t i o n from the p o p u l a t i o n mean f o r m u l t i f a c t o r i a l l y determined l i a b i l i t y than do those of the more o f t e n a f f e c t e d sex (Carter & Evans, 1969). In t h i s study, the p r o p o r t i o n of a f f e c t e d f i r s t degree r e l a t i v e s f o r males does not d i f f e r ; f r o m t h a t f o r females (Section 4.2). (b) For m u l t i f a c t o r i a l d i s e a s e s , the r i s k to r e l a t i v e s de-creases as the degree of the r e l a t i o n s h i p to the proband i n c r e a s e s . Although t h i s i s true when f i r s t and second degree r e l a t i v e s of the MS p a t i e n t s are compared, the trend does not continue when comparing second and t h i r d degree r e l a t i v e s . T h i s c o u l d be due, i n p a r t , to the probands' lack of informa-t i o n r e g a r d i n g t h i r d degree r e l a t i v e s , e.g. many were unsure of the t o t a l number of f i r s t c o u s i n s . A f t e r c o n s i d e r i n g the v a r i o u s ways MS agrees and d i s a g r e e s with the p r e d i c t i o n s of the m u l t i f a c t o r i a l model, i t was de-c i d e d that there was s u f f i c i e n t agreement to warrant t e s t i n g the " g o o d n e s s - o f - f i t " of these data to the model. The a c t u a l m u l t i f a c t o r i a l model being t e s t e d i s the two-threshold model as adapted by Kidd et a l . (1973). - 90 -( i i i ) G enetic I n t e r p r e t a t i o n s of the R e s u l t s from "PGOODFIT" The r e s u l t s from "PGOODFIT" r e j e c t the m u l t i f a c t o r i a l 2 2 model f o r a l l h estimates of 0.65 or l e s s . For h values 2 g r e a t e r than 0.65, r e j e c t i o n depends on the va l u e s f o r h and 2 II. An h value of 0.65 i s compatible with those u s u a l l y given i n the l i t e r a t u r e f o r MS. Using data from nine p o p u l a t i o n s t u d i e s and a p p l y i n g F a l c o n e r ' s (1965) method f o r e s t i m a t i n g 2 2 h , Berry (1969) c a l c u l a t e d t h a t h for these s t u d i e s ranged from 0.36-0.61, with the exception of one twin study (TABLE XXIX). The m u l t i f a c t o r i a l model was r e j e c t e d f o r a l l these h 2 estimates by "PGOODFIT". The r e j e c t i o n of the model by "PGOODFIT" can be i n t e r -p r e t e d as evidence f o r the e x i s t e n c e of a g e n e t i c mechanism other than the m u l t i f a c t o r i a l being i n v o l v e d i n the m a n i f e s t a -t i o n of MS. In no case was the model r e j e c t e d on the b a s i s of "PRL" values (TABLE XV). Such r e j e c t i o n would have been i n t e r -p r e t e d as evidence a g a i n s t a g e n e t i c component to the e t i o l o g y of MS. R e j e c t i o n was e n t i r e l y on the b a s i s of "PRG" valu e s (TABLE XIV), i . e . due to the o b s e r v a t i o n of "too many" m u l t i p l e a f f e c t e d s i b s h i p s than p r e d i c t e d under the model. These obser-v a t i o n s can be i n t e r p r e t e d as evidence for e i t h e r (a) a g e n e t i c model with a higher recurrence r i s k than the m u l t i f a c t o r i a l model or (b) g e n e t i c h e t e r o g e n e i t y . A p o s s i b l e a l t e r n a t i v e g e n e t i c model f o r MS c o u l d be the mixed model (Morton & MacLean, 1974) which d i f f e r s from the m u l t i f a c t o r i a l model i n t h a t there i s dominance between genes. TABLE XXIX:: COMPARISON OF THE HERITABILITY ESTIMATE FROM VARIOUS STUDIES STUDY HERITABILITY ESTIMATE (h ) B r i t i s h Columbia ( t h i s study) 0.58 * S w i t z e r l a n d ,0.61 England & Wales 0 .58 Sweden 0.59 Northern I r e l a n d 0.55 Northern S c o t l a n d 0.56 Northumberland & Durham 0.57 V e s t f o l d , Norway 0.36 M0re & Romsdal, Norway 0.47 USA & Canada (twin study) 0.86 * " P o s s i b l e " MS c o n s i d e r e d to be normal f o r t h i s c a l c u l a t i o n - 92 -Another a l t e r n a t i v e g e n e t i c model c o u l d be the s i n g l e major gene locus model (SML), which has been proposed for t r a i t s showing no c l e a r - c u t Mendelian p a t t e r n s (Kidd & Spence, 1976). 3* T h i s model d i f f e r s from the m u l t i f a c t o r i a l as f o l l o w s : The m u l t i f a c t o r i a l model assumes many segre-g a t i n g l o c i each of s m a l l e f f e c t , with both t r a n s m i t t e d and i n d i v i d u a l environmental f a c t o r s p o s s i b l e ; the SML model assumes onl y one two-a l l e l e locus with no other t r a n s m i t t e d f a c t o r s but with random environmental v a r i a t i o n a c t i n g independently w i t h i n f a m i l i e s . The p o s s i b i l i t y of g e n e t i c h e t e r o g e n e i t y comes from the r e a l i z a t i o n t h a t i f there a r e , g e n e t i c a l l y , s e v e r a l types of MS, i . e . a dominant form; a r e c e s s i v e form; a s p o r a d i c form; a m u l t i f a c t o r i a l form, then the o v e r a l l recurrence r i s k f o r a sample composed of persons with a l l these forms of MS would be g r e a t e r than that f o r the m u l t i f a c t o r i a l model, i . e . l e a d -ing to r e j e c t i o n of the model on the b a s i s of "PRG" v a l u e s . 5.4. PHENOTYPIC HETEROGENEITY For the three phenotypic f e a t u r e s of MS examined, there i s no evidence f o r h e t e r o g e n e i t y i n a s s o c i a t i o n with the sex of the proband. There are, however, i n d i c a t i o n s that such h e t e r o g e n e i t y e x i s t s i n a s s o c i a t i o n with the presence or absence of a f a m i l y h i s t o r y of " d e f i n i t e " or " c l i n i c a l l y * See f o o t n o t e s , page 101 - 93 -d e f i n i t e " MS. The mean age of onset i s s i g n i f i c a n t l y younger fo r those with a f a m i l y h i s t o r y when compared with those having no f a m i l y h i s t o r y of MS. As d i s c u s s e d i n s e c t i o n 4.4, age of onset i s r e l a t e d to whether the i n i t i a l course of the i l l n e s s i s p r o g r e s s i v e or f o l l o w s a r e m i s s i o n / e x a c e r b a t i o n c y c l e . I t i s a l s o r e l a t e d to the s e v e r i t y of the disease f o r a given d u r a t i o n . Since a s i g n i f i c a n t l y lower propor-t i o n of probands with f a m i l i a l ! MS i n i t i a l l y had a p r o g r e s -s i v e course when compared with probands having no f a m i l y h i s t o r y (19/73 : 130/322; X 2 = 5.17), i t i s not unexpected t h a t the former group has p r o p o r t i o n a t e l y more i n d i v i d u a l s in the "mild" d i s a b i l i t y category f o r MS than does the l a t t e r group (TABLE XIX), f o r a given d u r a t i o n . In c o u n s e l l i n g a p a t i e n t with f a m i l i a l MS who has e a r l y onset, i t should be poi n t e d out that the d i s e a s e i n i t i a l l y i s more l i k e l y t o f o l l o w a remiss i o n / e x a c e r b a t i o n c y c l e thus improving the pr o g n o s i s , f o r the e a r l y years, regarding d i s -a b i l i t y than in p a t i e n t s with no f a m i l y h i s t o r y . 5.5. PREGNANCY The d i a g n o s i s of MS i n females i s u s u a l l y made durin g the r e p r o d u c t i v e y e a r s . T h e r e f o r e , the e f f e c t of pregnancy on the h e a l t h of the mother i s of major concern to both p h y s i -c i a n s and MS p a t i e n t s . - 9 4 -V a r i o u s s t u d i e s have examined the e f f e c t of pregnancy on MS. The r e s u l t s of some (Leibowitz Se A l t e r , 1 9 7 3 ; Schapira e t a l . , 1 9 6 6 ; M i l l a r e t a l . , 1 9 5 9 ) i n d i c a t e t h a t there i s an inc r e a s e d r e l a p s e (exacerbation) r a t e during a pregnancy year whereas the r e s u l t s from other i n v e s t i g a t i o n s (McAlpine et a l . , 1 9 7 2 ) have not shown t h i s . The r e s u l t s from t h i s study support the o b s e r v a t i o n that pregnancy i n c r e a s e s the r i s k of exa c e r b a t i o n d u r i n g a pregnancy year (TABLE XXII). I t has a l s o been rep o r t e d (Leibowitz Sc A l t e r , 1 9 7 3 ; M i l l a r e t a l . , 1 9 5 9 ) that most of the ex a c e r b a t i o n s occur du r i n g the post-partum p e r i o d rather than d u r i n g the a c t u a l pregnancy. One p o s s i b l e e x p l a n a t i o n f o r t h i s i s that p h y s i -o l o g i c a l changes a s s o c i a t e d with labour and d e l i v e r y have;.a more d e t r i m e n t a l e f f e c t than those that occur during g e s t a t i o n . T h i s study a l s o concludes that the post-partum p e r i o d i s the most "dangerous". T h i r t y - f i v e out of 4 5 pregnancy-related e x a c e r b a t i o n s o c c u r r e d d u r i n g t h i s p e r i o d . As. shown by TABLE XXIV, women with f a m i l i a l MS have a gr e a t e r chance of f i r s t d e v e l o p i n g symptoms of the di s e a s e during a pregnancy year than do women without a f a m i l y h i s -t o r y . The former group has a l e s s e r chance of developing the disease a f t e r having completed a l l pregnancies than does the l a t t e r . These o b s e r v a t i o n s are, however, most probably a s s o c i a t e d with the f i n d i n g t h a t persons with a f a m i l y h i s -t o r y of MS tend to develop the di s e a s e at a younger age than - 95 -do those without such a f a m i l y h i s t o r y ( s e c t i o n 4.4.1) r a t h e r than being a d i r e c t r e s u l t of the presence or absence of f a m i l i a l MS. Although pregnancy can i n c r e a s e the r i s k of e x a c e r b a t i o n d u r i n g a pregnancy year, the long-term sever i t y of MS, taking age of onset and d u r a t i o n of the i l l n e s s i n t o account, i s not i n f l u e n c e d by the presence or absence of a pregnancy h i s t o r y . T h e r e f o r e , there i s no i n d i c a t i o n t h a t pregnancy should be avoided to improve the prognosis of the d i s e a s e f o r women. These f i n d i n g s are important f o r the r e p r o d u c t i v e coun-s e l l i n g of women with MS. Apart from any g e n e t i c r i s k s , the h e a l t h of the mother a f f e c t s the w e l l - b e i n g of her c h i l d . Pregnancy i n c r e a s e s the r i s k of an e x a c e r b a t i o n d u r i n g a preg-nancy year. There i s no guarantee that a r e m i s s i o n w i l l f o l l o w a p r e g n a n c y - r e l a t e d e x a c e r b a t i o n j u s t as there are no a s s u r -ances t h a t a r e m i s s i o n w i l l f o l l o w any e x a c e r b a t i o n . I t was not uncommon f o r the author to encounter women whose MS had so progressed a f t e r c h i l d b i r t h t h a t they were never able to care for t h e i r b a b i e s . Pregnancy does not a l t e r the long-term course of the d i s e a s e . In c o u n s e l l i n g , i t must be emphasized that r a i s i n g a c h i l d i s a long-term committment and i t i s very l i k e l y t h a t the mother's MS w i l l progress d u r i n g that time. The e f f e c t of the d i s e a s e ' s p r o g r e s s i o n on both the mother and c h i l d must be c o n s i d e r e d over a p e r i o d of many y e a r s . -. 96 -5.6. EPIDEMIOLOGY 5.6.1. Prevalence Rates Although the main aim of t h i s study was not to determine province-wide prevalence r a t e s ( t h i s would be an e n t i r e study i n i t s e l f ) , the author f e l t t h a t a s u f f i c i e n t number of MS p a t i e n t s were a s c e r t a i n e d to allow f o r the c a l c u l a t i o n of minimum prevalence r a t e s . In studying these f i g u r e s , i t i s important to remember that ascertainment was not 100% and that i t was only p o s s i b l e to check the accuracy of the d i a g n o s i s f o r 674 persons (68.6%) of the t o t a l 983 a s c e r t a i n e d . However, only e i g h t of these i n d i v i d u a l s (1.2%) proved to be " p o s s i b l e " cases of MS r a t h e r than " c l i n i c a l l y d e f i n i t e " . T h i s g i v e s some i n d i c a t i o n of the degree of accuracy r e g a r d i n g d i a g n o s i s for the v a r i o u s ascertainment sources. The province-wide prevalence r a t e , based on 983 cases, i s 39.9 per 100,000 p o p u l a t i o n , a f i g u r e which i s compatible with that expected f o r the geographic l o c a t i o n of B r i t i s h Columbia. TABLE XXX compares t h i s rate with those f o r other Canadian c e n t e r s . The prevalence r a t e s f o r Saskatoon, 110 per 100,000 i f " p o s s i b l e " cases are omitted and 133 per 100,000 i f "pos-s i b l e " cases are i n c l u d e d , are e x c e p t i o n a l l y high and when these r a t e s are compared with those reported throughout the world, Saskatoon ranks behind o n l y the Orkneys (309 per 100,000) and the Shetlands (184 per 100,000) (Poskanzer et a l . , 1977b). - 9 7.-" TABLE XXX: PREVALENCE RATES IN CANADA REGION PREVALENCE RATE* REFERENCE B r i t i s h Columbia Saskatoon Ottawa Winnipeg H a l i f a x Kingston ( c i t y ) Kingston (area) 39.9 110 (133)** 67 35.4 32.3 57 (77) 30 Th i s t h e s i s Hader, 1978 Bennett e t a l . , 1977 S t a z i o e t a l . , 1964 A l t e r e t a l . , 1960 White & Wheelan, 1959 White & Wheelan, 1959 * Rate per 100,000 p o p u l a t i o n ** Two prevalence r a t e s were c a l c u l a t e d , the second i n c l u d i n g " p o s s i b l e " cases of MS - 98 -5.6.2. Sex R a t i o s A preponderance of females among MS p a t i e n t s has been repor t e d i n the l i t e r a t u r e (Acheson, 1977; Bennett et a l . , 1977; Percy et a l . , 1971; P r a t t , 1951). A t o t a l of 983 per-sons were a s c e r t a i n e d on prevalence date and the female:male sex r a t i o was 1.90:1. Although the author does not c l a i m t o have a s c e r t a i n e d a l l the cases of MS l i v i n g i n the province on the prevalence date, i t i s i n t e r e s t i n g to note that the sex p r o p o r t i o n s f o r the 983 a s c e r t a i n e d do not d i f f e r s i g n i f i c a n t l y from those r e p o r t e d f o r Winnipeg ( S t a z i o e t a l . , 1964) and Saskatoon (Hader, 1978). Care was taken to avoid sources which would a s c e r t a i n one sex over another. T h i s preponderance of females i s not j u s t a r e f l e c t i o n of the B.C. p o p u l a t i o n which i s composed of 1,234,095 females and 1,232,510 males g i v i n g a sex r a t i o of 1.0013:1. - 99 -CHAPTER 6 CONCLUSIONS The B.C. p o p u l a t i o n of MS p a t i e n t s appears to be r e p r e -s e n t a t i v e of what i s expected f o r a northern, temperate r e g i o n i n terms of sex r a t i o and pr e v a l e n c e . Although a g e n e t i c e t i o l o g y t o MS has been suggested i n the p a s t , MS data have never f o r m a l l y been t e s t e d f o r "goodness-o f - f i t " t o any model of i n h e r i t a n c e . T h e r e f o r e , to gain i n -s i g h t i n t o the e t i o l o g y of the d i s e a s e , these data were t e s t e d fo r " g o o d n e s s - o f - f i t " to s i n g l e gene and m u l t i f a c t o r i a l models of i n h e r i t a n c e by both pedigree and computer a n a l y s e s . For these data, both autosomal dominant and r e c e s s i v e modes of i n h e r i t a n c e are r e j e c t e d . I n i t i a l l y , there was evidence t h a t the d a t a c o u l d be compatible with the m u l t i f a c t o r i a l model of i n h e r i t a n c e but f u r t h e r t e s t i n g r e j e c t e d t h i s on the b a s i s that too many m u l t i p l e a f f e c t e d s i b s h i p s were observed than expected under the model. T h i s i s i n t e r p r e t e d as evidence f o r e i t h e r (a) a g e n e t i c model with a higher recurrence r i s k than the m u l t i f a c t o r i a l model or (b) g e n e t i c h e t e r o g e n e i t y . T h i s study i s the f i r s t to d e r i v e e m p i r i c recurrence r i s k s , needed f o r g e n e t i c c o u n s e l l i n g and f o r t e s t i n g "good-n e s s - o f - f i t " of p o p u l a t i o n data t o models of i n h e r i t a n c e , f o r f i r s t , second, and t h i r d degree r e l a t i v e s of MS p a t i e n t s . - 100 -In summary, t h i s study, by being the f i r s t to t e s t "good-n e s s - o f - f i t " of MS data to a model of i n h e r i t a n c e , g i v e s i n s i g h t i n t o the e t i o l o g y of MS by p r o v i d i n g evidence f o r a g e n e t i c component to the e t i o l o g y of the d i s o r d e r . Genetic c o u n s e l l i n g i s o f f e r e d to f a m i l i e s with a . h i s t o r y of d i s o r d e r s with a m u l t i f a c t o r i a l e t i o l o g y , such as n e u r a l tube d e f e c t s . The r e s u l t s from t h i s study provide evidence that the g e n e t i c model i n MS c o u l d have a higher recurrence r i s k than the m u l t i -f a c t o r i a l model would p r e d i c t . Genetic c o u n s e l l i n g , t h e r e f o r e , should be o f f e r e d to MS p a t i e n t s . To enable complete g e n e t i c c o u n s e l l i n g , o b s e r v a t i o n s are made on other aspects of the d i s e a s e such as phenotypic h e t e r o g e n e i t y and the e f f e c t of pregnancy on the h e a l t h of female p a t i e n t s . - 101 -FOOTNOTES 1 N. Nathanson and A. M i l l a r . (1978) "Epidemiology of M u l t i p l e S c l e r o s i s : C r i t i q u e of the Evidence f o r a V i r a l E t i o l o g y . " American J o u r n a l of Epidemiology, 107, pp.452. 2 D. McAlpine, C E . Lumsden, and E.D. Acheson. M u l t i p l e  S c l e r o s i s : A R e A p p r a i s a l . (Edinburgh & London: C h u r c h i l l L i v i n g s t o n e , 1972), pp.219. 3 K.K. Kidd and M..A. 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(1976) "HLA Haplotypes in F a m i l i e s with High Frequency of M u l t i p l e S c l e r o s i s . " A r c h i v e s of Neurology, 33:808 Paty, D.W.; Cousin, H.K.; S t i l l e r , C.R.; Boucher, D.W.; Furesz, J . ; Warren, K.G.; Marchuk, L.; and Dossetor, J.B. (1977) "HLA-D Typing with an A s s o c i a t i o n of Dw2 and Absent Immune Responses Towards Herpes Simplex (Type 1) Antigen i n M u l t i p l e S c l e r o s i s . " T r a n s p l a n t a t i o n Proceedings, 9:1845 P a u l l e y , J.W. (1977) "The P s y c h o l o g i c a l Management of M u l t i p l e S c l e r o s i s . " The P r a c t i t i o n e r , 218:100 Percy, A.K.; Nobrega, F.T.; Okazaki, H.; G l a t t r e , E.; and Kurland, L.T. (1971) " M u l t i p l e S c l e r o s i s i n Rochester, Minn.: A 60 Year A p p r a i s a l . " A r c h i v e s of Neurology, 25:105 Pertschuk, L.P.; Cook, A.W.; Gupta, J.K.; Broome, J.D.; V u l e t i n , J . C ; Kim, D.S.; B r i g a t i , D.J.; R a i n f o r d , E.A.; and N i d s g o r s k i , F. (1977) " J e j u n a l Immunopathology i n Amytrophic L a t e r a l S c l e r o s i s and M u l t i p l e S c l e r o s i s . I d e n t i f i c a t i o n of V i r a l Antigens by Immunofluorescence." The Lancet, 1:1119 Poskanzer, D.D. " E t i o l o g y of M u l t i p l e S c l e r o s i s : Analogy Sug-g e s t i n g I n f e c t i o n i n E a r l y L i f e " i n Epidemiology of M u l t i p l e  S c l e r o s i s . E d i t e d by M. A l t e r and J.F. Kurtzke. S p r i n g -f i e l d , I I . : C h a r l e s C. Thomas, 1968 - n o -Poskanzer, D.C, Sever, J.L.; Terasaki, P.I.; Prenney, L.B.; and Sheridan, J.L. (1977a) "Multiple Sclerosis in the Orkney and Shetland Islands: I I . V i r a l Antibody T i t e r s , History of Infection, and Etiology." Neurology, 27:372 Poskanzer, D.C; Terasaki, P.I.; Park, M.S.; Sheridan, J.L.; and Prenney, L.B. 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Saunders Company, 1980 T i w a r i , J.L.; Hodge, S.E.; T e r a s a k i , P.I.; and Spence, M.A. (1980)"HLA and the I n h e r i t a n c e of M u l t i p l e S c l e r o s i s : Linkage A n a l y s i s of 72 P e d i g r e e s . " (Human G e n e t i c s , i n press) Verdes, F., P e t r e s c u , A., and Cernescu, C. (1978) "Epidemio-l o g i c Survey of M u l t i p l e S c l e r o s i s i n the Bucharest C i t y and Suburban Area." Acta N e u r o l o g i c a Scand., 58:109 - 112 -V i s s c h e r , B.R.; D e t e l s , R.; Coulson, A.H.; Malmgren, R.M.; and Dudley, J.P. (1977) " L a t i t u d e , M i g r a t i o n , and the Prevalence of M u l t i p l e S c l e r o s i s . " American J o u r n a l of Epidemiology, 106:470 V i s s c h e r , B.R.; D e t e l s , R.; Dudley, J . ; H a i l e , R.W.; Malmgren, R.M.; T e r a s a k i , P.I.; and Park, M.S. (1979) "Genetic S u s c e p t i b i l i t y to M u l t i p l e S c l e r o s i s . " Neurology 29:1354 White, D.N. and Wheelan, L. (1959) "Disseminated S c l e r o s i s : A Survey of P a t i e n t s i n the Kingston, O n t a r i o Area." Neurology, 9:256 Zanussi, C. and Scorza-Smeraldi, R. (1977) "The HLA System and M u l t i p l e S c l e r o s i s . " B o l l e t t i n o D e l l 1 I n s t i t u t o S i e r o t e r a -p i c o Milanese, 56:531 Z i b e t t i , A.; C a z z u l l o , C.L.; Smeraldi, E.; and S c o r z a -S m e r a l d i , R. (1977) "HLA Typing on I t a l i a n M u l t i p l e S c l e r -o s i s P o p u l a t i o n . " B o l l e t t i n o D e l l ' I n s t i t u t o S i e r o t e r a p i c o M i l a n e s e , 56:539 - 113 -APPENDIX A: L e t t e r D e s c r i b i n g the Intended Study to P o t e n t i a l Subjects The U n i v e r s i t y of B r i t i s h Columbia F a c u l t y of Medicine Department of M e d i c a l G e n e t i c s 2075 Wesbrook Place Vancouver, B.C., Canada V6T 1W5 Dear We, i n the Department of M e d i c a l Genetics at the U n i v e r s i t y of B r i t i s h Columbia, are c u r r e n t l y i n v o l v e d i n a study of M u l t i -p l e S c l e r o s i s i n B r i t i s h Columbia. The aim of t h i s study i s to enhance the b a s i c understanding of t h i s d i s e a s e and p o i n t to areas f o r f u t u r e r e s e a r c h . In order to o b t a i n data f o r t h i s study, we plan to compile medical and g e n e t i c h i s t o r i e s f o r p a t i e n t s with M u l t i p l e S c l e r -o s i s . Your c o o p e r a t i o n would be g r e a t l y a p p r e c i a t e d . There w i l l be no requests f o r e i t h e r a p h y s i c a l examination or the t a k i n g of blood samples. We only wish to arrange a meeting dur-ing which you w i l l be asked q u e s t i o n s r e g a r d i n g your h e a l t h and that of your c l o s e r e l a t i v e s . The i d e n t i t y of a l l i n d i v i d u a l s contacted d u r i n g the course of t h i s study i s s t r i c t l y c o n f i d e n -t i a l . In order that we may know whether or not you r e c e i v e d t h i s l e t t e r , we would a p p r e c i a t e your f i l l i n g out the attached form and r e t u r n i n g i t i n the envelop p r o v i d e d . I f you i n d i c a t e that you wish to p a r t i c i p a t e , I w i l l c o n t a c t you so that we may a r -range a meeting. Thank you f o r your a s s i s t a n c e . Yours t r u l y , (Mrs.) Adele D. Sadovnick - 114 -APPENDIX B: Form on Which P o t e n t i a l Subjects I n d i c a t e d T h e i r W i l l i n g n e s s to P a r t i c i p a t e THIS FORM IS TO BE RETURNED IN THE ENVELOPE WHICH IS PROVIDED NAME: ADDRESS: DO YOU WISH TO PARTICIPATE? YES NO IF YES: TELEPHONE NUMBER DO YOU REGULARLY ATTEND A CLINIC OR WORKSHOP? IF YES, DATES & TIMES P LAC E IF YOU LIVE OUTSIDE THE VANCOUVER AREA, DO YOU PLAN TO VISIT VANCOUVER? YES NO IF YES, DATES OTHER COMMENTS: I THANK YOU! - 115 -APPENDIX C: Qu e s t i o n n a i r e used f o r Obtaining Data GENERAL INFORMATION NAME: ADDRESS: PLACE OF BIRTH: DATE OF BIRTH: NAME & ADDRESS OF FAMILY PHYSICIAN: NAME OF NEUROLOGIST (IF ANY): PLACE OF BIRTH OF: YOUR MOTHER: YOUR MOTHER'S MOTHER: YOUR MOTHER'S FATHER: YOUR FATHER: YOUR FATHER'S FATHER: YOUR FATHER'S MOTHER: ; IS THERE A CHANCE THAT ANY OF THE FOLLOWING PAIRS OF INDIVIDUALS ARE RELATED IN ANY WAY OTHER THAN BY MARRIAGE (eg. COUSINS): NO YES IF YES, HOW YOUR PARENTS: YOUR MATERNAL GRANDPARENTS: YOUR PATERNAL GRANDPARENTS: DO YOU HAVE ANY ALLERGIES? NO: YES: SPECIFY - 116 " PREGNANCY HISTORY OF INDIVIDUAL WITH M.S. (IF FEMALE) OR (IF MALE) OF WIFE (OR MATE) WHILE LIVING WITH INDIVIDUAL WITH M.S. TOTAL # OF PREGNANCIES INCLUDING LIVE-BIRTHS, STILLBIRTHS, MISCARRIAGES, OR ABORTIONS: TOTAL # OF: LIVE-BORN DAUGHTERS: LIVE-BORN SONS: STILLBORN MALES: STILLBORN FEMALES: MISCARRIAGES: ABORTIONS: FOR EACH LIVE-BORN CHILD (A CHILD WHO IS ALIVE AT THE TIME OF DELIVERY) PLEASE GIVE COMPLETE NAME (INCLUDING MARRIED SURNAME; DATE OF BIRTH; DATE AND CAUSE OF DEATH IF APPLICABLE; INFORMA-TION REGARDING ANY HEALTH PROBLEMS OR BIRTH DEFECTS; ANY OTHER INFORMATION WHICH YOU CONSIDER RELEVANT: _ 117 _ HAVE YOU EVER HAD ANY FALLS OR ACCIDENTS INJURING YOUR BACK, NECK, OR SPINE? NO: YES: SPECIFY:_ WERE YOU IN GOOD HEALTH UNTIL YOU DEVELOPED THE M.S.? YES: NO: SPECIFY WHAT IS YOUR OCCUPATION? ARE YOU STILL WORKING? YES: NO: IF NO, YEAR AND REASON FOR STOPPING WORK: - 118 -COURSE OF THE M.S. WHAT WAS YOUR FIRST SYMPTOM AND WHEN DID IT OCCUR? HOW LONG DID THE FIRST SYMPTOM(S) LAST? NAME OF PHYSICIAN WHO DIAGNOSED THE M.S. AND YEAR OF THE DIAGNOSIS? HAVE YOU EVER USED ANY OF THE FOLLOWING: NO YES YEAR BEGAN USE ONE CANE: TWO CANES: WALKER: CRUTCHES: WHEELCHAIR: CAN YOU PRESENTLY (19 77): NO YES WALK WITHOUT AID: STAND WITH SUPPORT: STAND WITHOUT SUPPORT: STAND TO TRANSFER: USE THE TOILET: FEED YOURSELF: DRESS YOURSELF: WRITE: SEW: DRIVE A NORMAL CAR: DRIVE A CAR WITH HAND CONTROLS: WATCH TELEVISION: - 119 -HAVE YOU EVER SUFFERED FROM ANY OF THE FOLLOWING: NO YES IF YES, GIVE DETAILS VISUAL TROUBLE: PARALYSIS: COORDINATION PROBLEMS: STAGGERING GAIT: EXTREME FATIGUE: BLADDER PROBLEMS: SLURRED SPEECH: EPILEPSY: LACK OF FUNCTION IN YOUR HANDS: EXTREME MOODINESS: HAVE YOU TAKEN ANY SPECIFIC TREATMENTS FOR YOUR M.S. NO:_ YES: IF YES, PLEASE DESCRIBE: - 120 -HAS THE M.S. PROGRESSED SLOWLY OVER THE YEARS WITH NO MAJOR ATTACKS BUT JUST A GENERAL DETERIORATION? HAS THE M.S. STABILIZED AFTER THE INITIAL ATTACK? HAS THE M.S. BEEN EXPRESSED BY A SERIES OF ATTACKS AND RECOVER-IES ( i . e . REMISSIONS AND EXACERBATIONS): NO YES . IF YES, PLEASE GIVE THE NUMBER OF ATTACKS, THE DURATION OF EACH ATTACK, THE MAIN SYMPTOMS DURING EACH ATTACK, AND RESIDUAL PROBLEMS (IF ANY) REMAINING AFTER EACH ATTACK. - 121 -IS THERE ANYONE ANYWHERE IN YOUR FAMILY WHO HAS M.S.? NO_ YES . IF YES, PLEASE GIVE HIS (HER) NAME, ADDRESS (IF POSSIBLE), AND AS MUCH INFORMATION ABOUT THE COURSE OF HIS (HER) M.S. AS POSSIBLE: IS THERE ANYONE IN THE FAMILY WHO SUFFERS FROM ANY OF THE FOLLOW-I N G : NO YES IF YES, RELATIONSHIP OF THE PERSON TO YOU. EPILEPSY: CEREBRAL PALSY: PARKINSON'S DISEASE: JUVENILE DIABETES: ARTHRITIS (ONSET BY 20'S): AMYOTROPHIC LATERAL SCLEROSIS: NARCOLEPSY: YOUR GRANDCHILDREN: PLEASE GIVE THE FOLLOWING INFORMATION WHERE APPLICABLE FULL NAME NAME OF PARENT DATE OF DATE & CAUSE DESCRIBE ANY HEALTH WHO IS YOUR CHILD BIRTH OF DEATH (IF PROBLEMS OR BIRTH DEFECTS APPLICABLE) YOUR PARENTS: FULL NAME BIRTH DATE DATE & CAUSE OF DEATH IF APPLICABLE DESCRIBE ANY HEALTH PROBLEMS OR BIRTH DEFECTS YOUR BROTHERS NAME & DATE OF BIRTH & SISTERS: DATE & CAUSE OF DEATH IF APPLICABLE DESCRIPTION OF HEALTH PROBLEMS BIRTH DEFECTS FULL NAME, SEX, DATE OF BIRTH, (DATE OF DEATH & CAUSE OF DEATH), DESCRIP-TION OF ANY HEALTH PROBLEMS OF EACH OF THEIR CHILDREN FULL NAME, SEX DATE OF BIRTH, (DATE OF DEATH & CAUSE OF DEATH), DESCRIP-TION OF ANY HEALTH PROBLEMS OF EACH OF THEIR GRANDCHILDREN I M CO YOUR AUNTS & UNCLES: NAME & DATE DATE & CAUSE DESCRIPTION OF OF BIRTH OF DEATH IF HEALTH PROBLEMS APPLICABLE BIRTH DEFECTS FULL NAME, SEX, DATE OF BIRTH, (DATE & CAUSE OF DEATH), DE-SCRIPTION OF ANY HEALTH PROBLEMS OF EACH OF THEIR CHILDREN FULL NAME, SEX, DATE OF BIRTH, (DATE & CAUSE OF DEATH), DE-SCRIPTION OF ANY HEALTH PROBLEMS OF EACH OF THEIR GRANDCHILDREN 4^ I - 125 " APPENDIX D: D e s c r i p t i o n of Cases of " P o s s i b l e " M u l t i p l e S c l e r o s i s among R e l a t i v e s of Probands 1. SISTER OF FEMALE PROBAND (B2)* 29 year o l d female with a two year h i s t o r y of episodes of double v i s i o n , b l u r r e d v i s i o n , c o o r d i n a t i o n problems, and numbness of the hands and d i g i t s . She r e f u s e s to undergo t e s t s as she f e a r s a d i a g n o s i s of MS and would "rather not know". 2. NIECE OF FEMALE PROBAND (B25) 22 year o l d female whom p h y s i c i a n s have l a b e l l e d as "pos-s i b l e MS". At age 20, she experienced severe episodes c f numbness while'pregnant. Two weeks post-parturn, she became b l i n d and t o t a l l y p a r a l y z e d . A f t e r 4 months, she began to improve although one year l a t e r , primary care of the c h i l d i s s t i l l . w i t h the grandmother. 3. MOTHER OF FEMALE PROBAND (C9) In her 20's, the mother of the proband s u f f e r e d a " s t r o k e " c h a r a c t e r i z e d by sudden p a r a l y s i s . She recovered i n i t i a l l y but her symptoms r e c u r r e d and, at the time of her death at age 52, she was bedridden and unable to speak. 4. SON OF FEMALE PROBAND (E8) 17 year o l d male with a 2 year h i s t o r y of episodes of tremors, t i n g l i n g s e n s a t i o n s i n h i s f i n g e r s , and c o o r d i n a t i o n problems. The f a m i l y p h y s i c i a n suspects MS, e s p e c i a l l y s i n c e E8 1s i n i t i a l symptoms were tremors and t i n g l i n g s e n s a t i o n s . 5. MALE FIRST COUSIN OF FEMALE PROBAND (F10) 60 year o l d male s a i d to have MS but as the author was unable to confirm t h i s s i n c e F10 d i d not wish f a m i l y members " d i s t u r b e d " , he was c a t e g o r i z e d as p o s s i b l e MS. 6a. DAUGHTER OF MALE PROBAND ( F l l ) 15 year o l d female who, at age 13, awakened one morning completely p a r a l y z e d . She recovered w i t h i n a week and has had no f u r t h e r problems to date. 6b. BROTHER OF MALE PROBAND ( F l l ) 36 year o l d male with a f i v e year h i s t o r y of episodes of double v i s i o n , s t a g g e r i n g g a i t , weakness, and extreme f a t i g u e . He r e f u s e s to undergo n e u r o l o g i c a l t e s t s and "stays i n bed" u n t i l the symptoms pass. * - p a t i e n t i d e n t i f i c a t i o n code - 126 -7. SISTER OF FEMALE PROBAND (H9) Thi s lady d i e d undiagnosed i n Hungary at age 52 i n 1952. At age 32, she began to have problems with her balance and her symptoms progressed so that at the time of her death, she was bedridden and completely p a r a l y z e d from the neck down. The course of her i l l n e s s i s very s i m i l a r to H9's. H9 i s now bed-ridden i n an extended care h o s p i t a l . 8. AUNT OF FEMALE PROBAND (K18) This lady d i e d at age 40 a f t e r spending s e v e r a l years bed-ridden and unable to t a l k . She f i r s t experienced c o o r d i n a t i o n problems and numbness a f t e r the b i r t h of her son when she was 30. 9. MOTHER OF FEMALE PROBAND (L10) At age 40, a f t e r the b i r t h of her f i f t h c h i l d , she f i r s t e xperienced numbness i n her l e g s . Her symptoms progressed and when she d i e d i n 1950 at age 50, she was,bedridden and a l s o had severe v i s u a l problems. L10 remembers that her mother was s a i d to have MS but as the d i a g n o s i s was made i n Germany i n the 1940's, t h i s i s impossible to v e r i f y . 10. SISTER OF FEMALE PROBAND (L14) 35 year o l d female whose v i s u a l problems were f i r s t d i a g -nosed as " o p t i c n e u r i t i s " . She has si n c e moved to a r u r a l area and although she i s now e x p e r i e n c i n g episodes of numbness and c o o r d i n a t i o n problems, she has not been w i l l i n g to t r a v e l to a major medical c e n t r e f o r t e s t s . 11. FATHER OF FEMALE PROBAND (M21) At age 40, t h i s man began to drag one l e g and was i n i t i a l l y t o l d that he had a " b r a i n c l o t " . As time progressed, the doc-t o r s withdrew t h i s d i a g n o s i s and h i s symptoms progressed to in c l u d e extreme f a t i g u e , numbness, i n c o n t i n e n c e , and in c r e a s e d problems with walking. He d i e d at age 73, r e f u s i n g to seek a d d i t i o n a l medical help a f t e r the "b r a i n c l o t " d i a g n o s i s . 12. FEMALE, SECOND COUSIN 'OF FEMALE PROBAND (-P15) Th i s 30 year o l d female i s s a i d to have MS but the author was unable to do the necessary follow-up to confirm t h i s . 13a. FEMALE FIRST COUSIN OF FEMALE PROBAND (R6) 30 year o l d female, who at age 27, suddenly went b l i n d i n one eye. She recovered her v i s i o n a f t e r a few months but p h y s i c i a n s have l a b e l l e d her as " p o s s i b l e " MS. - 127 -13b. UNCLE OF FEMALE PROBAND (R6) 56 year o l d male whose p h y s i c i a n s are c u r r e n t l y t r y i n g to decide between two p o s s i b l e diagnoses: severe a r t h r i t i s or MS. 14. FEMALE FIRST COUSIN OF FEMALE PROBAND (R13) This lady d i e d at age 50, r e p o r t e d l y of MS, but the author was unable to do the necessary follow-up needed to confirm t h i s . 15a. SON OF FEMALE PROBAND (R14) 28 year o l d male who, at age 18, suddenly went b l i n d . His v i s i o n returned a f t e r two months and although he has had no f u r t h e r symptoms f o r 2 years, h i s p h y s i c i a n s f e e l t h a t i t was an e a r l y s i g n of MS. 15b. DAUGHTER OF FEMALE PROBAND (R14) 23 year o l d female who, at age 20, had a bout of double v i s i o n and p a r a l y s i s of one side of her body. She f u l l y r e -covered and has had no f u r t h e r problems to date. Her attack was post-partum and p h y s i c i a n s f e e l that i t was an e a r l y symptom of MS. 16. MOTHER OF FEMALE PROBAND (S8) At age 34, t h i s lady had the f i r s t of many r e c u r r e n t e p i -sodes of numbness, b l i n d n e s s , and p a r a l y s i s . She was diagnosed in Vienna as having " b r a i n f e v e r " . 17. UNCLE OF FEMALE PROBAND (S31) This man r e p o r t e d l y had MS. He di e d i n England i n the 1950's and i t was impossible to get any a d d i t i o n a l i n f o r m a t i o n . 18. SISTER OF FEMALE PROBAND (VI) 39 year o l d female who, at age 29, had an episode of numb-ness. Since age 36, she has had repeated episodes of b l u r r e d v i s i o n , c o o r d i n a t i o n problems, s t a g g e r i n g g a i t , and extreme f a t i g u e . She has refused to undergo f u r t h e r t e s t s . 19. MOTHER OF FEMALE PROBAND (W18) Th i s lady d i e d at "age 76. She had a h i s t o r y of r e c u r r e n t episodes of p a r a l y s i s . 20. MALE FIRST COUSIN OF FEMALE PROBAND (W23) 59 year numbness and o l d male with a 15 year h i s t o r y of episodes of l o s s of balance. H is p h y s i c i a n s suspect MS. - 128 -21. UNCLE OF MALE PROBAND (W24) This man died at age 66 of "sleeping sickness". His symp-toms, which recurred over many years, included extreme fatigue, blurred v i s i o n , tremors, and d i f f i c u l t y with walking. 22. FATHER OF FEMALE PROBAND (Kl) This man died in 1948. His symptoms were very similar to those of his daughter and son, both c l i n i c a l l y d e f i n i t e cases of MS. 23. FATHER OF FEMALE PROBAND (R5) This man died at age 55 with symptoms very similar to those of two of his children, both c l i n i c a l l y d e f i n i t e cases of MS. 24. FEMALE SECOND COUSIN OF FEMALE PROBAND (T2) This lady, now deceased, i s reported to have had MS but the author was unable to do the necessary follow-up to confirm t h i s . 25a. SISTER OF FEMALE PROBAND (L3) 25b. FATHER OF FEMALE PROBAND (L3) 25c. AUNT OF FEMALE PROBAND (L3) 25d. MALE FIRST COUSIN OF FEMALE PROBAND (L3) L3 and her s i s t e r both have c l i n i c a l l y d e f i n i t e MS. These 4 r e l a t i v e s have a l l had repeated episodes of numbness, vi s u a l problems, and ataxia. They a l l d i s t r u s t physicians and follow a regime prescribed by L3 of l i n o l e i c acid supplements and mega-vitamins in association with a gluten-free diet and no coffee or alcohol. It is the opinion of the author that L3 1s f a n a t i -cism about her die t and i t s effects have influenced her r e l a -tives to avoid physicans. A l l attacks are blamed on deviating from the regime. It is interesting to note that L3 1s s i s t e r does not follow the diet and yet the course of her i l l n e s s (remissions after severe exacerbations) p a r a l l e l s that of her s i s t e r . - 129 -APPENDIX E: PGOODFIT Programme A l l formulae are taken from Glads.tien e t a l . (1978). C a l c u l a t i o n of (the c o n d i t i o n a l p r o b a b i l i t y f o r the i f a m i l y of at l e a s t two a f f e c t e d s i b l i n g s under the model). P = p r o b a b i l i t y ns = number of sons i n f a m i l y i nd = number of daughters i n f a m i l y i g = d i s e a s e s t a t u s of the parents j = sex-dependent ascertainment j = 1 i f f a m i l y i s a s c e r t a i n e d v i a sons j = 2 i f f a m i l y i s a s c e r t a i n e d v i a daughters 11 = ascertainment p r o b a b i l i t y p^ = 1 - P ( e x a c t l y one a f f e c t e d sib/g,ns,nd) X P ( j / e x a c t l y one a f f e c t e d sib,g,ns,nd)/P(j/g,ns,nd) 1 - II'P(one a f f e c t e d son/g ,ns ,nd)/P ( j / g ,ns ,nd) j = 1 1 - II'P(one a f f e c t e d daughter/g , ns, nd)/P ( j / g ,ns ,nd) j = 2 The d i s t r i b u t i o n of the t e s t s t a t i s t i c can be determined using the p r o b a b i l i t y - g e n e r a t i n g f u n c t i o n : P(s) = ,3 (1 - Pi + ?±s) •1 = 1 ^ x - 130 -2 APPENDIX F: C a l c u l a t i o n of r and h by MULFAC Computer Programme Formulae are adapt a t i o n s of those developed by Falconer (1965) to f i t the two-threshold model developed by Reich e t a l . (1972). x = normal d e v i a t e s a = mean d e v i a t i o n of probands from p o p u l a t i o n mean 2 a = (1/2TT) ( e ~ 1 / 2 x p / K p ) t = c o r r e l a t i o n i n l i a b i l i t y between r e l a t i v e s K = prevalence p = s u b s c r i p t r e f e r r i n g to the g e n e r a l p o p u l a t i o n R = s u b s c r i p t r e f e r r i n g to r e l a t i v e s of probands The v a r i a n c e of a f f e c t e d i n d i v i d u a l s i s l e s s than the p o p u l a t i o n v a r i a n c e by: a(a - x p ) . The v a r i a n c e of r e l a t i v e s of a f f e c t e d i n d i v i d u a l s i s l e s s than the p o p u l a t i o n v a r i a n c e by: r ^ a ( a - x ) . The t o t a l v a r i a n c e of r e l a t i v e s of a f f e c t e d i n d i v i d u a l s i s : 1 - r 2 a ( a - x p ) . M o d i f i c a t i o n o f . F a l c o n e r 1s formula to allow f o r reduced v a r i a n c e of r e l a t i v e s i s : r = —— x_ - x / Q - r 2 a ( a - x f|' x :•- ar by rearrangement: ,.xR = -/ [ I - r 2 a ( a - x_)_' . x - x / Q - (x 2 - x 2 ) ( l - (x / a ) Q ' solving for r : r = — ^ a + x R ( a - x p ) taking the root g iv ing 0 < r < 1. - 131 -FOR TWO THRESHOLDS w = s u b s c r i p t r e f e r r i n g to wider form of d i s o r d e r , i . e . females i n MS n = s u b s c r i p t r e f e r r i n g to narrower form of d i s o r d e r , i . e . males i n MS K K = p o p u l a t i o n prevalence of wide and nar-^ row forms of the d i s o r d e r KRw KRn = P r e v a l e n c e °f wide d i s o r d e r i n r e l a -t i v e s of wide probands and narrow d i s -order i n r e l a t i v e s or narrow probands K' R n = prevalence of narrow d i s o r d e r i n r e l a -t i v e s of wide probands K' R w = prevalence of wide d i s o r d e r i n r e l a -t i v e s of narrow probands x r > , , x r > ~ = normal d e v i a t e s f o r and K_ Rw Rn Rw Rn = normal d e v i a t e s f o r K , and K „ pw pn pw pn x* x' = normal d e v i a t e s f o r K' and K' „ Rw Rn Rw Rn by i n s e r t i o n of a p p r o p r i a t e s u b s c r i p t s : (i) when d e r i v e d from Kp n and K R n x p n - XRn/H ~ <*pn ~ x R n } <2 ~ ^ ^ a r 7 ^  r _ . 2 n Rn v n pn ( i i ) when d e r i v e d from K and K_ pw Rw - Xpw " XRw^D- - ( x p W - XRW> ( 1 - <xpw/aw>Q' r _ _ aw + xRw ( aw " Xpw ) ( i i i ) when d e r i v e d from K _ and K' pn tin xP n - x ' R n / Q - ( * g n ~ ^ R n ^ 1 " <xPw/aw> 0' r ~ 2 a + x * (a - x ) w Rn v w pw' - 132 -(iv) when d e r i v e d from K „ and K' „ v ' pw KW xPw - ~ ^ - X ' R W ) ( 1 - ( xpn/ an)Q' r ~ 2 a + x' (a - x ) n Rw n pn' If the assumptions of the model are c o r r e c t , the four r values are expected t o be e q u a l . TABLE XXXI l i s t s the r e s u l t s of these c a l c u l a t i o n s done by MULFAC on the data from t h i s study. - 133 -TABLE XXXI: RESULTS OF MULFAC ANALYSIS ON DATA (a) POSSIBLE MS CONSIDERED TO BE "AFFECTED" * r * h 2 * * PREVALENCES USED IN CALCULATION*** Kpw " K R W ° ' 3 6 ° ' 7 3 K p n - K R n 0.36 0.73 Kpw - K ' R W ° ' 3 6 ° - 7 3 K p n - K' R n 0.36 0.73 (b) POSSIBLE MS CONSIDERED TO BE "NORMAL" r * h 2 * * PREVALENCES USED IN CALCULATION*** Rw Rn • Rw Rn K - K pw K - K pn K - K pw K - K pn 0.29 0.58 0.29 0.58 0.29 0.58 0.29 0.58 r = c o r r e l a t i o n i n l i a b i l i t y among r e l a t i v e s 2 ** h ( h e r i t a b i l i t y ) = r / c o e f f i c i e n t of the r e l a t i o n s h i p . For these data, the c o e f f i c i e n t of the r e l a t i o n s h i p i s 1/2. T h e r e f o r e , h 2 = 2r. *** K K = p o p u l a t i o n prevalence of wide and narrow forms of p the d i s o r d e r (rates from t h i s study and from D e t e l s e t a l . , 1978) KRw KRn = P r e v ^ l e n c e °f wide d i s o r d e r i n r e l a t i v e s of wide probands and narrow d i s o r d e r i n r e l a t i v e s of narrow probands K' R n = prevalence of narrow d i s o r d e r i n r e l a t i v e s of wide probands K ' R W = P r e v a 3 - e n c e °f wide d i s o r d e r i n r e l a t i v e s of narrow probands A l l K R v a l u e s c a l c u l a t e d by MULFAC based on data from t h i s study. APPENDIX G: Empiric Familial Recurrence Risks TABLE XXII EMPIRIC RECURRENCE RISKS FOR "DEFINITE" AND "CLINICALLY DEFINITE" MS RELATIONSHIP FEMALE MALE TO PROBAND PROBANDS PROBANDS ALL PROBANDS £ Q, "5 £ % £ % Mothers 3/276 1.1 3/137 2.2 6/413 1.5 Fathers 4/276 1.4 1/137 0.7 5/413 1.2 Sons 2/254 0.8 0/95 - 2/349 0.6 Daughters 1/231 0.4 0/8 7 - 1/318 0.3 Brothers 7/363 1.9 8/212 3.8 15/575 2.6 Sisters 9/408 2.2 3/196 1.5 12/604 2.0 Aunts 11/475 2.3 6/201 .3.0 17/676 2.5 Uncles 4/532 0.8 0/206 - 4/738 0.5 Nieces 1/598 0.2 1/291 0.3 2/889 2.2 Nephews 0/565 - 1/199 0.5 1/764 0.1 Grandsons 0/43 - 0/3 - 0/46 -Granddaughters 0/32 - 0/4 - 0/36 -1st cousins 17/1563 1.1 7/561 1.2 24/2124 1.1 TOTAL 59/5616 1.1 30/2329 1.3 89/7945 1.1 (±0 .3) * (±0.5)* (±0.2) * 95% confidence l i m i t s TABLE XXXIII: EMPIRIC RECURRENCE RISKS FOR "POSSIBLE" MS RELATIONSHIP FEMALE MALE TO PROBAND PROBANDS PROBANDS. ALL PROBANDS £ O. 1 i £ % Mothers 3/276 1.1 1/137 0.7 4/413 1.0 Fathers 4/276 1.4 0/137 4/413 1.0 Sons 2/254 0 .8 0.95 2/349 0.6 Daughters 1/231 0.4 1/8 7 1.2 2/318 0.6 Bro t h e r s 0/363 - 1/212 0.5 1/575 0.2 S i s t e r s 5/408 1.2 0/196 5/604 0.8 Aunts 2/475 0.4 0/201 2/676 0.3 Uncles 2/532 0.4 1/206 0.5 .3/738 0.4 Nieces 1/598 0.2 0/291 1/889 0.1 Nephews 0/565 - 0/199 0/764 -Grandsons 0/43 - 0/3 0/4 7 -Granddaughters 0/32 - 0/4 0/36 -1st Cousins 5/1563 0.3 0/561 5/2124 0.2 TOTAL 25/5616 0.4 4/2329 0.2 29/7945 0.4 (±0.2)* (±0.2)* (±0.1 * 95% confidence l i m i t s TABLE XXXIV: EMPIRIC RECURRENCE RISKS FOR AND "POSSIBLE" MS RELATIONSHIP FEMALE TO PROBAND PROBANDS # % Mothers 6/276 2.2 Fathers 8/276 2.9 Sons 4/254 1.6 Daughters 2/231 0.9 Brothers 7/363 1.9 S i s t e r s 14/408 3.4 Aunts 13/4 75 2.7 Uncles 6/432 1.1 Nieces 2/598 0.3 Nephews 0/565 -Grandsons 0/43 -Granddaughters 0/32 -1st c o u s i n s 22/1563 1.4 TOTAL 84/5616 1.5 (±0.3)* * 95% confidence l i m i t s "DEFINITE", "CLINICALLY DEFINITE", MALE PROBANDS i % 4/137 2.9 1/137 0.7 0/95 -1/8 7 1.1 9/212 4.2 3/196 1.5 6/201 3.0 1/206 0.5 1/291 0.3 1/999 0.5 0/3 -0/4 -7/561 1.2 34/2329 1.5 (±0.5)* ALL PROBANDS 1 % 10/413 2.4 9/413 2.2 4/349 1.1 3/318 0.9 16/575 2.8 17/604 2.8 19/676 2.8 7/738 0.9 3/889 0.3 1/764 0.1 0/46 -0/36 -29/2124 1.4 118/7945 1.5 (±0.3)* - 13 7 -APPENDIX H: PREGNANCY AND MS (i) C a l c u l a t i o n of Relapse Rates Relapse Rate = # Relapses/Years of Exposure "Years o f exposure" i s d e f i n e d as the sum of a l l women's exposure to MS estimated from onset of the dis e a s e u n t i l age 45 or age at p a r t i c i p a t i o n i n t h i s study, i f l e s s than 45. Relapse Rate f o r "Never Pregnant" Women N = 52 T o t a l # Years of Exposure = 535; T o t a l # Relapses = 73 Relapse Rate/Woman/Year = 73/535 =0.14 Relapse Rate f o r Women with at l e a s t One Pregnancy N = 183 T o t a l # Years o f Exposure = 2.465 ; T o t a l # Relapses = 273 Relapse Rate/Woman/Year = 273/2465 = 0>11 Relapse Rate i n a Pregnancy Year N = 30 T o t a l # Pregnancy Years = 192; T o t a l # Relapses = 43 Relapse Rate/Woman/Pregnancy Year = 43/192 = 0.22 . . 2 ( i i ) C a l c u l a t i o n of X 2 X was c a l c u l a t e d as d e s c r i b e d i n s e c t i o n 3.2.2. 2 x 2 contingency t a b l e s and 1 degree of freedom were used. The c r i t i c a l l e v e l was p = 0.05. Exposure Time Women without Pregnancies - 535 exposure years/52 women Women with Pregnancies - 2465 exposure years/181 women X 2 = 2.92 df = 1 not s i g n i f i c a n t - 138 -Relapse Rate Women without Pregnancies - 73 relapses/535 exposure years Women with Pregnancies - 273.relapses/2465 exposure years 2 X = 2.22 df = 1 not s i g n i f i c a n t Relapse Rate in Pregnancy Year (a) Women with Pregnancies = 273 relapses/2465 exposure years Women in a Pregnancy Year - 43 relapses/192 pregnancy years 2 X = 15.79 df = 1 s t a t i s t i c a l l y s i g n i f i c a n t (b) Women without Pregnancies - 73 relapses/535 exposure years Women in a Pregnancy Year - 43 relapses/192 pregnancy years 2 . X = 5.65 df = 1 s t a t i s t i c a l l y s i g n i f i c a n t 

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