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Identification of risk factors associated with cervical Intra-epithelial Neoplasia among women in British… Chew, Danielle Siew Yee 1992

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IDENTIFICATION OF RISK FACTORS ASSOCIATED WITHCERVICAL INTRA-EPITHELIAL NEOPLASIA AMONG WOMENIN BRITISH COLUMBIAByDANIELLE SIEW YEE CHEWB.Sc., Simon Fraser University, 1990A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE STUDIES(Department of Statistics)We accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIADecember 1992©Danielle Siew Yee Chew, 1992In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)Department of ^StatisticsThe University of British ColumbiaVancouver, CanadaDate^December 29, 1992DE-6 (2/88)AbstractMultiple etiologic factors have been described for invasive cervical cancer. The mostimportant ones being sexual activity and smoking. Less is known regarding the factorspredisposing to risk of Cervical Intraepithelial Neoplasia (CIN). The increasing incidenceamong women prompted a study of this disease in British Columbia in carrying out acase control study to identify the risk factors associated with the disease. Incidentally,that is the main focus of this paper.A case-control design was used with cases and controls identified from the Cytologydatabase of the British Columbia Cancer Agency which contains a complete record of allcervical cytology done in British Columbia. Cases were women with diagnosis of cervicaldysplasia or carcinoma in-situ whereas controls were women with no history of cervicalabnormality. Estimates of the relative risk together with its 95% confidence intervalare obtained from the maximum likelihood estimates of the binary logistic regressionmodels.The important risks factors associated with CIN that have been identified in thisstudy are current cigarette smoking, sexual frequency, number of different lifetime sexualpartners, combine usage of both condom and diaphragm and dietary intake of vitaminA.i iContentsAbstract^ iiContents  ^iiiList of Tables  ^vList of Figures ^  viiiAcknowledgement  ^ix1 INTRODUCTION^ 12 EPIDEMIOLOGY OF CERVICAL CANCER^ 43 STUDY DESCRIPTION^ 83.1 Study Objectives  ^83.2 Study design  ^93.3 Study population ^  103.4 Data collected  123.5 Statistical Methods ^  234 ANALYSIS^ 31iii5 Discussion and Conclusions^ 73Bibliography^ 77Appendix 1^ 82Appendix 2^ 91Appendix 3^ 92ivList of Tables3.1 Variable names and descriptions ^  143.2 Study group characteristics among 484 cases and 274 controls ^ 173.3 Percent distribution of cases and controls according to selected risk factors 194.1 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by Smoking variables* ^  404.2 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by Smoking variables* ^  414.3 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by indicators of sexual activity* ^  424.4 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by indicators of sexual activity* ^  434.5 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia according to methods of Contraception* ^  444.6 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia according to methods of Contraception* ^  45v4.7 Adjusted Relative Risks of various stages of cervical dysplasia accordingto Venereal Disease* ^  464.8 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by nutrient intake* ^  474.9 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by nutrient intake* ^  524.10 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and vitamin At ^ 574.11 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and vitamin At ^ 594.12 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and folatet ^  614.13 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and folatet ^  634.14 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and fl-carotenet. ^ 654.15 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia associated with selected nutrients and /3-carotenet ^ 674.16 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by supplement intakes* ^  694.17 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by alcohol intake* ^  70vi4.18 Adjusted Relative Risks of various comparison groups of cervical dyspla-sia by alcohol intake* ^  714.19 Pearson correlation coefficients for selected nutrients among controls . ^ 72viiList of Figures3.1 Stages in the Development of carcinoma in-situ ^  25viiiAcknowledgementI would like to express my appreciation to my supervisor, Dr. Andy Coldman forhis guidance, suggestions, and patience in the preparation of this thesis. I also like togive my thanks to Professor Jim Zidek for critical reading of the manuscript and thefinancial assistance provided by the UBC Department of Statistics.ixChapter 1INTRODUCTIONCervical dysplasia is generally regarded as a precursor lesion for cervical cancer. Alongwith carcinoma in-situ, it forms the entity known as cervical intra-epithelial neoplasia(CIN). Its identification and successful treatment has formed the basis of screening pro-grammes which have reduced the incidence and mortality from invasive cervical cancerin women, including those in British Columbia over the past decades.The natural history of cervical-cancer is believed to involve stepwise progressionof sequential epithelial changes from dysplasia to carcinoma in-situ which eventuallyresults in an invasive lesion. It is not known whether all lesions progress through eachstage of the disease. Diagnosis is usually made in two steps: First, women have a papsmear whereby a sample of cells is scraped form the cervix and transferred to microscopeslide. Here it is read by a technician and examined for the presence of cells suspiciousof dysplasia or malignancy. If such cells are recognised, then the subject is referredfor a biopsy, usually colposcopically directed, in which the cervix is directly examined1and suspicious areas excised for definitive diagnosis. Areas of disease are then treatedby cryotherapy (freezing), laser therapy , cone biopsy (excision of a large part of thecervix) or hysterectomy depending on the extent of the disease. The pap-smear screeningmethod, together biopsy has lead to characterising the dysplasia as mild, moderate ,severe or carcinoma in-situ. Analysis of histories of women who were not treated forthe disease has shown that spontaneous reversion is common. However, it is generallyrecognised that all invasive cancer develops from CIN so that some form of treatmentfor the more serious forms of CIN is always indicated.In British Columbia, the incidence rate of invasive cervical cancer has fallen from19.7 per /00,000 in 1960's to a value of 6.6 per /00,000 in 1980's. During this time,the number and incidence of histologically confirmed cervical dysplasia and carcinomain-situ has risen steadily in BC. The success of the screening program, in combinationwith changes in sexual activity, have resulted in CIN becoming a major health cost tothe province.Multiple etiologic factors have been described for cervical cancer. The most im-portant ones being sexual activity and smoking. Less is known regarding the factorspredisposing to risk of CIN. The division of Epidemiology, Biometry and OccupationalOncology of The British Columbia Cancer Agency (BCCA), was interested in identify-ing the risk factors associated with the development of cervical dysplasia and cervicalcancer among women in British Columbia. The study of this disease is of great interestboth practically and scientifically since the identification of factors which may influenceits development may increase our ability to control this disease. Moreover, a greater2understanding of its etiology may also allow a better appreciation of factors common toa number of pre-malignant conditions.3Chapter 2EPIDEMIOLOGY OF CERVICALCANCERThe Epidemiology of cervical cancer has been studied for many years. It was firstremarked in the 17th century that the disease was rare among nuns but common inprostitutes leading to early speculation on its relationship with sexual activity. This hasled to a large number of epidemiological studies which examine sexual frequency, ageat 1st intercourse and number of sexual partners as possible risk factors[1,3-4]. Becausecervical dysplasia is considered a precursor lesion of cervical cancer, they should beexpected to share important epidemiological features. More recently, studies of theeffect of sexual activity have been undertaken for cervical dysplasia; although the datais not as extensive, a similar relationship is seen to that for cervical cancerl 2l. Thefindings of all studies are not unanimous; however, the majority show that Multiplesexual partners has the strongest relationship to cervical dysplasia and cancer of all4factors reflecting sexual behavior.The relationship of the disease to sexual behavior suggests a sexually transmittedinfectious agent may be responsible for the initiation or promotion of cervical neoplasia.This inference is further strengthened by the finding that cervical cancer is higher inwives of males with penile cancerN and that a direct relationship with sexual activityof the subject's usual partner[ has been seen. Herpes simplex virus type 2 (HSV-2)has been considered as an etiologic agentK 6-71 and recent evidence suggests Humanpapilloma virus(HPV) or wart virus may play an important role in causing cervicalcancer[8-101 . A large number of sero-epidemiological studies have found a higher fre-quency of HSV-2 antibodies among cases with CIN than normal controls[ 4,6]. Similarevidence exists for HP TABA . However final evidence that any of these viruses is a primarycause of CIN is not yet available since their common sexually transmitted epidemiologyimplies they would be closely associated with cervical cancer risk.Since cervical cancer behaves like a sexually transmitted disease, certain methodsof contraception may afford some degree of protection against the disease. The role ofcontraceptive use in the epidemiology of cervical neoplasia has been an area of intensiveepidemiologic research and conflicting findings have been presented. Among the com-mon contraceptive methods (oral contraceptive, intrauterine device, diaphragm, chemicalspermicide, condoms), the method most frequently studied has been oral contraceptives.Several epidemiological studies find a positive relationship between oral contraceptiveusage and cervical dysplasia as well as cervical cancer[ 11-14]; a similar number find norelationship[1-2A. One study shows women with multiple sex partners have greater5protection using barrier methods of contraceptionN. The role of other contraceptivemethods has not been thoroughly explored. One impediment has been that the associ-ation of various contraceptive methods to cervical cancer is confounded by pap-smearutilization, smoking status and sexual behavior[ 151 . In summary, it seems reasonable toassume that contraceptive usage is a potential risk factor for CIN and should be includedin the studies of this disease.Cigarette smoking has been implicated as a risk factor for CIN and cervical cancer innumerous studies in past years[ 16,18-23]. It was originally supposed that the relationshipseen with cigarette consumption reflected confounding beween this factor and otherssuch as social-economic status and sexual habits known to be associated with CIN.However, control for these variables does not remove the effect of smoking. Similarresults are also reported for cervical dysplasia[ 2 ' 161 . In both studies, no dose-responserelationship is seen between smoking and CIN risk whereas one is found for cervicalcancer[2° ' 231 .Diet has been associated with many malignancies and with CIN in particular. Anumber of epidemiological studies have suggested that carotenoids, vitamin A, vitaminC and folic acid may reduce the risk of cervical cancer [19,26-32] Low levels of vitaminA, or its precursor 9-carotene could result in alterations of the cervical tissue thatcause the area to be more vulnerable to carcinogenesis. Several case-control studieshave found significantly decreased intake of 13-carotene among cases of cervical dysplasisand for invasive cervical cancer[26-27,29,33-34] , when compared to controls. However, therelationship with preformed vitamin A is not consistent"' 27 '351 . This may be due to6the anti-oxidant effect of /3-carotene with its ability to trap free radicals, and possiblyprevent malignant transformation[ 24]. Vitamin C is an essential nutrient in the synthesisof collagen, the major component of the extracellular matrix which is the first barrierof the body against tumor cell invasion. Levels of vitamin C have been found to beinversely associated with CIN with a relative risk of 6.8 seen in those consuming lessthan 50% of the recommended daily allowance (30 mg)[ 261 .Another nutrient which has attracted much attention with a role in CIN has beenFolic acid. Folic acid deficiency has been shown to produce megaloblastic changes inthe cervical epithelium[37]which have a similar appearance to dysplasia. Megaloblas-tic changes have also been seen in 19% of women using oral contraceptives[38]. Theseobservations lead to a clinical trial of folic acid supplementation in the treatment ofmild or moderate cervical dysplasia, which found a statistically significant reduction indisease present at biopsy compared to those not receiving folic acid[ 25]. Although norelationship has been seen between the development of CIN and dietary folic acid whereit has been examined[261 , these studies have been small, and the possibility exists thatthere is an effect among users of oral contraceptives.Total fat consumption has also been found to be related to invasive cervical cancer[ 1s]although this effect has not been seen for CIN[ 261 . This discrepancy may be due to thesupposed tumor promotional effects of fat. The previously mentioned (small) studiesindicate possible nutritional influence in the genesis of CIN and these relationships needfurther exploration. In the next Chapter, a detailed description of the British Columbiastudy is presented.7Chapter 3STUDY DESCRIPTION3.1 Study ObjectivesThe aims of this case control study were: 1. to identify using a case-control methology,risk factors which influence the development of cervical dysplasia and carcinoma in-situin BC; 2. to compare and contrast the risk factors for mild dysplasia, moderate dysplasia,severe dysplasia and carcinoma in-situ; 3. to identify factors which may influence theprogression of the disease.There is increasing evidence that Diet is a major contributor to cancer incidence andmortality. By retrospective examination of the use of vitamin and mineral supplementsand usual diet, we hope to identify dietary components which prevent the developmentof the disease.83.2 Study designA case control study was conducted to investigate the etiology of cervical cancer. Poten-tial study participants were identified from the Central Cytology database maintainedwithin the British Columbia Cancer Agency (BCCA) which keeps records on all womenreceiving pap-smears in BC. An introductory letter together with a self-administeredpostal questionnaire (see Appendix 1). was mailed to identified cases and controls uponconsent of their physicians. Detailed information on demographic characteristics, life-time cigarette smoking history, alcohol intake, sexual behaviour, reproductive history,contraceptive usage and diet was obtained. The smoking information included the cur-rency of smoking, the average number of cigarettes smoked per day, the age at whichsmoking started and the age at which smoking stopped. For the sexual history, womenwere asked the age at which they first had sexual intercourse, the average frequency ofsexual intercourse, the number of different sexual partners in the last year and in theirlifetime. Contraceptive information included the use of oral contraceptives, intrauterinedevice, diaphragm , chemical spermicide and condoms. Women were asked which con-traceptive devices they had ever used, the age when they first used them, the age whenthey last used them as well as the duration for which they had used. Information onvenereal diseases and genital infection was self reported by the study participants.Diet was assessed by asking the prospective subjects about their usual consumptionof 122 food items as given in the questionnaire in the Appendix 1. The dietary com-ponent of this questionnaire was developed using the National Health and Nutrition9Examination Survey(NHANES II) and included foods which represented major sourcesof total calories, vitamin A, carotenoids, vitamin C, total fat and total folate of U.S.population intake. Subjects were asked to respond in terms of serving size and foodfrequencies. Supplementary vitamin intake was assessed by obtaining the duration ofyears used, the number of tablets taken per day, brand names and dosages and whetherthey were currently taking it. Specifically supplements included vitamin A, vitamin Bcomplex, folate, vitamin C, vitamin E, carotene, cod liver oil and some minerals. Indicesof the relative intake of various nutrients (including total fat, total vitamin A, carotene,total folate and vitamin C) were estimated from the amount consumed of the foodsincluded in the questionnaire.3.3 Study populationCases eligible for this case-control study were selected from English-speaking Caucasianwomen aged 16 to 65 years, residing in the Greater Vancouver region who had anabnormal smear leading to a histologically confirmed diagnosis of cervical dysplasia(mild, moderate or severe) or carcinoma in-situ in the last 12 months prior to the study.Age and race matched "controls" were selected from women in the same community andwho had no history of abnormality. A random sample of 1 in 23 women among controlswas selected giving a total of 275 controls. A random sample of 1 in 12 women was drawnfrom women with mild dysplasia, 1 in 11 from those with moderate dysplasia and 1 in9 from those with either severe or carcinoma in-situ. Thus, the resulting sample sizes of10mild, moderate, severe and carcinoma in-situ were 145, 137, 104 and 104 respectively.The criteria used in classifying the four different stages of cervical dysplasia and normalswere:Stage I: normal : at least one previous negative cervical cytologic smear within thethree years prior to commencement of the study but no history of abnormal cytology orabnormal gynecologic pathology;Stage II: mild : pathologically proven mild cervical dysplasia in the last 12 months withno previous history of pathologically proven moderate or severe dysplasia or cervicalcancer;Stage III: moderate : pathologically proven moderate cervical dysplasia in the last 12months with no previous history of pathologically proven severe dysplasia or cervicalcancer;Stage IV: severe : pathologically proven severe cervical dysplasia in the last 12 monthswith no previous history of pathologically proven cervical cancer;Stage V: carcinoma in-situ : pathologically proven CIN in the last 12 months with noprevious history of pathologically proven invasive cervical cancer.Women who were pregnant at the diagnosis of abnormality or pregnant at the timeof smears were excluded to improve comparability of subjects.113.4 Data collectedThe data set contains information on 765 patients with 490 patients identified as havingCIN (cases) and 275 normal patients (controls). Among those with CIN (stage 2 orhigher), the distribution by stage was as follows: stage II 145 (30%); stage III 137(28%); stage IV 104 (21%) and stage V 104 (21%). There are 180 variables recordingpatient information on social status, details of smoking and sexual habits, contraceptivepractices, diet and disease level. Our response variable is the polytomous variable knownas disease level. It refers to the five stages of the disease: normal, mild, moderate, severe,carcinoma in-situ. A sample coding sheet together with the questionnaire are includedin the Appendix 2.A certain amount of data cleaning and correction was necessary before any attemptswere made to examine the variables. Variables which were thought to be irrelevant tothe development of the disease (eg. weights, birthdates, exercises) were identified by Dr.A. Coldman of the BCCA and were eliminated from the data files, leaving 60 variablesto be examined.Due to ambiguities in the coding values, a careful examination of each of the remain-ing variables was necessary. For example, a "blank" was not always a missing values; itsometimes meant that the "event is still ongoing" or that it was a code dependent onprevious variable. Examples: for non-smokers, the variable "the number of cigarettessmoked per day" had to be blank; for current-smokers, the variable "age at which smok-ing was terminated" had to be blank also to mean "currently still smoking". The use12of several missing value codes (blank, 9, 99) was misleading; they were all recoded as"99" for uniformity. Examples: for the variable "number of lifetime sexual partners","9" meant nine partners in the subjects's lifetime; for the variable "contraceptive everused ", "9" meant a missing value code. Values not listed as coding options ("0" for"number of lifetime sexual partners") were checked and recoded appropriately. Somevariables, whose proportion of "Yes" responses relative to "No" was low (for example,the variable syphillis, where percent of Yes = 0.13) were eliminated. New variables werecreated from existing variables when appropriate and redundant variables were deleted.Examples: "duration of smoking"; "age at which smoking was terminated". Thus thefinal number of variables included in the preliminary analysis was 44 and these are listedin Table 3.1. For the purpose of our analysis, the data were divided into five hierachicalgroups: the first group consisted of age and smoking variables; the second of age, smok-ing and sexual variables; the third of age, smoking, sexual behaviour and contraceptiveusage; the fourth of age, smoking, sexual behaviour and sexually transmitted disease vari-ables; and the fifth of age, smoking, sexual behaviour and diet. Due to the substantialnumber of missing values present for some of the variables, deletions of missing valueswere done sequentially from groups 1 to 5 to avoid unnecessary loss of information. Thisresulted in 7 missing values deleted from Group 1 and 52 from Group 2. For Group 3,there were 47, 108, 62, 70, 66 and 122 missing values eliminated from contraceptive everused , oral contraceptive, intrauterine device, diaphragm, chemical spermicide, condomsrespectively. For Group 4, 48, 49, 50, 51 missing values were deleted from gonorrhoea,oralherpes, genital warts, genital herpes respectively. For the final group, 138 missing13Table 3.1: Variable names and descriptionsdlevel^disease levels (normal, mild, moderate, severe,carcinoma in-situ)age^age of patients at time of questionnairesmkcur^currently smoking (no/yes)smkage^age at which the patient began smokingsmkstop^age at which the patient stopped smokingsexage^age at first intercoursesex month intercourse: number of times per monthsexpart^number of sex partners in a yearsexli f e^number of sex partners in lifetimecontracpt ever used contraceptive (no/yes)oralcpt^duration of oral contraceptive used (years)iud^duration of intrauterine device used (years)diaphram duration of diaphragm used (years)spcide^duration of chemical spermicide used (years)gonor^ever have Gonorrhoea (no/yes)oralherp^ever have Oral Herpes (cold sores) (no/yes)genwarts ever have Genital Herpes (no/yes)genherp^ever have Condylomata (HPV) (no/yes)carotdly^estimated daily intake of carotene in mgsretequiv^estimated daily intake of retinol equivalentsf atpc^% of total calories from fattotcal^estimated total daily calory intake14Table 3.1(cont'd)est_vitA^estimated daily vitamin A intake in I.U.s'est_vitC^estimated daily vitamin C intake in mgsalpha_car estimated daily alpha-carotene intake in mgsbeta_car^estimated daily beta-carotene intake in mgslycopene^estimated daily lycopene intake in mgstot f of^estimated daily total folate intake in mgsest_f ib^estimated daily dietary fiber in gramscit fr _wk^estimated weekly consumption of citrus fruitveg _wk^estimated average weekly consumption of vegetablesnonlycar estimated daily nonlycopene carotenoids intake in mgsvitamin^do you regularly take multivitamins or megavitamins (no/yes)vitbcur^currently taking vitamin B supplement (no/yes)vitccur^currently taking vitamin C supplement (no/yes)alc^do you usually consume alcoholic beverages (no/yes)winecur^currently still taking wine (no/yes)winenum average number of bottles of wine taken per weekbeercur^currently still taking beer (no/yes)beernum average number of bottles of beer taken per weekBelow are some of the additional variables created for each patient:smkstat^smoking status (non, ex-smokers, current smokers)smklong^duration of (years) smoking for current smokerssmk quit^years since quittingbarrier^either condom and/or diaphragm usedcondiaph combined usage of both condom and diaphragm15values were removed. Descriptive statistics for the five groups (normal, mild, moderate,severe or carcinoma in-situ) of patients appear in Table 3.2 and the percent distributionin Table 3.3.16Table 3.2: Study group characteristics among 484 cases and 274 controlsVariable Stage I Stage II Stage III Stage IV Stage Vtotal number N 274 141 136 104 103age 38(13) 36(11) 33f(11) 32f(9) 34f(8)smkstat %non 50 49 34 32 22%ex 27 18 25 16 26%current 23 33 41 52 52smknum current 15(7) 18(9) 17(8) 19f(7) 18(8)ex 15(7) 16(7) 14(12) 20(11) 15(4)smklong^current 18(10) 15(9) 16(9) 15(8) 16(8)ex 14(13) 15(7) 13(10) 16(10) 15(4)sexage 19(3) 18(4) 18f(3) 17f(3) 17f(2)sexmonth 7(6) 8(7) 8(7) 10(10) llf(14)median 5 5 5 7 8sexpart 1(1) lf(1) 2f(2) 1(1) 2f(9)median 1 1 1 1 1sexlife 6(10) 8f(11) 12f(16) 13f(16) 13f(20)median 3 5 7 8 7% report> 6 28 49 57 59 62contracpt % used 85 86 92 97 96barrier^% used 34 27 27 27 2217Table 3.2(cont'd)Variable Stage I Stage II Stage III Stage IV Stage VVit C 154(97) 171(112) 150(93) 133(90) 140(99)Vii A 11300(7075) 10800(6322) 10451(7456) 9600(6049)f 9200(4849)fa_carotene 756(790) 655(4660) 661(695) 580(503)f 534(425)fXcarotene 3098(2695) 2841(2050) 2842(2967) 2495(2085) 2338(1931)flycopene 412(370) 377(387) 369(315) 365(286) 306(217)fnonlycar 4392(3662) 3979(2632) 3972(3636) 2654(3459)f 2431(3322)ftotfol 303(180) 323(193) 286(146) 303(228) 253(131)fcitfr_wk 6(7) 6(5) 6(6) 5(5) 5(5)est_fib 15(8) 16(9) 13(7)f 14(9) 13(6)fveg_wk 23(13) 23(14) 23(15) 22(10) 20(10)*All values tabulated are means with standard deviation given in parenthesis except otherwise stated.ft_testsignificantly different between the means of stages I and that of the corresponding stage (p< 0.05).18Table 3.3: Percent distribution of cases and controls according to selected risk factorsVariable Stage I Stage II Stage III Stage IV Stage VAge,yr< 25 9 11 16 12 1025-29 19 23 31 37 2530-34 22 21 17 25 2435-39 14 14 15 10 2040-49 17 21 10 12 16> 49 19 11 10 6 5Smkstatnon 66 57 45 38 38ex 10 8 11 6 7currentsmknum1-102432352644225626552111-20 58 54 58 50 63> 20smklong, yrs1-101124203220282421162611-15 26 30 27 41 37> 15 50 38 45 38 37Sexage< 17 26 35 35 47 3717-20 44 39 50 39 52> 20 30 26 15 15 1119Table 3.3(cont'd)Variable Normal Stage II Stage III Stage IV Stage VSexmonth<= 1 23 16 17 11 202-3 14 17 15 12 84-6 21 23 27 27 167-11 25 23 14 22 21> 11 16 21 27 29 36Sexpart<= 1 92 83 78 86 742-3 6 10 15 9 23>3 2 8 7 5 3Sexlife<= 1 35 23 13 11 52-3 22 19 10 16 164-5 15 10 20 14 176-10 17 28 25 24 36> 10 11 21 32 36 25est_vitC, mg's< 87 24 20 27 28 3187-131 23 23 26 31 23131-186 27 23 18 28 27> 186 26 34 29 14 1920Table3.3(cont'd)Variable^Stage I Stage II Stage III Stage IV Stage Va-carotene, mg's< 262 21 22 33 28 24262-487 20 26 27 30 29487-913 30 24 14 20 34> 913 29 28 27 22 13[3-carotene, mg's< 1236 22 22 33 28 231236-2138 20 25 26 22 382138-3592 29 23 17 29 24> 3592 29 29 25 21 14total folate, mg's< 189 24 21 25 24 33189-263 21 20 27 34 30263-352 28 27 27 17 21> 352 27 32 22 24 16est_vitA in I.U.s'< 6103 20 25 29 28 306103-9080 24 24 28 22 289080-13355 28 24 17 31 22> 13355 28 27 26 19 2021Table 3.2 reveals we see that the total number of women in the control group wasabout twice that for each of the cases at four stages of the disease (mild, moderate, severe,carcinoma in-situ). Cases from stage III to stage V of the disease were significantlyyounger (mean age = 34) than controls (mean age = 38). Differences between the casesand controls with respect to indices of smoking and sexual behaviour were marked.We had defined the non-smokers to include those who had never smoked and thosewho had quit for more than 5 years at the time of questionnaire. Ex-smokers werethose who had quit for 2 to 5 years. Current smokers included those still smoking andthose who had quit for 1 year or less. In general, cases (stages II to V) had a greaterproportion of current smokers than controls (stage I), with the highest proportion inthe severe and carcinoma in-situ (approximately 52% in each case, 23% in controls).Among current smokers, cases smoked more heavily than controls (mean smknum =18 versus 15 in controls). But the duration of smoking was shorter for them than forcontrols because they were younger. The number of cigarettes smoked per day and theduration of smoking for ex-smokers varied only slightly among the five groups. Controlshad a significantly higher mean age at first intercourse "sexage" (19) than cases (18).Cases reported a higher frequency of sexual intercourse per month, a greater numberof partners in previous year and a higher number of different sexual partners in theirlifetime. Among all cases, women who had carcinoma in-situ had the highest frequencyof sexual intercourse and most sexual partners in the last year and in their lifetime,the means being 11; 2 and 13 respectively. Women in the severe and carcinoma in-situ groups both had a mean number of 13 sexual partners in their lifetime, with the22median being 8 for severe dysplasia, 7 for carcinoma in-situ and 3 for controls. Morethan 85% of all women in this data set had previously used some form of contraceptivesregularly, the proportion being higher in cases than controls; 97% in severe dysplasia vs85% in control. A greater proportion of controls (34%) than cases (26%) used either acondom or a diaphragm or both methods of contraception. The proportion decreasedwith increasing severity of the disease.The remainder of Table 3.2 presents the mean values of the nutrient indices for casesat various stages of the disease compared with controls. In general, cases in stage Vconsumed significantly less vitamin A, a-carotene, /3-carotene, lycopene, nonlycopenecarotenoids, total folate and daily dietary fiber than controls. Cases in stage IV alsoconsumed significantly less vitamin A, a-carotene and nonlycopene carotenoids thancontrols. Ingestion of the other nutrients (vitamin C, citrus fruit, vegetables per week)was similar among all cases and controls.3.5 Statistical MethodsIn this study, we seek to find the risk factors associated with the development of cervicalcancer. A basic epidemiological approach to this problem involves the notion of RelativeRisk as the natural measure of association of cervical cancer and exposure to potentialrisk factors.In general, relative risk relates the presence or absence of a specific disease to ex-posure levels for some possible risk factors[31 . The exposure levels can be dichotomous23(exposed vs non-exposed) or polychotomous with more than 2 exposure levels. A rela-tively high risk of disease among an exposed subgroup points to that factor as a possiblecause of disease.Let X be a random variable denoting the levels of exposure to a particular risk factor.For expository simplicity, X is assumed to take only 2 levels: X = 1 for exposed, X = 0for unexposed.Definition 3.1: Relative risk is defined as:P(disease I X = 1)RR —P(disease I X = 0)RR > 1 implies that the probability of disease in the exposed subgroup is greater thanthe probability of disease in the unexposed subgroup. The reverse is true for RR < 1.Using case control study design, it is possible to estimate the odds ratio so thatwhen the disease is rare, it approximates the RR well. The odds ratio of the diseaseprobabilities is defined as the ratio of the 'odds' of disease occurrence in the exposed andnon-exposed subgroups.Cervical cancer is thought to arise by a stepwise progression from dysplasia to car-cinoma in-situ to cervical cancer; however we do not know whether all lesions progressthrough each stage of the disease. In other words, the disease could progress from a nor-mal stage to any one of the dysplasia or from any one stage of the dysplasia to carcinomain-situ without going through all stages. Moreover given their biological differences wemay reasonably assume the response categories (ie the five stages of disease level) arearranged in the hierarchical format illustrated in Fig 3.1.24normal CINmildmoderatesevere1st stage2nd stage3rd stage4th stagemoderate-carcinomasevere-carcinomacarcinomaFigure 3.1: Stages in the Development of carcinoma in-situStudy population25The response at stage 1 represents the dichotomy between diseased and normal,that at stage 2 the dichotomy between the mild and moderate forms of the disease, thatat stage 3 between the moderate and more severe forms and finally that at stage 4 isbetween the severe form and carcinoma in-situ.The special structure of the hierachical representation of the response variables en-ables us to subdivide each multinomial observation into 4 binomial components. The 1stcomponent specifies the number of disease cases as a proportion of the total number ofpatients at risk (1 vs 2-5), the 2nd, the number of moderate or more severe disease casesas a proportion of those with the disease (2 vs 3-5), the 3rd, the number of cases withsevere or more severe disease forms as a proportion of those with an above moderateform of the disease (3 vs 4-5) and finally the number of carcinoma in-situ cases as aproportion of those with severe disease comprises the 4th component (4 vs 5). Sinceeach stage of the hierarchy corresponds to a simple dichotomy, it is natural to adopt abinary logistic regression modelM:Let Yt, be a binary random variable which for i^1,... ,N; j^1,... ,5 is given by:with E /iv_ i^yii = N and P{E =1 yij = 1} = 1; i = 1,... ,N.Let pad = P{patient i will be in disease state j} and let Tij^P{Yi = 11^Yii, = 1}for j = 1,2,3,4,5.The likelihood function for the N independent multinomial observations{ 1, if patient i has disease jYij =0, otherwise.26M ( 1, P115 1)12 , Pi3, P14 , Pi5) is :ThenN^yii Yi2 Yi3 Yt4 YisL(13.;^=II  Pil Pi2 Pi3 Pi4 Pi5 i=1^Yil!Yi2!Yi3!Yi4!Yi5!5whereEpij = 1.^(3.1)j=iPii 7i3 — 5Substituting (3.2) into (3.1) yieldsv.N5L(*;^= fly) H riril (1 — rii)z-j=2 yii H^(1 — iri2) L'i=3^i=1^ 1=1N-1 7ri:i3(1 — ri3 )E3=4 yij H^(1 —i=iFrom equation (3.3), we see that the product of the N independent multinomial distri-butions can be reduced to the product of N independent binomial distributions. By theFactorization theorem, we see that (y ii , E35. =2 yii ) is a sufficient statistic for 7 i1 ; (yi2 ,El=3 yii ) for ri2 ; (yi3, yii) for r i3 and (yi4 , yi5 ) for R-24 .We will fit the following binary logistic regression model:ln( ) =^ j = 1,...,4,i =^N, k =1,^, K.^(3.4)1 — rii =1here the {a3 } and {/33k} are unknown parameters to be estimated while the {x ik } arethe observed covariates for each i. To estimate the parameters, {/33k }, we write thelog likelihood function for the N independent binomial observations (equation 3.3) asfollows:N 4 5^l (*; = E E E^[yia In ^i=1 j=1 j'>=3^1 — rijln(1 — 71- 23 )1^(3.5)(3.2)(3.3)27Substituting (3.4) into (3.5) yieldsN 4 5^f K^ Kl(71 , d; = E E E Yiii I Yii > xioik + yiact; — ln(1 exp(aj E Pikxik)i=1 j=1 ji>=j^L^k=1^ k=1-The maximum likelihood estimates of the log odds ratio as denoted by the vector )3can be obtained by using the Newton-Raphson procedure. The result is a consistentestimate of the log odds ratio along with asymptotic estimates of the 95% confidenceinterval. Based on the sufficient statistics obtained above, we obtain the following fourlogit functions i.e. (1 vs 2-5, 2 vs 3-5, 3 vs 4-5, 4 vs 5). They derive from the assumptionthat the disease progresses through each transition stage from mild to carcinoma in-situin the following manner stage 1 —> stage 2 —+ stage 3 —> stage 4 stage 5. Denote therelative risks of developing the next stage of the disease by (1) 1 , 02, (1)3, 4)4 respectively.Assume €1:1 i > 1 for all i. Denote the relative risks of the first 4 comparison groups (1 vs2-5, 2 vs 3-5, 3 vs 4-5, 4 vs 5) by 1 , 412, 1I3 and 41 4 . If the O's are all equal, it can beshown that (see Appendix3)> 11/2 >^>^> 1.Potential confounders were controlled by incorporating them into the logistic model(3.1). The risk estimates of the 'age' variable are of no particular interest to us. Butdue to its epidemiological importance, it was included in all logistic regressions in ouranalyses to adjust for the difference in ages between cases and controls. In this study,we divided the 'age' variable into 6 categories based on the combined distributions ofcases and controls. They are less than or equal to 24 years, 25-29, 30-34, 35-39, 40-49and greater or equal to 50 years. Discrete variables like smoking status are grouped into(3.6)28categories. Continuous variables are assessed by grouping them into quartiles based onthe combined frequency distribution of the cases and controls. Tests for significance ofindividual regression coefficients were single degree of freedom tests for trend; they wereachieved by entering quartiles of a giving continuous variable into the logistic model asdifferent values of a single ordinal values. Interactions between variables were analysedby constructing the appropriate variables in the continuous scale and including them inthe model.Because of the large number of initial variables, it is impossible to carry out thestepwise selection of variables using all the main factors and interactions at the sametime. Hence, to make the problem manageable, we identify the important variables ina sequential manner as shown below:Smoking variables —* Sexual variables --4 Diet variables.We begin the selection procedure with univariate analysis of each of the initial variableswhile controlling for the 'age' variable. A stepwise selection procedure was used in eachof the 3 blocks of variables (smoking, sexual, diet). Smoking variables identified assignificant after adjustment for age are included in the next block. Sex variables foundsignificant in the univariate analyses are added to the multiple logistic regression one ata time while controlling for age and smoking. Sex found to be most significant are thenincluded in the model to see if other sex variables were still significant after controllingfor those variables already found to be significant. Finally, significant variables identifiedin blocks 1 and 2 are further incorporated in the regression model together with each29diet variable to help identify the significant diet variables. Let 1H, denote the likelihoodfunction under any given model H.Definition 3.2: The deviance function is defined asD = 2logiHo — (3.7)where Ho designates the saturated model, H1 the logistic model to be fitted. Thedeviance function is twice the difference between the maximum achievable log likelihoodand that attained under the fitted model.At each step of the selection process, the adjacent models which are nested withrespect to the terms in the linear predictor are compared with respect to the differencein deviances between successive nested model to see if the addition of a further covariatesignificantly improved the fit.Definition 3.3: The difference in deviance is defined asA D = 2 log 1H2 — 2 log iHo (3.8)where H2 designates the extended model with additional covariates and Ho the modelunder test. The difference in deviance AD has an asymptotic x 2 distribution whosedegrees of freedom is the difference between the number of parameters in H2 and Ho .Covariates significant for some but not all logit functions, are forced into all logit func-tions for uniformity of comparisons among different comparison groups. Analyses werealso carried out for the following comparison groups: 1 vs 2, 1 vs 3, 1 vs 4, 1 vs 5due to their epidemiological significance. In the next chapter, results obtained from ouranalyses are presented.30Chapter 4ANALYSISWomen in the case groups were significantly younger than controls (mean of 34 vs 38years of age). We begin the analyses with current smokers referred to smokers who werecurrently smoking and those who quit for less than 1 year. Ex-smokers are referred tothose who had quit for 1 year or more. Relative risks adjusted for age are estimated interms of smoking status, number of cigarettes smoked per day, how long since quit andduration of smoking. Looking at the adjusted relative risk estimates we get for how longsince quitting using non-smokers as the baseline, we notice those who quit smoking formore than 5 years had adjusted relative risks close to 1, ie they behaved like non-smokers.Those who quit for 1 year had adjusted relative risks close to those for current smokers.Based on out results, it seems reasonable to pool those who quit for 1 year into thesmoking category and those who quit for more than 5 years into non-smokers category.Based on the pooled data, we see a significantly greater proportion of the cases (43%)than controls (23%) stating that they were current smokers and the proportion seemed31to increase with the severity of the disease. It ranged from 33% in the mild dysplasiato 52% in carcinoma in-situ. Among current smokers, cases smoked significantly moreheavily than controls (18 vs 15 cigarettes a day). Age adjusted relative risk estimates forthe association of different comparison groups (1 vs 2-5, 2 vs 3-5, 3 vs 4-5, 4 vs 5, 1 vs 2, 1vs 3, 1 vs 4, 1 vs 5) with cigarette smoking are shown in Table 4.1 and 4.2. Relative riskstend to be higher for current smokers than ex-smokers in all comparison groups. Amongcurrent smokers, women with more severe lesions had a higher risk than women withmilder dysplasia (3.91 vs 1.64) compared to ex-smokers (those who quit between 2 to 5years). Across the first four comparison groups (1 vs 2-5, 2 vs 3-5, 3 vs 4-5, 4 vs 5), thereseems to be a linear decrease in risks among current smokers compared to nonsmokers(2.50, 1.80, 1.53, 1.24). However, ex-smokers do not show elevated risk compared tonon-smokers. In fact, they behave rather like non-smokers. Current smokers amongcases smoke significantly more cigarettes a day compared to current smokers amongnormals. Nevertheless current smokers who smoked more than 20 cigarettes a day inthe first four comparison groups do not show an increase in risk compared to those inthe same group who smoked less that 10 cigarettes a day (Table 4.1). Except in 1 vs2-5, a barely significant increase in risk at the 5% level (p = 0.056) was observed. Forthe second group of comparison groups in Table 4.2, current smokers show an elevatedrisk with an increased number of cigarettes smoked a day except that none of themwere significant at the 5% significant level. Also, current smokers who smoked morethan 20 cigarettes a day showed a linear decrease in relative risks compared to thosewho smoked less than 10 cigarettes a day as we moved across the 1st four comparison32groups (2.61, 1.14, 0.95, 0.77). This is consistent with the findings for current smokersversus non-smokers. In terms of duration of smoking among current smokers, there isno significant difference between cases and controls though controls seemed to smokefor a longer period than cases. From Tables 4.1 and 4.2, current smokers who smokedfor a longer period of years (say more than 15 years) did not have higher risk comparedto those who smoked for a shorter period of time (say less than 10 years).The next group of variables that we examined relate to sexual behavior . Consistentwith the literature reviewed, sexual activity turned out to be one of the major riskfactors to the disease. Fifty percent or more of each of the cases and 28% of the controlsreported having 6 or more sexual partners during their lifetime. The average numberof lifetime sexual partners was significantly different among cases and controls (13 forcarcinoma in-situ vs 6 for normals). In general, cases also had more frequent sexualintercourse and had their first sexual intercourse at an earlier compared to normals17 vs 19 age years of age). The relative risks adjusted for age and the confoundingeffect of smoking associated with sexual activity are tabulated in Table 4.3 and 4.4.Five categories relating to smoking are created for the smoking variable and used inall future analyses. They were: 0 for nonsmokers; 1 for ex-smokers; 2 for current andsmoked < 10; 3 for current and smoked between 11-20; 4 for current and smoked > 20cigarettes a day. When compared to women who had one or less lifetime sexual partners,women with 10 or more sexual partners had a significant 5 fold increase in risk in thecomparison group (1 vs 2-5), RR = 4.93 and a significant 3 fold increase in risk inthe comparison group (2 vs 3-5), RR = 2.64. Similarly, a significant 3 fold increase in33adjusted risk was observed in mild dysplasia (RR = 2.72), 6 fold increase in moderatedysplasia (RR = 5.95), 7 fold increase in severe dysplasia (RR = 6.40) and 11 foldincrease in carcinoma in-situ (RR = 10.53) compared to normals. In fact, an increasinglinear pattern in adjusted relative risks among women with 10 or more lifetime sexualpartners is seen from mild to carcinoma in-situ (RR = 2.72, 5.95, 6.40, 10.53) comparedto those with 1 or less sexual partners in their lifetime. On the other hand, an inversepattern is seen in the first 4 comparison groups (RR = 4.93 ,2.64, 1.21, 0.56) whichsuggests that a large number of lifetime sexual partners seems to promote the onsetof the disease. A significant 3 fold increase in adjusted risk is observed among womenwith 3 or more sexual partners in the last year compared to those with 1 or less sexualpartners in the following comparison groups (1 vs 2-5, 1 vs 3). A significant 4 foldincrease in risk is observed in 1 vs 2. Other interesting variables relating to sexualbehavior are examined (sexmonth and sexage). We see that women with 11 or moreepisodes of sexual intercourse have an adjusted relative risk of 3.41 of developing severedysplasia compared to women with 1 or less episodes. Compared to women who had1 or less episodes, women with 11 or more episodes have an adjusted relative risk of2.22 of developing carcinoma in-situ. Sexmonth and sexpartners seem to be confoundedby lifetime number of sexual partners. After simultaneous adjustment for age, smokingand sexlife, sexpartners are found to be insignificant while the adjusted relative risksassociated with sexmonth remain significant in some comparison groups (1 vs 4 and 1vs 5). For uniformity of comparison among various groups, we control for both sexlifeand sexmonth in subsequent analyses. Contrary to findings in some previous studies,34no increase in risk is observed in women who had had 1st intercourse at an early ageafter adjustment for age and smoking.Because sexual activity is such a strong risk factor for cervical cancer, it is possiblethat certain contraceptive methods may offer some protective barrier against the disease.As Tables 4.5 and 4.6 show, women who use any form of contraceptives seem to decreasetheir risks of developing the disease compared to those who never used any, though noneof the results was significant at the 5% level except in 1 vs 5 (RR = 0.31). Among thevarious methods of contraceptives, the greatest protective effect is seen in women whoused a diaphragm and who reported that their partners were using condoms (afteradjustment for age, smoking, sexmonth and sexlife). The adjusted relative risks are0.47 in the 1st comparison group 1 vs 2-5, 0.39 in 1 vs 2, 0.34 in 1 vs 3, 0.49 in 1 vs 4and 0.49 in 1 vs 5.Table 4.7 presents information on cervical cancer risks associated with certain typesor venereal disease. In general, few women reported ever having any of the diseases. Sixpercent of women reported genital herpes or gonorrhoea. This low proportion results inunstable estimates of relative risks. Similary, 12% of the women reported condylomata(genital warts). Women who had genital wart infections increased their risk of developingthe disease compared to those who did not have them in the comparison groups (1 vs2, 1 vs 3, 1 vs 4 and 1 vs 2-5). The corresponding relative risks and confidence intervalsare 2.28(1.02,5.09), 2.03(0.90,4.55), 1.51(0.60,3.77), 1.80(0.94,3.44) respectively. Twentynine percent of the women reported oral herpes, however, no significant increase in riskis observed.35The major risk factors identified so far have been smoking, sexlife, sexmonth andboth condom and diaphragm usage. The role of diet as a risk factor for invasive cervicalcancer in other research raises the question whether it may play a role in CIN. Usingthe Health Habits and History Questionnaire Personal Computer System Package, esti-mates of various dietary components are obtained from the dietary questionnaire. Themean values of the nutrients by stage of disease are shown in Table 3.2. Cases witha higher stage (stage V) of the disease have a significantly lower intake of vitamin A,a-carotene, 3-carotene, lycopene, nonlycopene carotenoids, total folate and fiber thannormals. However, cases in general did not consume less vitamin C, citrus fruit andvegetable per week than normals. Across the different stages of disease (stage II tostage V), we notice that the nutrient level of selected nutrients (vitamin C, vitaminA, 0-carotene, lycopene, nonlycopene carotenoids, total folate, estimated fiber, veg-etable per week) decrease with an increase in severity of the disease. Tables 3L8 and 4.9shows the relative risks associated with increasing levels of dietary nutrients for the 8comparison groups after adjustment for age, smoking, sexmonth, sexlife , both condomand diaphragm usage. Dietary components are categorised into quartiles based on thecombined frequency of cases and controls.No clear reduction in risk among the 8 comparison groups is noted with an increase inintake of carotene, retinol, fat percent, total calories, citrus fruit per week and vegetableper week. A significant reduction in adjusted relative risk is observed with an increasein intake of vitamin A in the moderate dysplasia and carcinoma in-situ compared tonormals, with risk decreasing to 0.53 for the highest versus lowest quartile (p-value for36trend = 0.038) among moderate dysplasia and 0.31 among carcinoma in-situ (p-value fortrend = 0.008), respectively. Increasing levels of vitamin C intake only seem to have asignificant reduction in risk among those women with moderate or more advanced stagesof the disease compared to those with mild dysplasia (2 vs 3-5), the RR being 0.45 inthe highest quartile compared to the lowest quartile (p-value = 0.013). Higher levels offiber intake also seem to decrease the risk in the comparison groups 2 vs 3-5, 1 vs 3, 1vs 4 and 1 vs 5. Significant trends of decreasing risk are evident for a-carotene with riskdecreasing to 0.33 for the highest vs lowest quartile of intake (p-value of trend = 0.027),0-carotene (RR = 0.38, p = 0.010), nonlycopene carotenoids (RR = 0.34, p = 0.005),total folate (RR = 0.36, p = 0.010) among the comparison groups 1 vs 5. An increasinglevel of total folate and lycopene also seem to decrease the risk among those in group2 vs 3-5 (p-value for trend = 0.038) and 1 vs 2 (p-value = 0.036) respectively. Table4.19 shows the correlation of nutrient indices among controls. The correlation between0-carotene and vitamin A was 0.900, it was therefore impossible to reliably determinetheir independent effects. For 0-carotene and vitamin C, the correlation coefficient is0.359. Likewise for vitamin A and folate, the correlation is 0.354. Table 4.10 and Table411 shows the results of the analyses when carotenoids, vitamin C, folate are eachincluded with vitamin A in the multiple regression model. The association observedwith a-carotene, /3-carotene, nonlycopene carotenoids and total folate is weakened andthe trend test becomes insignificant in all the comparison groups. But the associationwith vitamin C remains virtually unchanged in the 2nd comparison groups (2 vs 3-5),p-value = 0.014.37Results for repeated analyses controlled additionally for folate and 0-carotene re-spectively, are tabulated in Tables 4.12, 4. 1 3, 4.14, 4.15. The reduced risks associatedwith vitamin A and folate are evident among cases in 1 vs 2-5, 1 vs 2 and 1 vs 3 com-parison groups with the adjusted relative risks in the highest quartile compared to thelowest quartile being 0.50, 0.40, 0.33, respectively. Controlling for 0-carotene reducethe adjusted risks for nonlycopene carotenoids and lycopene in the 1 vs 2-5 and 1 vs 2comparison groups, respectively. No significant trends are observed in other carotene,vitamin C and vitamin A.Few women took any vitamins supplements (78% of no vs 22% yes). Eighty onepercent of women did not take multivitamin while less than 1% of the women tookmegavitamins. After adjusting for age, smoking, sexmonth and sexlife, the log oddsratios of the variable multivitamin fails to converge to some value due to collinearlitiespresent among the various variables in the model. Hence, we cannot obtain any esti-mates of the log odds ratios for the multivitamins. Among the normals in this study,10% were currently taking vitamin B supplement and 15% were taking vitamin C sup-plement currently. A reduction in risk is observed with current users of vitamin B andvitamin C supplements compared to non vitamin B and non vitamin C users, respec-tively. Nevertheless, none of the reduction is significant in all 8 comparison groups atthe 5% level ( Table 4.16).The effect of alcohol intake on cervical cancer risk is shown in Tables 4.17 and 4.18.Adjusted relative risk of cervical cancer (adjusted for age, smoking, sexmonth, sexlife,both diaphragm and condom usage) by wine intake showed that women in the compar-38ison groups 1 vs 2-5, 1 vs 2 have a significant increase in risk if they are current winedrinkers compared to non drinkers. However, no significant increase in risk is observedwith increasing number of bottles of wine consumed per week. Current beerdrinkersalso exhibited significantly elevated risk compared to non drinkers in the comparisongroups 1 vs 2-5, 4 vs 5 and 1 vs 3, the RR being 1.53, 2.38 and 1.82 respectively. Nodose response relationship was seen with the amount of beer consumed.Later in chapter 5, a summary of the results and conclusions will be discussed. Beforethat we present our detailed findings in a series of tables.39Table 4.1: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby Smoking variables*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5smoking status §Ex smokers 1.04(0.61,1.78) 1.37(0.65,2.93) 0.66(0.30,1.53 ) 1.13(0.33,3.88)Current smokers 2.50(1.76,3.55) 1.80(1.17,2.77) 1.53(0.94,2.34) 1.24(0.67,2.30)No. of cig smoked per day f11-20 1.25(0.66,2.36) 1.16(0.54,2.50) 0.88(0.40,1.96) 1.64(0.64,4.20)> 20 2.61(1.02,6.72) 1.14(0.44,2.97) 0.95(0.36,2.52) 0.77(0.24,2.48)Ptrend 0.056 0.769 0.905 0.738No. of years of smoking $11-15 1.60(0.63,4.06) 1.15(0.41,3.20) 1.71(0.58,5.01) 0.85(0.24,3.01)> 15 1.64(0.56,4.81) 1.37(0.40,4.64) 1.21(0.32,4.54) 0.46(0.10,2.19)Ptrend 0.390 0.617 0.770 0.312* relative risks (95% CI) adjusted for age.§non-smokers was used as reference category.ex refers to those who quitted between 2 to 5 years. current refers to those currently smoking and thosewho quitted for less than or equal to 1 year. non refers to non smokers and those who quitted for morethan 5 years.f current smokers who smoked less than or equal to 10 cigarettes per day was used as reference.current smokers who smoked less than or equal to 10 years was used as reference.40Table 4.2: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby Smoking variables*Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5smoking status §Ex smokers 0.82(0.38,1.77) 1.28(0.62,2.63) 0.75(0.28,1.99 ) 1.15(0.45,2.89)Current smokers 1.64(1.03,2.63) 2.41(1.51,3.85) 3.28(1.97,5.45) 3.91(2.32,6.60)No. of cig smoked per day f11-20 1.07(0.44,2.59) 1.51(0.65,3.52) 0.82(0.34,1.99) 1.67(0.70,3.94)> 20 2.57(0.75,8.85) 2.85(0.86,9.41) 2.93(0.90,9.57) 2.41(0.68,8.48)Ptrend 0.188 0.085 0.137 0.137No. of years of smoking I11-15 1.29(0.40,4.17) 1.34(0.37,4.86) 2.65(0.71,9.91) 1.84(0.55,6.13)> 15 1.17(0.31,4.42) 1.77(0.37,8.42) 3.51(0.73,16.96) 1.20(0.30,4.74)Ptrend 0.829 0.471 0.126 0.840* relative risks (95% CI) adjusted for age.§non-smokers was used as reference category.ex refers to those who quitted between 2 to 5 years. current refers to those currently smoking and thosewho quitted for less than or equal to 1 year. non refers to non smokers and those who quitted for morethan 5 years.f current smokers who smoked less than or equal to 10 cigarettes per day was used as reference.current smokers who smoked less than or equal to 10 years was used as reference.41Table 4.3: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby indicators of sexual activity*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5Sexage §17-20 0.90(0.60,1.34) 1.20(0.73,1.96) 0.77(0.46,1.31) 1.46(0.75,2.83)> 20 0.70(0.42,1.16) 0.64(0.33,1.24) 0.82(0.36,1.86) 0.71(0.25,2.07)Ptrend 0.176 0.317 0.465 0.996Sexmonth §2-3 1.24(0.70,2.19) 0.67(0.32,1.42) 0.76(0.32,1.85) 0.30(0.08,1.14)4-6 1.59(0.96,2.63) 1.01(0.51,1.98) 0.90(0.43,1.90) 0.32(0.11,0.93)7-11 0.92(0.55,1.54) 0.70(0.34,1.41) 1.67(0.73,3.85) 0.48(0.16,1.38)> 11 1.93(1.12,3.30) 1.27(0.63,2.54) 1.45(0.68,3.09) 0.71(0.26,1.93)Ptrend 0.106 0.430 0.084 0.812Sexpart §2-3 1.88(1.03,3.42) 1.40(0.71,2.74) 1.05(0.54,2.02) 3.66(1.48,9.03)> 3 2.94(1.10,7.86) 0.60(0.26,1.40) 0.55(0.19,1.56) 0.69(0.14,3.28)Ptrend 0.002 0.648 0.443 0.128Sexlife §2-3 1.63(1.00,2.66) 1.41(0.69,2.91) 2.33(0.87,6.25) 2.03(0.55,7.54)4-5 2.09(1.23,3.57) 3.25(1.43,7.41) 1.05(0.40,2.76) 2.51(0.63,9.98)6-10 3.25(1.96,5.37) 1.74(0.86,3.54) 1.41(0.56,3.53) 3.31(0.92,11.85)> 10 4.93(2.81,8.65) 2.64(1.25,5.56) 1.21(0.48,3.07) 0.56(0.42,5.74)Ptrend 0.000 0.020 0.753 0.795* relative risks (95% CI) adjusted for age, smoking status (non, ex, current & smoke 1-10, current &smoke 11-20, current & smoke(> 20) cigarettes per day).§ All values are compared with the lowest level. For sexage (<= 16)years was used. For sexmonth,sexpart and sexlife, their respective lowest level (<= 1) were used as the reference category.42Table 4.4: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby indicators of sexual activity*Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5Sexage §17-20 0.78(0.45,1.35) 1.18(0.68,2.04) 0.66(0.37,1.19) 1.08(0.58,2.01)> 20 0.90(0.47,1.76) 0.68(0.32,1.45) 0.61(0.27,1.37) 0.48(0.19,1.21)Ptrend 0.753 0.418 0.171 0.192Sexmonth §2-3 1.69(0.79,3.62) 1.13(0.51,2.49) 1.59(0.58,4.41) 0.36(0.12,1.05)4-6 1.64(0.81,3.34) 1.75(0.86,3.55) 2.65(1.08,6.50) 0.86(0.35,2.13)7-11 1.17(0.57,2.38) 0.69(0.32,1.51) 1.71(0.68,4.30) 0.71(0.30,1.67 )> 11 1.71(0.81,3.62) 1.70(0.80,3.59) 3.41(1.34,8.63) 2.22(0.95,5.18)Ptrend 0.463 0.512 0.020 0.024Sexpart §2-3 1.41(0.63,3.14) 2.18(1.02,4.64) 1.13(0.45,2.87) 3.78(1.71,8.36)> 3 4.23(1.37,13.08) 3.25(1.00,10.61) 2.680.64,11.21) 1.16(0.22,6.11)Ptrend 0.011 0.007 0.232 0.014Sexlife §2-3 1.33(0.70,2.52) 1.08(0.48,2.42) 2.48(1.04,5.94) 5.10(1.73,15.02)4-5 0.98(0.46,2.13) 2.78(1.32,5.86) 2.41(0.96,6.03) 6.39(2.13,19.00)6-10 2.35(1.24,4.46) 3.29(1.60,6.76) 3.56(1.54,8.24) 11.09(3.96,31.04)> 10 2.72(1.33,5.56) 5.95(2.80,12.64) 6.40(2.69,15.20) 10.53(3.56,31.13)Ptrend 0.002 0.000 0.000 0.000* relative risks (95% CI) adjusted for age, smoking status (non, ex, current & smoke 1-10, current &smoke 11-20, current & smoke(> 20) cigarettes per day).§ All values are compared with the lowest level. For sexage (<= 16)years was used. For sexmonth,sexpart and sexlife, their respective lowest level (<= 1) were used as the reference category.43Table 4.5: Adjusted Relative Risks of various comparison groups of cervical dysplasiaaccording to methods of Contraception*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5Contracpt §ever 0.74(0.40,1.37) 1.03(0.45,2.32) 0.68(0.25,1.81) 0.53(0.16,1.79)Condoms §ever 0.66(0.43,1.01) 1.19(0.66,2.15) 1.12(0.60,2.10) 0.91(0.40,2.06)Diaphrain(only) §ever 1.03(0.49,2.16) 0.56(0.23,1.37) 0.59(0.21,1.64) 0.47(0.08,2.88)Spcide §ever 0.87(0.50,1.51) 0.88(0.45,1.74) 1.16(0.52,2.58) 0.84(0.32,2.20)Oralcpt §ever 0.78(0.47,1.28) 1.37(0.72,2.59) 0.72(0.32,1.60) 1.08(0.41,2.86)Ind §ever 0.89(0.58,1.37) 0.74(0.45,1.24) 0.85(0.47,1.53) 0.84(0.39,1.80)Condiap §ever 0.47(0.22,0.97) 1.01(0.33,3.11) 1.28(0.35,4.73) 1.14(0.22,5.98)* relative risks (95% CI) adjusted for age, smoking status (non, ex, current & smoke 1-10, current &smoke 11-20, current & smoke(> 20) cigarettes per day), sexmonth and sexlife.§ women who had never used the respective contraceptive were used as reference category.44Table 4.6: Adjusted Relative Risks of various comparison groups of cervical dysplasiaaccording to methods of Contraception*Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5Contracpt §ever 0.71(0.31,1.65) 0.83(0.32,2.18) 0.65(0.21,2.04) 0.31(0.10,0.96)Condoms §ever 0.54(0.29,0.99) 0.65(0.36,1.20) 0.63(0.32,1.24) 0.75(0.37,1.51)Diaphram(only) §ever 1.33(0.53,3.34) 0.87(0.34,2.26) 1.10(0.34,3.50) 0.21(0.03,1.46)Spcide §ever 0.93(0.46,1.90) 0.58(0.25,1.38) 0.78(0.33,1.86) 0.68(0.28,1.66)Oralcpt §ever 0.62(0.32,1.18) 1.22(0.57,2.62) 0.91(0.40,2.04) 0.61(0.25,1.48)Iud §ever 1.00(0.56,1.77) 0.86(0.46,1.59) 0.83(0.41,1.68) 0.61(0.30,1.24)Condiap §ever 0.39(0.13,1.14) 0.34(0.10,1.09) 0.49(0.14,1.68) 0.49(0.14,1.70)* relative risks (95% CI) adjusted for age, smoking status (non, ex, current & smoke 1-10, current &smoke 11-20, current & smoke(> 20) cigarettes per day), sexmonth and sexlife.§ women who had never used the respective contraceptive were used as reference category.45Table 4.7: Adjusted Relative Risks of various stages of cervical dysplasia according toenereal Disease*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5Genherps §ever 1.08(0.53,2.33) 1.99(0.78,5.10) 0.69(0.30,1.61) 2.01(0.61,6.64)Genwarts §ever 1.80(0.94,3.44) 0.72(0.39,1.34) 0.83(0.42,1.63) 0.83(0.33,2.07)Gonor §ever 1.07(0.48,2.39) 1.62(0.59,4.49) 1.69(0.65,4.38) 0.53(0.18,1.53)Oralherps §ever 1.13(0.78,1.64) 0.72(0.46,1.14) 1.27(0.76,2.14) 0.38(0.19,0.77)1 vs 2 1 vs 3 1 vs 4 1 vs 5Genherps §ever 0.69(0.23,2.08) 1.29(0.49,3.43) 0.63(0.19,2.04) 1.35(0.45,4.00)Ptrend 0.504 0.605 0.43 2 0.594Genwarts §ever 2.28(1.02,5.09) 2.03(0.90,4.55) 1.51(0.60,3.77) 1.04(0.40,2.69)Gonor §ever 0.63(0.19,2.07) 0.72(0.24,2.19) 1.89(0.69,5.17) 1.23(0.39,3.90)Oralherps §ever 1.48(0.90,2.43) 0.94(0.55,1.61) 1.62(0.92,2.85) 0.59(0.30,1.15)Pirend 0.122 0.819 0.097 0.118* relative risks (95% CI) adjusted for age, smoking status (non, ex, current & smoke 1-10, current &smoke 11-20, current & sinoke(> 20) cigarettes per day), sexmonih and sexlife.§ Women who never had the disease were used as reference category.46Table 4.8: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby nutrient intake*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5carotdly (mg's)< 1901 1.00 1.00 1.00 1.001901-3101 1.53(0.88,2.65) 1.00(0.52,1.92) 1.50(0.79,2.88) 1.85(0.75,4.54)3101-5150 1.19(0.53,2.71) 0.34(0.07,1.60) 2.08(0.76,5.70) 1.75(0.75,4.54)> 5150 1.73(0.76,3.95) 0.20(0.04,0.93) 0.94(0.34,2.56) 1.10(0.25,4.85)Ptrendreteguiv (unit)< 9320.0761.000.0311.000.9751.000.6471.00932-13.8 1.39(0.79,2.42) 0.53(0.27,1.05) 0.88(0.45,1.73) 0.56(0.21,1.46)13/,8-1910 1.29(0.71,2.35) 0.47(0.22,0.98) 1.51(0.71,3.21) 0.84(0.31,2.31)> 1910 1.35(0.72,2.53) 0.70(0.31,1.58) 0.87(0.40,1.91) 0.79(0.28,2.24)Ptrendfatpc (percent)< 330.4651.000.4101.000.9001.000.8161.0033-38 1.33(0.80,2.19) 1.51(0.79,2.87) 1.14(0.56,2.35) 2.25(0.82,6.14)38-42 1.44(0.86,2.39) 1.37(0.73,2.59) 1.36(0.66,2.83) 1.85(0.68,5.01)> 42 1.12(0.66,1.88) 1.95(0.98,3.90) 0.98(0.47,2.01) 1.53(0.55,4.28)Ptrend 0.564 0.091 0.984 0.61947Table 4.8(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5tot_cal (cal)< 1393 1.00 1.00 1.00 1.001393-1783 0.76(0.45,1.29) 0.82(0.42,1.60) 1.15(0.59,2.27) 0.79(0.31,2.02)1783-2223 0.84(0.51,1.41) 0.61(0.32,1.16) 0.96(0.48,1.92) 0.23(0.08,0.67)> 2223 0.76(0.45,1.28) 0.81(0.41,1.58) 1.26(0.64,2.47) 0.67(0.27,1.66)Ptrendest_vitA (I. U.^)< 61030.3901.000.3681.000.6351.000.2031.006103-9080 0.78(0.46,1.32) 1.00(0.53,1.91) 0.81(0.42,1.56) 0.85(0.34,2.11)9080-13355 0.64(0.38,1.08) 0.87(0.46,1.67) 1.80(0.88,3.69) 0.57(0.23,1.44)> 13355 0.67(0.40,1.14) 0.81(0.42,1.55) 0.78(0.38,1.56) 0.82(0.31,2.15)Ptrendest_vitC (mg's)< 870.1021.000.4681.000.9251.000.4711.0087131 1.17(0.70,1.97) 0.87(0.44,1.70) 0.97(0.50,1.89) 0.61(0.24,1.55)131-186 0.92(0.54,1.55) 0.73(0.37,1.45) 1.27(0.62,2.59) 0.54(0.21,1.37)> 186 1.12(0.67,1.88) 0.45(0.23,0.87) 0.49(0.24,1.00) 1.14(0.40,3.30)Ptrend 0.913 0.013 0.119 0.90148Table 4.8(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5est_fib (g's)< 10 1.00 1.00 1.00 1.0010-13 0.73(0.43,1.23) 0.62(0.31,1.23) 2.41(1.21,4.79) 0.61(0.26,1.44)13-17 0.94(0.55,1.60) 0.41(0.21,0.81) 0.95(0.49,1.88) 1.05(0.40,2.78)> 17 0.54(0.32,0.91) 0.41(0.21,0.82) 0.84(0.41,1.70) 1.03(0.37,2.85)Ptrendcitfr_wk< 20.0561.000.0041.000.3901.000.7561.002-5 1.41(0.84,2.36) 0.81(0.45,1.75) 1.16(0.58,2.31) 1.66(0.63,4.39)5-8 1.27(0.75,2.14) 0.55(0.28,1.06) 0.75(0.37,1.52) 0.69(0.25,1.88)> 8 1.30(0.77,2.18) 0.80(0.41,1.57) 0.98(0.48,1.98) 1.78(0.65,4.86)Ptrendveg_wk< 140.4481.000.2891.000.6331.000.6491.0014-20 0.82(0.49,1.37) 0.79(0.41,1.52) 0.92(0.45,1.88) 0.58(0.23,1.47)20-27 0.92(0.55,1.54) 0.94(0.49,1.80) 0.61(0.30,1.21) 0.71(0.27,1.89)> 27 0.83(0.53,1.50) 0.96(0.50,1.85) 0.81(0.40,1.63) 0.35(0.13,0.95)Ptrend 0.784 0.970 0.346 0.06149Table 4.8(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5cr-carotene (mg's)< 262 1.00 1.00 1.00 1.00262-487 1.13(0.66,1.91) 0.84(0.44,1.60) 1.46(0.76,2.81) 0.94(0.39,2.29)487-913 0.62(0.37,1.03) 0.77(0.39,1.51) 2.47(1.19,5.13) 1.95(0.77,4.93)> 913 0.79(0.47,1.33) 0.60(0.31,1.17) 0.87(0.43,1.76) 0.51(0.17,1.50)Ptrend 0.118 0.136 0.793 0.7240-carotene (mg's)< 1236 1.00 1.00 1.00 1.001236-2138 1.15(0.68,1.95) 0.86(0.45,1.65) 1.57(0.82,3.00) 1.99(0.81,4.87)2138-3592 0.77(0.46,1.30) 0.89(0.45,1.76) 2.32(1.12,4.80) 1.02(0.41,2.57)> 3592 0.81(0.48,1.37) 0.57(0.29,1.10) 0.99(0.48,2.00) 0.67(0.24,1.89)Ptrendlycopene (mg's)< 1700.2301.000.1191.000.6281.000.3091.00170-312 0.80(0.48,1.35) 1.49(0.78,2.84) 1.45(0.74,2.84) 0.59(0.24,1.49)312-484 0.75(0.34,1.69) 1.12(0.60,2.11) 1.49(0.74,2.99) 0.91(0.36,2.26)> 484 0.62(0.36,1.05) 1.05(0.55,2.00) 0.74(0.37,1.47) 0.46(0.17,1.26)Ptrend 0.075 0.946 0.465 0.29550Table4.8(cont'd)Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5nonlycar (mg 's)< 1895 1.00 1.00 1.00 1.001895-3096 1.42(0.83,2.45) 1.00(0.53,1.89) 1.41(0.74,2.67) 1.76(0.74,4.19)3096-549 0.57(0.34,0.95) 1.00(0.51,1.99) 1.78(0.87,3.66) 1.18(0.47,2.96)> 5149 0.81(0.48,1.37) 0.59(0.31,1.14) 0.79(0.39,1.63) 0.64(0.22,1.87)Ptrendtotfol (mg's)< 1890.0721.000.1351.000.8471.000.4331.00189-263 1.58(0.93,2.69) 1.43(0.72,2.85) 1.11(0.57,2.18) 0.55(0.23,1.34)263-352 1.04(0.62,1.75) 0.75(0.39,1.48) 0.60(0.30,1.23) 0.71(0.26,1.98)> 352 1.15(0.68,1.94) 0.61(0.32,1.18) 0.88(0.43,1.80) 0.37(0.14,1.00)Ptrend 0.949 0.038 0.355 0.088* relative risks (95% CI) adjusted for age, smoking stains, sexmonth, sexlife, both condom and diaphragmusage.51Table 4.9: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby nutrient intake*Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5carotdly (mg's)< 1901 1.00 1.00 1.00 1.001901-3101 1.51(0.70,3.27) 1.31(0.63,2.75) 1.55(0.67,3.55) 2.35(0.96,5.80)3101-5150 3.50(0.70,17.50) 0.57(0.19,1.69) 0.96(0.30,3.00) 1.93(0.51,7.39)> 5150 6.55(1.31,32.70) 1.17(0.41,3.36) 1.16(0.36,3.70) 1.24(0.30,5.15)Ptrendretequiv (unit)< 9320.0051.000.4581.000.5901.000.5841.00932-1348 2.35(1.05,5.24) 0.99(0.47,2.08) 1.29(0.55,3.03) 0.66(0.26,1.68)1348-1910 2.54(1.03,6.22) 0.81(0.34,1.92) 0.93(0.38,2.29) 1.04(0.39,2.77)> 1910 1.85(0.70,4.86) 1.15(0.48,2.73) 1.09(0.43,2.78) 0.80(0.30,2.15)Ptrendfatpc (percent)< 330.3561.000.8111.000.9801.000.8451.0033-38 1.10(0.57,2.14) 1.12(0.56,2.24) 1.05(0.47,2.32) 2.24(0.91,5.55)38-42 1.22(0.62,2.38) 1.08(0.52,2.25) 1.12(0.50,2.53) 3.00(1.20,7.50)> 42 0.70(0.34,1.46) 1.26(0.62,2.54) 1.23(0.55,2.78) 1.60(0.61,4.16)Ptrend 0.505 0.557 0.603 0.27952Table 4.9 cont'dComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5tot_cal (cal)< 1393 1.00 1.00 1.00 1.001393-1783 0.72(0.35,1.50) 0.53(0.25,1.10) 0.72(0.31,1.67) 0.57(0.24,1.33)1783-2223 0.92(0.46,1.86) 0.62(0.31,1.26) 1.14(0.52,2.50) 0.33(0.13,0.84)> 2223 0.79(0.38,1.66) 0.58(0.28,1.19) 0.89(0.39,2.02) 0.63(0.27,1.46)Ptrendesi_vitA (I. U.^)< 61030.7511.000.1891.000.9041.000.1851.006103-9080 0.74(0.37,1.50) 0.64(0.28,1.47) 0.64(0.28,1.47) 0.65(0.28,1.53)9080-13355 0.39(0.18,0.86) 0.98(0.45,2.12) 0.98(0.45,2.12) 0.48(0.20,1.14)> 13355 0.53(0.25,1.10) 0.63(0.27,1.48) 0.63(0.27,1.48) 0.31(0.12,0.76)Ptrendest_vitC (mg 's)< 870.3091.000.0381.000.5081.000.0081.0087-131 1.21(0.58,2.56) 1.04(0.51,2.14) 1.32(0.59,2.93) 0.67(0.28,1.58)131-186 0.96(0.45,2.04) 0.65(0.30,1.42) 1.17(0.51,2.67) 0.90(0.37,2.16)> 186 1.80(0.89,3.64) 1.16(0.57,2.36) 0.51(0.20,1.29) 0.42(0.16,1.06)Ptrend 0.146 0.914 0.167 0.11953Table 4.9 cont'dComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5esi_fib (g's)< 10 1.00 1.00 1.00 1.0010-13 0.78(0.36,1.69) 0.28(0.13,0.61) 1.14(0.53,2.45) 0.59(0.25,1.38)13-17 1.46(0.69,3.07) 0.64(0.32,1.31) 0.64(0.27,1.50) 0.79(0.33,1.90)> 17 0.88(0.42,1.85) 0.34(0.16,0.70) 0.95(0.14,0.85) 0.30(0.12,0.75)Ptrendciifr_wk< 20.8981.000.0231.000.0081.000.0211.002-5 1.22(0.59,2.54) 1.27(0.62,2.60) 1.77(0.79,3.98) 2.32(1.00,5.34)5-8 1.78(0.87,3.62) 1.22(0.28,2.59) 1.17(0.52,2.64) 1.13(0.44,2.87)> 8 1.36(0.66,2.80) 1.26(0.60,2.63) 1.12(0.49,2.56) 1.34(0.56,3.21)Ptrendveg_wk< 140.2791.000.5901.000.9651.000.8631.0014-20 0.90(0.45,1.80) 0.73(0.35,1.52) 0.80(0.36,1.76) 0.77(0.33,1.78)20-27 0.92(0.46,1.84) 1.06(0.51,2.19) 0.82(0.35,1.91) 0.80(0.34,1.88)> 27 0.83(0.40,1.69) 0.78(0.37,1.64) 1.39(0.62,3.12) 0.52(0.21,1.27)Ptrend 0.642 0.763 0.427 0.17854Table 4.9 cont'dComparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5a-carotene (mg 's)< 262 1.00 1.00 1.00 1.00262-487 1.24(0.60,2.58) 0.83(0.41,1.70) 1.45(0.66,3.21) 1.05(0.44,2.52)487-913 0.68(0.33,1.40) 0.25(0.11,0.55) 0.63(0.28,1.43) 0.78(0.34,1.77)> 913 0.98(0.48,2.00) 0.66(0.32,1.34) 0.90(0.40,2.05) 0.33(0.12,0.90)Ptrend 0.590 0.048 0.373 0.027,3-carotene (mg 's)< 1236 1.00 1.00 1.00 1.001236-2138 1.12(0.54,2.33) 0.96(0.47,1.96) 0.95(0.41,2.21) 2.06(0.87,4.90)2138-3592 0.85(0.41,1.76) 0.40(0.18,0.85) 0.97(0.44,2.12) 0.77(0.32,1.85)> 3592 1.10(0.54,2.24) 0.66(0.32,1.35) 0.90(0.39,2.04) 0.38(0.14,1.04)Ptrendlycopene (mg 's)< 1700.9801.000.0781.000.8191.000.0101.00170-312 0.55(0.27,1.13) 0.56(0.27,1.15) 1.28(0.57,2.89) 0.62(0.26,1.47)312-484 0.57(0.28,1.16) 0.57(0.27,1.19) 0.96(0.40,2.30) 0.71(0.30,1.70)> 484 0.44(0.21,0.90) 0.72(0.35,1.45) 0.96(0.41,2.28) 0.33(0.13,0.86)Ptrend 0.036 0.407 0.722 0.04155Table4.9(cont'd)Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5nonlycar (mg's)< 1895 1.00 1.00 1.00 1.001895-3096 1.33(0.63,2.80) 1.31(0.64,2.68) 1.51(0.66,3.45) 2.32(0.96,5.60)3096-5149 0.57(0.51,2.08) 0.36(0.17,0.77) 0.74(0.34,1.61) 0.69(0.30,1.61)> 5149 1.03(0.51,2.08) 0.73(0.36,1.51) 0.91(0.39,2.09) 0.34(0.12,0.94)Ptrendtotfol (mg's)< 1890.5841.000.0751.000.4541.000.0051.00189-263 1.01(0.47,2.16) 1.65(0.80,3.39) 2.02(0.91,4.46) 1.26(0.55,2.90)263-352 1.16(0.56,2.37) 1.11(0.54,2.30) 0.78(0.33,1.86) 0.53(0.22,1.26)> 352 1.41(0.70,2.84) 1.03(0.49,2.18) 1.18(0.51,2.74) 0.36(0.14,0.92)Ptrend 0.292 0.807 0.702 0.010* relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage.56Table 4.10: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and vitamin AtComparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5a-carotene< 262 1.00 1.00 1.00 1.00262-487 1.24(0.69,2.22) 0.78(0.38,1.57) 1.61(0.80,3.27) 1.13(0.44,2.91)487-913 0.73(0.37,1.44) 0.64(0.27,1.54) 2.33(0.92,5.86) 3.36(0.98,11.57)> 913.0 0.94(0.42,2.11) 0.42(0.14,1.25) 0.74(0.23,2.40) 0.64(0.13,3.26)Ptrend 0.634 0.130 0.719 0.782)3-carotene< 1236 1.00 1.00 1.00 1.001236-2138 1.47(0.78,2.75) 0.75(0.34,1.66) 2.12(0.95,4.72) 2.78(0.90,8.63)2138-3592 1.14(0.53,2.43) 0.69(0.26,1.84) 2.42(0.85,6.87) 1.51(0.39,5.90)> 3592 1.20(0.47,3.05) 0.26(0.07,0.94) 1.17(0.29,4.70) 0.35(0.05,2.31)Ptrendnonlycar< 18950.7941.000.0771.000.3701.000.4301.001895-3096 1.61(0.84,3.07) 0.94(0.43,2.04) 1.59(0.73,3.46) 2.44(0.85,7.02)3096-5149) 0.61(0.27,1.35) 0.82(0.29,2.33) 1.29(0.44,3.79) 2.13(0.49,9.27)> 5149 0.83(0.31,2.25) 0.23(0.06,0.89) 0.49(0.11,2.15) 0.34(0.05,2.39)Ptrend 0.423 0.084 0.711 0.69657Table4.10(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5lycopene< 170 1.00 1.00 1.00 1.00170-312 0.86(0.50,1.45) 1.55(0.80,3.01) 1.34(0.67,2.70) 0.63(0.25,1.61)312-484 0.84(0.48,1.46) 1.22(0.62,2.37) 1.33(0.64,2.76) 0.98(0.38,2.52)> 484 0.70(0.40,1.24) 1.16(0.58,2.30) 0.67(0.32,1.41) 0.51(0.18,1.48)Ptrendtotfol< 1890.2391.000.8501.000.3201.000.4351.00189-263 0.52(0.20,1.35) 1.35(0.64,2.84) 0.98(0.47,2.01) 2.50(1.04,6.03)263-352 0.62(0.19,2.03) 0.67(0.31,1.45) 0.48(0.20,1.12) 1.01(0.36,2.83)> 352 0.32(0.09,1.11) 0.51(0.22,1.18) 0.63(0.25,1.63) 1.48(0.51,4.24)Ptrendest_vitC< 870.2121.000.0361.000.1851.000.1111.0087-131 1.35(0.78,2.31) 0.84(0.42,1.67) 0.80(0.40,1.63) 0.69(0.26,1.87)131-186 1.17(0.66,2.07) 0.68(0.33,1.42) 1.06(0.49,2.30) 0.61(0.23,1.66)> 186 1.50(0.83,2.72) 0.41(0.20,0.86) 0.41(0.18,0.93) 1.31(0.40,4.29)Ptrend 0.276 0.014 0.072 0.867f relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage and vitamin A.58Table 4.11: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and vitamin AComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5a-carotene< 262 1.00 1.00 1.00 1.00262-487 1.52(0.67,3.45) 0.87(0.40,1.91) 1.60(0.65,3.92) 1.31(0.51,3.34)487-913) 0.98(0.37,2.56) 0.33(0.12,0.88) 0.54(0.18,1.62) 1.33(0.45,3.97)> 913.0 1.46(0.47,4.49) 1.11(0.35,3.54) 0.85(0.25,2.91) 0.66(0.16,2.69)Ptrend 0.648 0.929 0.496 0.7360-carotene< 1236 1.00 1.00 1.00 1.001236-2138 1.64(0.69,3.85) 1.14(0.51,2.54) 1.26(0.46,3.49) 2.95(1.08,8.05)2138-3592 1.84(0.63,5.40) 0.63(0.21,1.90) 1.10(0.32,3.81) 1.21(0.34,4.29)> 3592 2.99(0.83,10.75) 1.15(0.28,4.69) 1.59(0.35,7.28) 0.55(0.11,2.81)Ptrendnonlycar< 18950.1051.000.9291.000.6111.000.4691.001895-3096 1.69(0.69,4.14) 1.61(0.69,3.75) 1.71(0.61,4.80) 3.10(1.11,8.62)3096-5149 0.85(0.27,2.67) 0.56(0.18,1.73) 0.53(0.14,2.02) 0.94(0.28,4.00)> 5149 1.92(0.49,7.53) 1.48(0.33,6.66) 0.89(0.17,4.58) 0.32(0.05,1.99)Ptrend 0.493 0.995 0.643 0.29059Table 4.11(cont'd)Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5lycopene< 170 1.00 1.00 1.00 1.00170-312 0.56(0.27,1.15) 0.62(0.29,1.29) 1.36(0.60,3.12) 0.66(0.28,1.60)312-484 0.62(0.30,1.30) 0.76(0.34,1.68) 1.01(0.41,2.48) 0.85(0.34,2.14)> 484 0.46(0.21,1.01) 0.99(0.46,2.17) 1.10(0.44,2.73) 0.48(0.17,1.34)Ptrendtotfol< 1890.0781.000.8591.000.9301.000.2561.00189-263 1.62(0.66,3.97) 2.22(1.02,4.86) 1.35(0.59,3.10) 1.62(0.66,3.97)263-352 0.79(0.29,2.19) 2.05(0.85,4.94) 1.79(0.78,4.11) 0.79(0.29,2.19)> 352 0.60(0.19,1.90) 2.20(0.84,5.77) 2.56(1.05,6.27) 0.60(0.84,5.77)Ptrendesi_vitC< 870.0321.000.1371.000.9651.000.2451.0087-131 1.46(0.68,3.13) 1.35(0.64,2.83) 1.30(0.55,3.04) 0.87(0.35,2.15)131-186 1.37(0.60,3.12) 1.00(0.42,2.36) 1.17(0.48,2.88) 1.25(0.49,3.21)> 186 2.90(1.25,6.72) 2.05(0.89,4.76) 0.49(0.17,1.42) 0.68(0.24,1.92)Arend 0.017 0.140 0.188 0.689frelat ve risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage and vitamin A.60Table 4.12: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and folatetComparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5est_vitA< 6103 1.00 1.00 1.00 1.006103-9080 0.63(0.35,1.12) 1.10(0.54,2.24) 0.97(0.47,1.20) 1.12(0.42,2.98)9080-13355 0.49(0.26,0.89) 1.19(0.55,2.59) 2.45(1.05,5.73) 0.90(0.31,2.60)> 13355 0.50(0.25,0.96) 1.35(0.58,3.14) 1.20(0.48,3.01) 1.50(0.44,5.16)Ptrenda-carotene< 2620.0361.000.4741.000.3221.000.6551.00262-.87 1.08(0.63,1.88) 0.87(0.45,1.69) 1.68(0.86,3.28) 1.08(0.43,2.72)487-913) 0.56(0.32,0.97) 0.85(0.42,1.71) 2.93(1.36,6.33) 2.65(0.95,7.45)> 913.0 0.72(0.40,1.28) 0.76(0.36,1.59) 1.02(0.46,2.27) 0.70(0.22,2.29)Ptrend 0.077 0.484 0.436 0.8200-carotene< 1236 1.00 1.00 1.00 1.001236-2138 1.08(0.62,1.86) 0.89(0.45,1.74) 1.74(0.89,3.41) 2.51(0.96,6.53)2138-3592 0.69(0.39,1.22) 0.99(0.48,2.07) 2.96(1.34,6.51) 1.39(0.49,3.91)> 3592 0.74(0.41,1.35) 0.75(0.35,1.60) 1.27(0.56,2.91) 0.96(0.29,3.22)Ptrend 0.169 0.535 0.248 0.77161Table 4.12(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5nonlycar< 1895 1.00 1.00 1.00 1.001895-3096 1.26(0.71,2.22) 1.03(0.53,2.02) 1.60(0.82,3.15) 2.39(0.93,6.11)3096-5149 0.48(0.27,0.85) 1.16(0.55,2.46) 2.31(1.04,5.12) 1.71(0.60,4.90)> 5149 0.68(0.36,1.25) 0.80(0.37,1.72) 1.01(0.43,2.37) 0.99(0.28,3.53)Arendlycopene< 1700.0351.000.6321.000.6371.000.9741.00170-312 0.78(0.46,1.33) 1.70(0.88,3.31) 1.60(0.80,3.20) 0.61(0.24,1.54)312-484 0.70(0.41,1.21) 1.30(0.67,2.53) 1.57(0.77,3.20) 1.01(0.39,2.56)> 484 0.57(0.33,0.99) 1.28(0.64,2.53) 0.80(0.39,1.66) 0.56(0.20,1.59)Ptrendest_viiC< 870.0461.000.6711.000.6061.000.5321.0087-131 0.67(0.36,1.24) 1.20(0.55,2.64) 0.51(0.23,1.15) 0.48(0.15,1.52)131-186 0.58(0.27,1.25) 1.30(0.50,3.39) 1.04(0.37,2.91) 0.48(0.12,1.86)> 186 0.61(0.24,1.56) 2.49(0.70,8.87) 0.72(0.18,2.83) 1.91(0.32,11.32)Ptrend 0.257 0.222 0.748 0.806f relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage and total folate.62Table 4.13: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and folatetComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5est_vitA< 6103 1.00 1.00 1.00 1.006103-9080 0.61(0.28,1.34) 0.54(0.24,1.20) 0.51(0.20,1.31) 0.66(0.26,1.65)9080-13355 0.41(0.18,0.93) 0.27(0.11,0.67) 0.86(0.34,2.17) 0.56(0.20,1.55)> 13355 0.40(0.16,0.98) 0.33(0.13,0.88) 0.57(0.20,1.67) 0.41(0.13,1.29)Ptrenda-carotene< 2620.0371.000.0151.000.5541.000.1351.00262-487 1.14(0.54,2.41) 0.80(0.38,1.69) 1.57(0.67,3.65) 1.25(0.50,3.10)487-913) 0.57(0.26,1.23) 0.22(0.09,0.52) 0.64(0.26,1.56) 1.08(0.44,2.64)> 913.0 0.77(0.35,1.69) 0.60(0.27,1.35) 0.98(0.39,2.49) 0.50(0.17,1.46)Ptrend 0.268 0.044 0.480 0.223)3-carotene< 1236 1.00 1.00 1.00 1.001236-2138 1.04(0.49,2.20) 0.91(0.44,1.90) 0.92(0.38,2.24) 2.42(0.97,6.00)2138-3592 0.73(0.33,1.60) 0.36(0.16,0.81) 0.96(0.41,2.27) 1.00(0.38,2.63)> 3592 0.86(0.38,1.95) 0.60(0.26,1.37) 0.98(0.38,2.56) 0.60(0.20,1.82)Ptrend 0.561 0.072 0.981 0.15763Table 4.13 cont'dComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5nonlycar< 1895 1.00 1.00 1.00 1.001895-3096 1.17(0.53,2.54) 1.18(0.55,2.51) 1.39(0.58,3.36) 2.64(1.05,6.63)3096-5149 0.45(0.20,1.02) 0.31(0.13,0.71) 0.71(0.29,1.73) 0.88(0.34,2.26)> 5149 0.72(0.31,1.67) 0.64(0.27,1.52) 0.92(0.34,2.48) 0.52(0.16,1.66)Ptrendlycopene< 1700.1841.000.0601.000.5421.000.1031.00170-312 0.50(0.24,1.03) 0.54(0.26,1.14) 1.39(0.61,3.17) 0.72(0.29,1.75)312-4 84 0.47(0.22,0.99) 0.53(0.25,1.16) 0.93(0.38,2.25) 0.86(0.34,2.15)> 484 0.35(0.16,0.75) 0.68(0.47,1.46) 0.93(0.38,2.29) 0.45(0.16,1.24)Ptrendest_vitC< 870.0091.000.3821.000.6181.000.1941.0087-131 0.55(0.23,1.29) 0.76(0.34,2.90) 0.57(0.21,1.57) 0.44(0.16,1.21)131-186 0.36(0.12,1.06) 0.54(0.18,1.63) 0.87(0.25,3.00) 0.51(0.15,1.79)> 186 0.30(0.08,1.06) 0.50( 0.12,2.09) 0.44(0.09,2.05) 0.56(0.12,2.57)Ptrend 0.054 0.280 0.377 0.418* relative risks (95% CI) adjusted for age, smoking status, sermonih, sexlife, both condom and diaphragmusage and total folaie.64Table 4.14: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and -carotenetComparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5est_vitA< 6103 1.00 1.00 1.00 1.006103-9080 1.08(0.62,1.90) 0.79(0.38,1.67) 1.01(0.47,2.19) 0.87(0.31,2.47)9080-13355 0.86(0.46,1.61) 0.71(0.31,1.60) 1.35(0.56,3.26) 0.89(0.30,2.66)> 13355 1.17(0.58,2.37) 0.51(0.21,1.26) 0.47(0.17,1.28) 3.26(0.76,14.00)Ptrenda-carotene< 2620.8501.000.1461.000.2491.000.2171.00262-487 0.94(0.49,1.79) 0.87(0.40,1.90) 1.24(0.58,2.68) 0.77(0.27,2.22)487-913) 0.52(0.25,1.11) 0.78(0.30,2.05) 1.53(0.55,4.32) 3.14(0.78,12.63)> 913.0 0.74(0.28,1.97) 0.96(0.26,3.47) 0.50(0.12,2.12) 1.09(0.15,7.62)Ptrendnonlycar< 18950.2401.000.8031.000.8691.000.4031.001895-3096 1.06(0.42,2.66) 1.45(0.47,4.44) 0.63(0.19,2.13) 1.91(0.22,16.42)3096-5149 0.24(0.07,0.78) 1.44(0.30,6.89) 0.24(0.04,1.48) 3.60(0.22,58.73)> 5149 0.37(0.08,1.85) 0.65(0.06,6.55) 0.05(0.00,0.98) 2.34(0.06,95.57)Ptrend 0.040 0.968 0.047 0.52365Table 4.14(cont'd)Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5lycopene< 170 1.00 1.00 1.00 1.00170-312 0.80(0.47,1.35) 1.55(0.80,2.97) 1.35(0.68,2.67) 0.59(0.23,1.50)312-484 0.76(0.44,1.31) 1.25(0.65,2.40) 1.38(0.67,2.83) 0.94(0.36,2.43)> 484 0.64(0.37,1.10) 1.21(0.62,2.36) 0.72(0.35,1.47) 0.44(0.16,1.26)Ptrendesi_viiC< 870.1161.000.7121.000.4271.000.2951.0087-131 1.24(0.73,2.12) 0.87(0.44,1.73) 0.78(0.39,1.58) 0.63(0.23,1.71)131-186 1.03(0.58,1.80) 0.77(0.37,1.58) 1.14(0.54,2.43) 0.61(0.23,1.66)> 186 1.32(0.74,2.36) 0.49( 0.24,1.01) 0.42(0.19,0.90) 1.58(0.47,5.34)Arendtotal folate< 1890.4871.000.0471.000.0861.000.6701.00189-263 1.73(1.00,3.00) 1.33(0.56,3.16) 0.90(0.45,1.81) 0.47(0.18,1.20)263-352 1.21(0.69,2.12) 0.62(0.24,1.60) 0.45(0.21,0.98) 0.68(0.22,2.13)> 352 1.40(0.77,2.55) 0.51(0.18,1.49) 0.75(0.32,1.72) 0.36(0.11,1.14)Ptrend 0.545 0.135 0.224 0.141'relative risks (95% CI) adjusted for age, smoking status, sezrnonth, sexlife, both condom and diaphragmusage and )3-carotene.66Table 4.15: Adjusted Relative Risks of various comparison groups of cervical dysplasiaassociated with selected nutrients and 8-caroteneComparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5est_vitA< 6103 1.00 1.00 1.00 1.006103-9080 1.23(0.56,2.69) 0.91(0.41, 2.03) 1.18(0.49,2.82) 0.77(0.30,1.98)9080-13355 0.98(0.41,2.34) 0.59(0.22, 1.55) 0.97(0.37,2.56) 1.29(0.45,3.66)> 13355 1.84(0.70,4.82) 1.37(0.48, 3.90) 0.31(0.09,1.06) 0.93(0.26,3.33)Ptrenda-carotene< 2620.3101.000.6951.000.0891.000.7951.00262-487 1.01(0.41,2.50) 0.66(0.28,1.55) 1.35(0.53,3.44) 0.73(0.27,2.00)487-913) 0.51(0.18,1.44) 0.24(0.08, 0.74) 0.42(0.13,1.32) 0.78(0.24,2.47)> 913.0 0.61(0.17,2.21) 0.90(0.21,3.83) 0.55(0.13,2.34) 0.71(0.13,3.90)Ptrendnonlycar< 18950.2551.000.2411.000.2071.000.6741.001895-3096 0.82(0.24,2.83) 1.41(0.48, 4.18) 1.45(0.47,4.44) 1.28(0.22,7.44)3096-5149 0.19(0.04,0.92) 0.40(0.09, 1.80) 1.44(0.30,6.87) 0.36(0.04,3.06)> 5149 0.33(0.04,2.70) 1.21(0.12,12.56) 0.65(0.06,6.55) 0.16(0.01,3.77)Arend 0.082 0.632 0.102 0.13067Table 4.15(cont'd)Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5lycopene< 170 1.00 1.00 1.00 1.00170-312 0.52(0.25,1.08) 0.54(0.26,1.14) 1.29(0.57,2.93) 0.63(0.26,1.54)312-484 0.54(0.26,1.13) 0.64(0.30,1.39) 0.97(0.40,2.36) 0.68(0.27,1.74)> 484 0.40(0.19,0.87) 0.84(0.40,1.76) 0.98(0.41,2.36) 0.38(0.13,1.05)Ptrendest_vitC< 870.0291.000.7661.000.7531.000.0911.0087-131 1.27(0.59,2.73) 1.22(0.58,2.55) 1.29(0.55,3.00) 0.73(0.29,1.82)131-186 1.07(0.47,2.45) 0.83(0.36,1.93) 1.13(0.46,2.78) 1.09(0.43,2.76)> 186 2.10(0.93,4.73) 1.62(0.73,3.60) 0.47(0.17,1.34) 0.64(0.23,1.80)Ptrendtotal folate< 1890.0891.000.3361.000.1491.000.6411.00189-263 1.07(0.49,2.35) 1.86(0.89,3.91) 2.04(0.90,4.63) 1.33(0.56,3.16)263-352 1.25(0.58,2.69) 1.43(0.66,3.11) 0.79(0.31,2.03) 0.62(0.24,1.60)> 352 1.59(0.71,3.56) 1.43(0.61,3.38 ) 1.19(0.45,3.10) 0.51(0.18,1.49)Ptrend 0.231 0.501 0.762 0.132*relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage and /3-carotene.68Table 4.16: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby supplement intakes*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5vitB current f 0.76(0.38,1.52) 0.50(0.20,1.23) 0.55(0.19,1.57) 0.88(0.18,4.40)Ptrend 0.442 0.137 0.265 0.876vitC current I 0.66(0.38,1.15) 0.44(0.21.0.91) 1.08(0.43,2.67) 0.90(0.27,3.00)Ptrend 0.145 0.030 0.873 0.8691 vs 2 1 vs 3 1 vs 4 1 vs 5vitB current f 1.23(0.50,3.00) 0.81(0.31,2.12) 0.98(0.28,3.43) 0.66(0.18,2.42)Ptrend 0.659 0.665 0.967 0.530vitC current t 1.17(0.57,2.43) 0.44(0.19,1.06) 0.73(0.28,1.86) 0.48(0.17,1.36)Ptrend 0.667 0.057 0.500 0.154* relative risks (95% CI) adjusted for age, smoking status,sexmonth, sexlife, both condom and diaphragmusage.f Non vita user was used as reference category.t Non vitC user was used as reference category.69Table 4.17: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby alcohol intake*Comparison groups1 vs 2-5 2 vs 3-5 3 vs 4-5 4 vs 5wine currentt 1.59(1.09,2.32) 0.88(0.54,1.42) 0.91(0.54,1.53) 0.91(0.45,1.84)Ptrendwinenum I0.014 0.592 0.721 0.7802-4 1.07(0.54,2.13) 1.25(0.55,2.81)) 0.80(0.54,1.53) 0.62(0.15,2.56)> 4 0.81(0.38,1.73) 2.13(0.78,5.78) 1.21(0.43,3.42) 0.15(0.03,0.83)Ptrend 0.609 0.143 0.825 0.022beer current § 1.53(1.01,2.31) 0.82(0.50,1.35) 0.74(0.43,1.27) 2.38(1.12,5.07)Ptrendbeernum t0.045 0.438 0.278 0.0222-4 0.66(0.29,1.50) 2.57(0.90,7.34)) 0.32(0.10,0.98) 1.14(0.15,8.44)> 4 1.29(0.46,3.62) 1.03(0.35,2.99) 0.70(0.20,2.39) 1.14(0.21,6.06)Ptrend 0.778 0.143 0.471 0.858* relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage.j- Non wine drinkers were used as reference category.§ Non beer drinkers were used as reference category.t. The lowest level (<= 1) bottles was used as reference category.70Table 4.18: Adjusted Relative Risks of various comparison groups of cervical dysplasiaby alcohol intake*Comparison groups1 vs 2 1 vs 3 1 vs 4 1 vs 5wine currentf 1.88(1.12,3.13) 1.59(0.95,2.67) 1.29(0.72,2.31) 1.19(0.65,2.18)Ptrendwinenum t0.016 0.080 0.385 0.5822-4 1.09(1.12,3.13) 0.65(0.24,1.79) 1.11(0.34,3.57) 0.49(0.15,1.62)> 4 0.54(0.19,1.57) 0.64(0.20,2.04) 2.29(0.66,7.99) 0.34(0.08,1.42)Ptrend 0.311 0.420 0.205 0.126beer current § 1.67(0.96,2.92) 1.82(1.03,3.23) 0.93(0.49,1.77) 1.77(0.89,3.50)Ptrendbeernum t0.072 0.041 0.816 0.1012-4 0.41(0.12,1.35) 1.09(0.33,3.59) 0.49(0.09,2.59) 1.19(0.26,5.52)> 4 1.08(0.28,4.16) 1.67(0.35,8.02) 3.19(0.56,18.10) 3.09(0.44,21.71)Ptrend 0.756 0.542 0.243 0.286* relative risks (95% CI) adjusted for age, smoking status, sexmonth, sexlife, both condom and diaphragmusage.Non wine drinkers were used as reference category.§ Non beer drinkers were used as reference category.The lowest level (<= 1) of bottles per week was used as reference .71Table 4.19: Pearson correlation coefficients for selected nutrients among controlsvitA vitC a-carotene )3-carotene nonlycar f olatevitA 1.000 0.438 0.867 0.900 0.911 0.354vitC 0.438 1.000 0.287 0.359 0.364 0.504a-carotene 0.867 0.287 1.000 0.935 0.968 0.290/3-carotene 0.900 0.359 0.935 1.000 0.987 0.374nonlycar 0.911 0.364 0.968 0.987 1.000 0.385f olate 0.354 0.504 0.290 0.374 0.385 1.00072Chapter 5Discussion and ConclusionsThe important risk factors found to be associated with CIN in this case-control studyare: current smoking, sexual frequency, number of different lifetime sexual partners,combined usage of both condom and diaphragm and dietary vitamin A intake. Becausecervical dysplasia is often considered to be a precursor lesion for invasive cervical cancer,it is not surprising that risk factors similar to those for cervical cancer are found.Our finding of an association between cigarette smoking and CIN is similar to that ofseveral other studies which analysed women with cervical dysplasia [2 ' 16] and carcinomain-situ[18]. Our study indicates that current cigarette smoking affects disease progression.The decreasing pattern of relative risk adjusted for age across the first four comparisongroups in Table 4.1 suggests that current smoking has a greater effect on earlier stages ofthe disease. Cigarette smoking may initiate or promote CIN and current smokers have ahigher risk of developing into the more advanced stages of the disease than non smokers.Likewise, dysplasia is more likely to progress to carcinoma in-situ among current smokers73than non smokers (see Table 4.2). However, no dose response relationship with currentcigarette smoking is found in out study unlike that found for invasive cervical cancer andcarcinoma in-situ in other studies [18,2°,23]Contrary to several case control studies[2,18,21 ]which find ex-smokers at increased risk of cervical cancer compared to non smokers, ourstudy has not established this effect. The accumulation of tobacco products in cervicalepithelial cells and a local immunologic deficiency of smoking may explain how cigarettesmoking contributes to the development of CIN.The findings of an increased risk of CIN associated with an increased number oflifetime sexual partners after controlling for the confounding effect of age and smokingare consistent with those for invasive cervical cancer[ 1-3-4]. Our study, is the first toreport a relationship between episodes of sexual intercourse (denoted by sexmonth in thisstudy) and CIN. Sexmonth is found significant even after controlling for age, smokingand sexlife. These findings (i.e. both sexmonth and sexlife) support the hypothesis thatcervical cancer and it's percursors behave as a sexually transmitted disease.If cervical cancer is a sexually transmitted disease, would barrier forms of contracep-tion reduce risk for the disease? In this study, we find in answer to this natural questionthat women who use diaphragms concurrently with their current sexual partners usingcondoms had the greatest protective effect against the disease. As shown in Tables 4.5and 4.6, both condom and diaphragm usage had the greatest effect in protecting womenagainst developing the disease, the RR was 0.47 in 1 vs 2-5. For those who already haddysplasia, the adjusted relative risks of condom and diaphragm usage are close to unity,suggesting that both condom and diaphragm usage does not offer any protection against74further development into the latter stage of dysplasia. The reasons for this pattern areunclear. Also, women who used a diaphragm alone reduced their risk of developingcarcinoma in-situ compared to non users (RR = 0.21). One of the limitations of thisstudy is that information obtained on condom use is limited to the womans' currentpartners. No information was elicited about condom usage by former partners whereasfor diaphragm usage, information was obtained on the history of lifetime usage. Hence,results obtained about the effects of condom usage might not be comparable with thosefor diaphragms. Like most studies on oral contraceptive usage, our study finds no re-lationship between oral contraception and CIN [1 '2-4]. The study of contraceptive usageand cervical cancer risk in one which has entails considerable methodological difficulty.The choice of a contraceptive is considered to be related to sexual practice, lifestyle etc.so determining the underlying reasons for any altered risks is complex. Also, none of theseveral venereal diseases are significantly associated with the risk of CIN. Self reportingof venereal disease is potentially open to bias. In particular the main disease of interest,HPV infection, can frequently be symptomless so that disease status cannot be trulydetected without tissue sampling and typing. Thus all results on venereal infection mustbe considered inconclusive. Moreover, it should be noted that the results presented hereare generally in agreement with those found elsewhere.Vitamin A plays an important role in cell differentiation. Deficiency in vitamin A orcarotene may allow more rapid proliferation of malignant cells. The results of previousstudies on vitamin A and the risk of invasive cervical cancer are controversial withprotective effects being detected in some studies[ 27] but not in others[33,35].75Our study finds lower levels of dietary vitamin A associated with an elevated risk.The association appears stronger than carotene, vitamin C and folate. The correlationsbetween vitamin A and carotene and other carotenoids were relatively high, particularlyfor 0-carotene and vitamin A where the correlation is 0.90 and between nonlycopenecarotenoids and vitamin A, they are 0.91. A high correlation between the nutrientshampered interpretation of their independent associations with risk, but neverthelessvitamin A appears to be the strongest determinant. This can also be seen when wecontrol for folate when vitamin A still appeared significant. No evidence of protectionby high dietary intake of vitamin C is revealed in this study. Moreover, no reduction inrisk is observed with women taking vitamin B and vitamin C supplements. However,alcohol drinkers seem to increase their risk of developing the disease although the resultsare not conclusive.As with most cancers, it appears cervical cancer is the result of several interre-lated factors working together to cause the disease. The findings in this study furtherstrengthened the importance of smoking, sexual activity, barrier form of contraceptiveusage and vitamin A as significant etiologic factors in CIN.76Bibliography[1] Swan S.H., Brown W.L., Oral contraceptive use, sexual activity and cervical carci-noma. Am. J. Epidemiol., 1981; 139:52-57.[2] Clarke E.A., Hatcher J., Mckeown-Eyssen G.E., Lickrish G.M., Cervical dyspla-sia: Association with sexual behavior, smoking and oral contraceptive use?. Am. J.Obstet. 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Epidemiol.,1990; 132:432-435.[34] Bendich A., Antioxidant micronutrients and immune response. Ann N. Y. Acad.Sci., 1990; 587:168-180.[35] Potischman N., Herrero R., Brinton L.A., Reeves W.C., Brenes M.M., Tenorio F.,de Briton R.C., Gaitan E., A case-control study of nutrients status and invasivecervical cancer, I.Dietray Indicators. Am. J. Epidemiol., 1991; 134:1335-1346.[36] Herrero R., Potischman N., Brinton L.A., Reeves W.C., Brenes M.M., Tenerio F.,de Briton R.C., Gaitan E., A case-control study of nutrients status and invasivecervical cancer, II: Serologic Indicators. Am. J. Epidemiol., 1991; 134:1347-1355.[37] Von Niekerk WA., Cervical cytological abnormalities caused by folic acid deficiency.80Acta. Cyt., 1966; 10:67-73.[38] Whitehead N, Reyner F and Lindenbaum J., Megaloblastic changes in the cervicalepithelium. J. Am. Med. Assoc., 1973; 226:1421-1424.[39] Breslow N, Day N.E., Statistical Methods in Cancer Research 1. The Analysis ofcase-control studies. International Agency for Research on Cancer. 1980; 32.[40] McCullagh P., Nelder J.A., F.R.S., Generalised Linear Models. 2nd Edition. Mono-graphs on Statistics and Applied Probability 37.81APPENDIX 1: POSTAL QUESTIONNAIRE USED BY THE BCCAStudy of Cervical Intra-Epithelial NeoplasiaThis form asks a variety of questions on your diet, your habits and your life-style. Information on this questionnaire will be used to help us understand moreabout the causes of diseases of the female cervix.We ask you to be as careful as possible in answering these questions. If youare presently pregnant, please indicate your usual diet prior to pregnancy. If you areuncertain of the meaning of the question, or if your answers do not fit into the spaceprovided, write any comments you may have alongside the question. If you need anyassistance in completing the questionnaire please telephone $7 7- 6c/0 by_AL 3657 c,<:.3065Your answers on this questionnaire will be kept completely confidential andwill be used for the purposes of this study only.OFFICE USE1. When were you born? ^ /^^Day^Mo.^Yr.2. How old are you? ^ years3. How many years have you been a resident of B C 7 ^4. Please indicate the highest grade you completed in school ^5. Please check any post-secondary education:Trade School^ College^ University^6. What is your marital status? Single^ Married^Widowed^ Divorced/Separated^7. How many times have you moved or changed residence in the last 10 years' times8. Have you ever smoked cigarettes daily for more than 3 months? No_ Yes —If no: Continue with question 9.If yes: How many cigarettes did you smoke on average'—number/day^At what age did you start smoking cigarettes'^ yearsDo you currently smoke cigarettes? No_ Yes _If you have stopped smoking, how old were you when you stopped' ^ years2324 _25_ _27 _28 -30 _3233 _S2Appendix 1 (cont'd)9. Do you usually consume alcoholic beverages?^No _ YesIf yes: Please complete the following table.- Averagenumberper week.Total yearsyou consumedalcoholicbeveragesAt what agedid you beginto consumealcoholicbeveragesIf stoppedat whatage did youpermanentlystop?Are youcurrentlyconsumingalcoholicbeverages?Beer(bottles)Wine(glosses)Spirits(shots)pir,Lo.USZ3538 _38 _40 —4245 _47 —49 _51 _54 _58 —58 —80 _10. Do you regularly take multivitamins or megavitamins?^No^_ Yes —^ 63If yes: Please complete the following table^a of Tablets BRAND NAMES -i- Total Time Used^Presently^ Aper day^Dosage mg/Ili^years / months Using 79^soMultivitamins y-s/^mths^no^yes It ^Megavitamins yrs/^mths^no^yes 10Do you regularly take other supplements? No Yes _If yes: Please complete the following tableVitamin A y-s/^m'hs __no__ yes 28Vitamin B complex yrs!^mths _no_yes 36 _Folate yrs/^mths^yes_no_ 44Vitamin C yrsi_ mths _no_yes 52 _ _Vitamin E yrS/^rnths^yes_no_ 60 _Iron yrs/^mths^yes__no__ 68 _Betacarotene yrs/^mths _no_yes 11Cod Liver Oil yrs/_ mths _nc__yes 19^__Zinc yrs/^mths^yes -^27Calcium yrs/^mths^no^yes ,Magnesium yrs/^mths^no_yes 43 _Selenium—yrs/^rn,hs^no^yes 51 ^Other yrs/^mths^no^yes so ^_——__S3Appendix 1 (cont'd)11. Are you on a special diet?1^No 2 ^ Weight loss 3^For medical condition 4^Vegetarian 5^Low salt6^Low cholesterol 7^ Weight gain12. How often do you eat foods from the following restaurants?I -^1s-4orres^:Doc2 aTYPE OF RESTAURANT^Almost^2, every oar^a weer^Avek41-3 tames^5-10 times^1-4 limesa month^a year^I a year7Never, or lessthan once a yearFried chickenBurgersPizzaChinese food Mexican foodFried Fish Other restaurants13. This section is about your usual eating habits. Thinking back over the past year, how often do you usually eatthe foods listed on the next page?First, check (^ whether your usual serving size is small, medium or large. (A small portion is about one-halfthe medium serving size shown. or less: a large porton is about one-and-a-half times as much, or more.)Don't check any serving size if you eat the food less than once a year. Some items mention several foods (forexample. "bread, rolls, crackers.") Check :he serving size for the one you eat most often.Then, put a NUMBER in the most appropriate column to indicate HOW 01- I LIN, on the average, you eatthe food. You may eat bananas twice a week a 2 in the "week" column) and sweet potatoes or yamsthree times a month (put a 3 in the "month" column). If you never eat the food, check "Rarely/Never".Some items say "in season". Indicate how often you eat these just in the 3-4 month time when that food isin season. For example, you may eat cantaloupe once a week when it is in season. but only once a monthduring the rest of the year. (See example)Please look at the example below. This person1) eats a medium serving of cantaloupe once a week, in season2) eats a medium serving of cantaloupe once a month, the rest of the year3) has 1/2 grapefruit about once a week. and grapefruit juice about once a month.That is about 5 times a month for that item.4) has a small serving of sweet potatoes about 3 times a year.5) has a large hamburger or cheeseburger or meat !oaf about 4 times a week.EXAMPLE:4 7;re:.:41,,,.-- ,'-.&f 11F rCantaloupe^(in season) 1/4 medium VICantaloupe^(out of season) 1/4 medium k./1Grapefruit, grapefruit juice (1/2) or 6 oz. 1^1^1Sweet potatoes. yams 1/2 cup^,\/l^1^IHamburger, cheeseburger. meat loaf^ 1 medium^I^1^1./5I^t '^I^IPLEASE GO TO NEXT PAGE84Appendix 1 (cont'd) Sang1.144:144Intoi"164.11i V41/2^f.1:41 1) or^CUDL Zr__JPSapplesauce. pears•FBananas 1) mediumPeaches. atancots (canned. frozen or (Med. whole cearl^(II or '•2 cuoPeaches. aencots. nectannes (fresh. 'n season,^11 mediurnCantaloupe (in season)^ Li mediumCantaloupe (out of season) mediumWatermelon (in season) 1 sliceSPawbernes (frozen or canned...ehoie cean^ 1•2 CUDSoawoemes (fresh. in season)^ 1•2 cupOranges^ . 1 mediumOrange juice : b oz. glassGrapefruit. grapefruit juice l'•:) or 6 oz.7-• s 'Tang. Start breakfast drinks 6 oz. classOther fruit juices. fortified fruit drinks - 6 oz. glass I I^IAnv other fruit. including berries. fruit cocktail CupMost frecuent other fruit or juice? z .me:43 —17 1Sp-mg beans. green beans .:.2 cue 'ill!Peas cueOther beans such as baked beans. pintos. kidnev beans rna.s^cuP ICorn CUD i^I:Mixed vegetables '2 am •Winter squash. baked squash 1• 2 cuDTomatoes. tomato mice (It or 0 oz• Ref:. zr:iies. :rushed. sauces-exclude pican:e. :aco sauce rdlso. sauce51'6S-71:92.737ss5761.6369!•73  Brcccoii CCDC.Juliflo'.‘er or bruss-ei sprouts CUDSpinach :raw) CUOSpinach ;conked) • •2 CUDMustard tgeens. turnip 'greens. collards '7 C.U0Gale 513 . V. cabbage. sauerkraut z^uC3(17013. or ,peas and carrots it cupGreen salad med. bo'.v1French fres and fried potatoes •( CUPSweet potatoes. yams '7 cueOther potatoes. including boiled, baked. pcta.to salad i^11 or 1 ;2 cuo^IRice : 14 cuoAny oth e r vegetable. including cooked onions. summer scuash !1/2 CUDMost frecuent other venerable?Buner. margarine or other fat added to veceiables 2 Dais 1Fs 1W KerYrIF•flo-{ a^tesHamburgers. cheeseburgers. meat loaf 11 medium^I j I I 1Beef—steaks. roasts !4 oz.^I ! I^I I I !Beef stew or pot pie with carrots, other vecte:abies !I^cup I. , !Liver. including chicken livers 4 oz. ! IPork. including chops. roasts chops or -I oz.Fried chicken 2 sm. 7:r^I :q^diectr'Chicken or turkey. roasted, stewed or brciled 12 m'.. gr^I !g^piece! I I IFnecffish or fish sandwich 14 oz. or^I sand.^I I I jTuna 'fish. tuna salad. tuna casserole 1• ^cup^I I 1 1 1Shell fish (shrimp. lobster. crab. oysters. etc.! I IS) 1 '7 cup or 3 oz.l I j 1[1 1 ! iOther fish. broiled. baked l 2 pieces^I I I l I I I !J47 —5 [___'79 30- 7813:Ank.^.S5Office Use1519 _ -23 -2731 _ -3539 -43 - -47^_S I --55 - -59----63 -6771.75 _1115 -19 -23 L.. -2731 - - -35 •394347 _515559 -63 -677175^11 -15 _19 -27 •3135394751 -555963 -67 -71----7579 90GW79 60Appendix 1 (cont'd)Medium• •^ServingYourServingSizeMIXED DISHES/LUNCH ITEMS S 14 I.Spaghetti, lasagna, other pasta with tomato sauce 1 cupPizza 2 slicesMixed dishes with cheese (such as macaroni and cheese) 1 cupLiverwurst 2 slicesHot dogs 2 dogsHam, lunch meats 2 slicesVegetable soup. vegetable beef, minestrone, tomato soup 1 medium bowlOther soups 1 medium bowl Ii:...74AREADB1SALTY SNACKS / SPREADS N LWhite bread, rolls, crackers. (including sandwiches) 2 slices. 3 crackDark bread, incl. whole wheat, rye, pumpernickel 2 slicesCorn bread, corn muffins, corn tortillas 1 medium piece !Salty snacks (such as chips, popcorn) 1 handfulPeanuts, peanut butter 2 Tblsp.Butter on bread or rolls 2 pats^L1_Margarine on bread or rollsSalad dressing, mayonnaise^(including on sandwiches,2 pats I2 Tblsp.Gravies made with meat drippings, or white sauce 2 Tblsp.1‘1#?ftli;; ,:i.,': ,  BREAKFAST FOODS --- •^• ; ' "...^S -111.. I: -High fiber, bran or granola cereals. shredded wheat 1 med. bowlHighly fortified cereals, such as Special K. Total 1 med. bowlOther cold cereals, such as Corn Flakes. Rice Krispies 1 med. bowlCooked cereals 1 med. bowlSugar added to cereal 2 teaspmEggs 2 eggsBacon 2 slicesSausage 2 patties or links;4V• 1 ;4 ie.'1 ' -''s . -^l'' -- . - . SWEETS 1 S N L ,Ice cream 1 scoopDoughnuts, cookies, cake, pastry 1 pce or 3 cookPumpkin pie, sweet potato pie 1 med. sliceOther pies 1 med. sliceChocolate candy small bar. 1 ozOther candy, jelly, honey, brown sugar 3 pce, or 1 Tblsp•.-_:q::= .:,';',- . 7 ...7: - DAIRY PRODUCTS S id LCottage cheese 1/2 cupOther cheeses and cheese spreads 2 slice or 2 oz.Flavored yogurt 1 cupWhole milk and beverages with whole milk 8 oz. glass2% milk and beverages with 2% milk 8 oz. glassSkim milk, 1% milk or buttermilk 8 oz. glass, ..^: -•./., .^•^• ^.^BEVERAGES IS12 oz.can or bottle!P4 LRegular soft drinksDiet soft drinks 12 oz.can or bottle!Beer 12 oz.can or bottle lWine 1 med. glassLiquor 1 shotDecaffeinated coffee 1 med. cupCoffee, not decaffeinated 1 med. cupTea (hot or iced) 1 med. cupNon-dairy creamer in coffee or tea 1 Tblsp.Milk in coffee or tea 1 Tblsp.Cream (real) in coffee or tea 1 Tblsp.Sugar in coffee or tea 2 teaspn.Artificial sweetener in coffee or tea 1 packet86HowOften?Day Week3OFFICE USECode^Amts11•^17 23 ^29 35 ^41 6869Appendix 1 (cont'd)14. Think about your diet over the last year and the responses you have just made on this questionnaire. Are there any foods notmentioned which you eat at least once a week, even in small quantities. or eat frequently in a particular season? Consider othermeats, breakfast foods, catsup, green chilies or jalapenos, salsa picante or taco sauce, avocado (guacamole), Mexican dishes.Chinese or other ethnic foods, other fruits or vegetables, as well as nutritional supplements (bran, etc.). Please take a look at thelist of foods at the bottom of the page. FOODYOU"'ServingSizeS M L1^ 215. How often do you eat the skin on chicken?How often do you eat the fat on meat?How often do you add salt to your food?How often do you add pepper to your food?16. How often do you eat raw vegetables (carrots, cauliflower, etc.) as a snack or in salad?1Almostevery day22-4 timesa week3Once aweek41-3 timesa month55-10 timesa year61-4 timesa year7Never. or lessthan once a year17. How often do you use fat or oil in cooking?For example, in frying eggs, meat or vegetables?^ times per^day. wk., month18. What do you usually cook with? 1^ Don't know or don't cook 2^Soft margarine3 _Stick margarine 4 _Butter 5^Oil 6^Lard, fatback, bacon fat 7^Pam or no oil19. What kind of fat do you usually add to vegetables, potatoes, etc.?1 _ Don't add fat 2 _ Soft margarine 3^ Stick margarine 4 _ Butter5 _ Half butter, half margarine 6^Lard, fatback, bacon fat20. If you eat cold cereal, what kind do you eat most often?  ^5921. Are you now losing or gaining weight?1^No 2^Yes, losing 3 _Yes, gainingHave you gained or lost more than five pounds in the past year?1 _ No 2^Lost 5-15 lbs. 3 _ Lost 16-25 lbs. 4^Loot more than 25 lbs.5 _ Gained 5-15 lbs. 6^Gained 16-25 lbs. 7^Gained more than 25 lbs.Seldom/Never Sometimes^Often/AlwaysPLEASE GO TO NEXT PAGE I-87Appendix 1 (cont'd)OFFICE USE22. How did your weight compare with others of your height and age at thefollowing times during your life?Lighter than^About^Heavier than_ average average averageAs a childAs a teenagerAs a young adult70 ^79^80111213Now we would like you to answer some questions about your lifestyle.23. How many hours of sleep do you usually get at night?6 hours or less 7 hours^ 8 hours 9 hours or more ^ 14 ____24. Here is a list of active things that people do in their free time.How often do you do any of these things?More than About A few A few Rarelyonce a once a times times orweek week a month a year neverActive sports^ 15Doing physical exercise^ 18Jogging or running 17Swimming or taking^ 18long walksGardening, fishing, hunting^ 19 —Something else 20 —25. How many close friends do you have? (People that you feel at ease with, can talk to aboutprivate matters and can call on for help).none ^ 1 or 2 ^3 or 5 ^ 6 to 9 ^ 10 or more^ 21How many relatives do you have that you feel close to?none ^ 1 or 2 ^ 3 or 5 ^ 6 to 9 ^ 10 or more^ 22 ____How many of these friends or relatives do you see or talk to at least once a month? none ^ 1 or 2 ^ 3 or 5 ^ 6 to 9 10 or more 2388Appendix 1 (cont'd)OMCE USE26. How often do you feel under stress which makes you tense or worried, or causes physicalproblems such as stomach or back trouble or headaches?Every day^ Several times a week^ 24 —Several times a month^ Several times a yearRarely or never27. Do you regularly have any of the following complaints? If so, please indicate how many dayson average you have them per month.Yes^No^No. of Days Sore or chapped lipsHeadachesDizzinessLoss of appetiteNauseaBreast painDepressionSleeplessnessSore eyes or conjunctivitisDry skinOther 25283134374043 _46 - - -49 _525528. Please check if you have or have ever had any of the following diseases:Yes^No^ Yes^NoAsthma^ Syphilis^ 58 — —Diabetes Gonorrhoea so — —Hepatitis^ Oral Herpes^ 62 — —(cold sores)Condylomata Genital Herpes^ 64(Human papilloma virus)89Appendix 1 (cont'd)OFFICE USE29. No we would like you to answer some questions about your reproductive life.How many pregnancies have you had? ^ number^ 66 —If you have been pregnant, how old were you when you had your first pregnancy?age   not applicable -^ 67Are you currently pregnant?^No^ Yes —^ 69 -30. Have you previously regularly used any contraceptives?^No_ Yes —(i.e.. the pill, I.U.D., diaphragm etc.)^ 70 -Has your usual sexual partner regularly used contraceptives?^No _ Yes _^ 71 -If you have used contraceptives, please complete the following table.K If you are continuing to use any of these methods, please leave the^ 79^BO"age when last used" column blank.Age when^Age when^Total time^Presentlyfirst used last used used (yrs.) usingOral Contraceptives(the pill) Yes^NoYes^NoYes^NoYes^NoYes^NoYes^NoI.U.D.(loop, coil, etc.)DiaphragmChemical spermicide ^Condom (partner)Other (specify)182532 ____3946The following questions asks for information of a personal nature.Sexual activity has previously been found to be related to disease of the cervix and werequest that you make every effort to give a complete response to this question.31. How old were you when you first had sexual intercourse? years^ 53Over the last year approximately how many times per month (on average)have you had sexual intercourse?^ number/monthHow many different sexual partners have you had in the last year? ^and how many have you had in your lifetime^5557 - -59 - -L79^80Thank you very much for taking the time to complete the questionnaire.v‘Thr ro_nnprntinn is sincerely annreciated.90APPENDIX 2: SAMPLE CODING SHEETItem^Card Column Variable^Code Contents  A 7-10 Cytology ID1 A 11-12 Birth Day1 A 13-14 Birth MonthA 15-16 Birth Year2 A 17-18 Age3 A 19-20 Residentsin B.C.4 A 21-22 Education5 23 Post-Secondary6^A^24^Marital Status 1 = Single2 = Married3 = Widowed4 = Divorced/separated9 = Unknown, or no response7^A^25-26^Moves^00-20 = times99 = Unknown, or no response8^A^27^Smoking^1 = No2 = Yes9 = Unknown, or no responseA^1 - 4^Study ID^0001-1066 - Study numbersA^5-6 CP =^- Chemoprevention^- CN =^= Cervical Neoplasia0001-9998 = Cytology ID 1101-31 = Day99 = Unknown, or no response01-12 = Month99 = Unknown, or no response1911-1969 = Year999 = Unknown, or no response17-55 = Years99 = Unknown, or no response01-65 = Years99 = Unknown, or no response1-13 = Grades99 = Unknown, or no response1 = Trade school2 = College3 = University9 = Unknown, or no responseif more than one tick codeto highest91APPENDIX 3:Let n 1 denotes the number of individuals in the exposed subgroup; n 2 denotes the numberof individuals in the nonexposed subgroup. Let p i.; denotes the probability of developingdisease j in the exposed subgroup; Let p 23 denotes the probability of developing diseasej in the non-expposed subgroup, j= 1,2,3,4,5. Let r 3 denotes the sampling proportionsfor disease stage j.Denoting the relative risks of developing the subsequent stage of the disease by 0 i andthe relative risks of the 1st 4 comparison groups by W i for 1=1,2,3,4. Assuming the 0i> 1 for all i,We show that if the ts's are all equal, then 413 > W4 > 1The relative risks of developing the disease from stage 3 to 4, i.e. (1)341'3 =1113 =^n4n1P13(1 —P14)r3n2(1-1:023)^P13(1—P23)(1—P14) ^r3n1(1-1313)r4n2P23(1 — P24)^(1-1313)P23(1-1324)(r4n013(1 —p14)-1-rsniPi3p14)(r3 112(1-P23)(r4n2P23(1 —P24) -1-r5n2P23P24)(r3n1(1 —p13)If r4 = r3 ,Then kI13 = 03 [1 + (0 4 — 1)p241 = 113[(1 — p24) (1)4P24]Hence we see that I13 > (1)4^> 192

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