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Designing and implementing a longitudinal study of children with neurological, genetic or metabolic conditions:… Siden, Harold; Steele, Rose; Brant, Rollin; Cadell, Susan; Davies, Betty; Straatman, Lynn; Widger, Kimberley; Andrews, Gail S Sep 20, 2010

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STUDY PROTOCOL Open AccessDesigning and implementing a longitudinal studyof children with neurological, genetic ormetabolic conditions: charting the territoryHarold Siden1,3*†, Rose Steele2†, Rollin Brant3, Susan Cadell4, Betty Davies5, Lynn Straatman1, Kimberley Widger6,Gail S Andrews3AbstractBackground: Children with progressive metabolic, neurological, or chromosomal conditions and their familiesanticipate an unknown lifespan, endure unstable and often painful symptoms, and cope with erratic emotional andspiritual crises as the condition progresses along an uncertain trajectory towards death. Much is known about thegenetics and pathophysiology of these diseases, but very little has been documented about the trajectory ofsymptoms for children with these conditions or the associated experience of their families. A longitudinal studydesign will help to close this gap in knowledge.Methods/Design: Charting the Territory is a longitudinal descriptive, correlational study currently underway withchildren 0-19 years who are diagnosed with progressive neurological, metabolic, or chromosomal conditions andtheir families. The purpose of the study is to determine and document the clinical progression of the conditionand the associated bio-psychosocial-spiritual experiences of the parents and siblings age 7-18 years. Approximately300 families, both newly diagnosed children and those with established conditions, are being recruited in sixCanadian cities. Children and their families are being followed for a minimum of 18 months, depending on whenthey enroll in the study. Family data collection will continue after the child’s death if the child dies during thestudy period. Data collection includes monthly parental assessment of the child’s symptoms; an annual functionalassessment of the child; and completion of established instruments every 6 months by parents to assess familyfunctioning, marital satisfaction, health status, anxiety, depression, stress, burden, grief, spirituality, and growth, andby siblings to assess coping and health. Impact of participation on parents is assessed after 1 year and at the endof the study. Chart reviews are conducted at enrollment and at the conclusion of the study or at the time of thechild’s death.Discussion: Knowledge developed from this study will provide some of the first-ever detailed descriptions of theclinical symptom trajectory of these non-curable progressive conditions and the bio-psychosocial-spiritual aspectsfor families, from diagnosis through bereavement. Information about developing and implementing this study maybe useful to other researchers who are interested in designing a longitudinal study.Almost half of non-traumatic deaths in childhood inCanada are from progressive metabolic, neurological, orchromosomal conditions (n = ~1250/year) [1] and finan-cial costs associated with caring for these children areestimated at $1.17 billion annually [2]. Children withthese conditions and their families anticipate anunknown lifespan, endure unstable and often painfulsymptoms, and cope with erratic emotional and spiritualcrises as the condition progresses along an uncertaintrajectory towards death.For the majority of children, a cure for these diseases,or a specific treatment that will significantly prolong life,does not exist despite the treatment options that havebecome increasingly available. Pediatric palliative care,therefore, should begin at diagnosis and focus on antici-pating and relieving the child’s symptoms while* Correspondence: hsiden@cw.bc.ca† Contributed equally1Faculty of Medicine, University of British Columbia, Vancouver, BC, CanadaFull list of author information is available at the end of the articleSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67© 2010 Siden et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.supporting the family to ensure the best possible out-comes in the face of certain death. Unfortunately, there isa lack of research evidence on which to base such care[3-7]. The terminal outcome of the disease may beknown, but the onset, timing, patterns, and severity ofsymptoms are not; consequently, best practices and stra-tegies for symptom relief are also unknown. Furthermore,little is understood about the bio-psychosocial-spiritualimpact on these families and how to support them.There is a critical need to develop a solid understand-ing of disease progression and the experiences of thesechildren and their families over time. We are currentlyconducting an innovative 5-year longitudinal study toidentify and track children diagnosed with progressivemetabolic, neurological, or chromosomal conditions andtheir families to determine and document the clinicalprogression of the condition and the associated bio-psy-chosocial-spiritual experiences of the family. Our goal isto close the key knowledge gaps and provide new infor-mation about the best care for these vulnerable childrenand their families. Our purpose in this paper is todescribe the rationale, development, design, and imple-mentation of this study to assist other researchers whomay be interested in conducting longitudinal research.BackgroundOur research team, Transitions in Pediatric PalliativeCare and End of Life, was funded by the Canadian Insti-tutes of Health Research (CIHR) under the New Emer-ging Team Program (NET) (PET-697#). Led by Dr. HalSiden and known as PedPalNet, this team was conceivedto develop a sustainable research program focused oncreating knowledge to optimize provision of care forchildren with life-threatening conditions. As far as weare aware, this is the first interprofessional, multi-centreteam of researchers in pediatric palliative care in theworld. We work together to develop specific researchprojects, obtain project operating funds, attract newresearch collaborators, and increase research capacitythrough trainee support and mentoring.In an early PedPalNet project, we conducted a Delphiprocess to identify high-value areas for Canadianpediatric palliative care clinicians and researchers.Through that project, we identified four thematic areas,three of which have particular relevance to this currentstudy: (1) identifying what matters most to families; (2)providing relief of symptoms; and (3) developing evi-dence to support best practice [8]. A foundationalcohort study to identify family experiences and symp-tom courses is a logical sequela to the Delphi project.Dr. Rose Steele, one of the co-principal investigatorsfor the current study, previously conducted researchwith families living with a child who has a neuro-degen-erative illness. The resulting grounded theory identifiedthe basic social process of ‘navigating uncharted terri-tory’ and outlined the trajectory, impact on the family,factors that modified the experience, and strategies usedby families to manage the experience [9-13]. Lack ofinformation about what could be expected in the illnesstrajectory was identified as seriously hampering afamily’s ability to manage the experience. The currentstudy, Charting the Territory, builds on the groundedtheory study by focusing on children with a wider rangeof progressive metabolic, neurological, or chromosomalconditions and by using a longitudinal design todescribe the symptom trajectory and further understandthe whole experience for the child, siblings, and parentsfrom a quantitative perspective.Life-Threatening Conditions in ChildrenTwo seminal reports from the United Kingdom [14] andthe United States [7] described the broad spectrum ofdiagnoses of life-threatening conditions encountered inchildren. These conditions are physiologically diverse,vary in life expectancy and treatments, and more or lessfall into four Quadrants [14] (see Table 1).Our study focuses on children with Quadrant 3-typeconditions. Quadrant 3-type conditions are those with-out cure or life-prolonging treatment; good symptommanagement and treatment of comorbid illnesses areemphasized (e.g., aspiration pneumonia) but do not alterthe underlying pathophysiological process. The processremains inherent in the disease condition. Examples ofdiseases that are commonly thought of as fitting intoTable 1 Quadrants of Life-Threatening Conditions in Children[14]Quadrant 1 Quadrant 2Life-threatening conditions for which curative treatment may befeasible but can fail.Conditions where premature death is inevitable, but long periods ofintensive treatment aimed at prolonging life and allowing participation innormal activities(e.g., cancer, irreversible organ failures) (e.g., cystic fibrosis)Quadrant 3 Quadrant 4Progressive conditions without curative treatment options, wheretreatment is exclusively palliative and may extend over many years.Irreversible but non-progressive conditions with severe disability susceptibleto health complications and premature death.(e.g., neurodegenerative, metabolic disease) (e.g., anoxic brain injury, severe cerebral palsy)Siden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 2 of 12this category include: leukodystrophies, spinocerebellardegenerative diseases, and some chromosomal anoma-lies, including aneuploid states. Even though the specificdiagnoses that tend to fall into Quadrant 3 are variedand numerous, clinically they are similar in functionalimpairments and diversity of symptoms that limit qual-ity and duration of life.The number of children with rare, progressive diseasesthat fall into Quadrant 3 is large relative to the otherQuadrants and these children require significant healthcare attention, yet surprisingly little has been compre-hensively explored and documented about the illnesstrajectory of these conditions. The onset of the diseaseand symptoms and the length of survival time for thesechildren are virtually unexplored. We chose to conductresearch with this group for several reasons:• These children and their families are major usersof health care services for acute, chronic, and end-of-life care [2].• There is a major impact on families caring forthese children [15].• These children account for about 50% of childrenreceiving palliative care [16-22].• As a group, Quadrant 3-type conditions are a sig-nificant cause of death in childhood [1,19,23,24].• There is a lack of research in this group comparedwith other areas, such as cancer [25].Knowledge GapsBoth positive and negative outcomes of the experiencehave been documented for parents and siblings of thesechildren [9-11,13,26-32] but there is a paucity ofresearch addressing the overall experience of the childand family. It is unclear if outcomes are isolated to spe-cific times, if they are present throughout the experi-ence, or if/how they may change over time. A holisticapproach that concurrently examines bio-psychosocial-spiritual dimensions for family members would allow fora more complete picture of the experience.Given the prevalence of Quadrant 3-type conditionsand the associated physical, psychological, and financialcosts, it became clear that a longitudinal, prospectivestudy that follows the child and family for as long aspossible as they move from diagnosis through death andinto bereavement was imperative to document the nat-ural course of the child’s condition and the experienceof the family. This study was conceived as a way toaddress this important research area. Results of thisstudy will inform families and clinicians about what theymight anticipate during the child’s trajectory towardsdeath.Methods/DesignStudy ObjectivesOur study is a prospective longitudinal study with threeobjectives:a) Establish a cohort of children with non-curable,life-threatening conditions.b) Determine and document the natural history ofthe symptom progression of these conditions.c) Determine and document the bio-psychosocial-spiritual trajectory of parents and siblings.Specific research questions include:1. What is the clinical illness trajectory, and itsimpact, for children with non-curable, life-threaten-ing conditions, specifically: pain, breathing orrespiratory problems, feeding difficulties, alertnessand interaction changes, sleep problems, seizures,constipation, and functional abilities?2. What is the bio-psychosocial-spiritual trajectory,and its impact, for families when a child has a non-curable, life-threatening condition, specifically out-come variables of: family functioning; marital satis-faction; parent health, anxiety, depression, stress,burden, spirituality, grief, and growth; and siblinghealth and coping?3. Do these child and family outcome variableschange over time?4. What relationships exist among the child andfamily outcome variables and do these relationshipschange over time?Study DesignIn this longitudinal research study, we are using quanti-tative methods with established instruments and chartreviews. Data collection is taking place along two paral-lel streams: one examining the child’s clinical symptoms,and the other examining bio-psychosocial-spiritualaspects of the experience for family members. Under thecurrent funding, children and their families will be fol-lowed for a minimum of 18 months, based on whenthey enter the study. However, we hope to obtainfurther funding beyond this initial 5-year study andextend this cohort for a longer duration. We also hopeto expand data collection in the future to include quali-tative interviews that capture other aspects of theexperience. We are recruiting children and families withnew diagnoses in order to maximize understanding ofthe condition trajectory, but we also are including thosewith established diagnoses as some symptoms may onlyarise later in the condition course. This approach shouldSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 3 of 12provide an opportunity to better understand symptomsand parent/sibling experiences at different times alongthe trajectory. Some children may die during the studyperiod, but the intent is to follow those families throughthe course of the illness and into bereavement. Thisdescriptive, correlational design will allow for efficientand effective collection of large amounts of data withina naturalistic setting and for investigation of complexrelationships that may exist among the clinical and bio-psycho-social variables.Eligibility CriteriaOnly children with Quadrant 3-type conditions that fallinto the group of progressive metabolic, neurological, orchromosomal conditions are eligible for the study. Chil-dren who have been provided with potentially curativetherapies, such as stem cell transplantation for metabolicconditions, are excluded. The inclusion list was devel-oped from a literature review, palliative care programdata (Canuck Place Children’s Hospice, Vancouver), andan iterative review process involving pediatric palliativecare physicians and specialists in the fields of Neurology,Genetics, and Metabolic Diseases. The resultant list is inaccordance with current approaches to pediatric pallia-tive care [14] and work on mortality in childhood Com-plex Chronic Conditions [23,33].Determining who is eligible for recruitment from atheoretical “Quadrant” of conditions initially provedchallenging. The Quadrant model, first described as“Categories” by the British charity ACT, is primarilyuseful as a conceptual framework for understanding thebroad variety of children and families receiving pediatricpalliative care. Clinically, the model maps broadly ontoan identifiable population of eligible children. Beforerecruitment started, the clinicians began to generate alist of sample eligible diseases in order to establish whowould be specifically eligible. From the original list, asystem of categories was further developed by geneti-cists, neurologists, and biochemical disease specialists inour study sites. This list included a category for thoseconditions that could be treated with curative therapies,but where the child would be eligible if the treatmentwas failing, and those conditions where the trajectorymay not always display the progressive component thatis classic for Quadrant 3. The list quickly became itera-tive in that the clinicians and researchers continue tomake notes and compare their new diagnoses to the ori-ginal list, adding and noting where there is disagree-ment. This purposive sampling of diagnoses allows theinclusion of children whose disease is progressive, andthe constant iterations permit a theoretical modelto translate into a practical, useful clinical document todetermine eligibility. Potential participants are comparedto the list and to an Eligibility Criteria Checklist todetermine whether or not to approach the family (seeFigure 1).Families may have various ways of determining who isa member of their family, but for the purposes of thisstudy, “family” includes only the biological, adoptive,step-parents, or legal guardian and biological, adoptive,or step-siblings with whom the affected child lives mostof the time. Children in foster care are not eligiblebecause some foster parents only provide short-termcare, the foster setting may change during the course ofthe study, or there may be legal issues with obtainingconsent. Families who have multiple children affectedwith these conditions are eligible, but only those affectedchildren 0-19 years of age are included in the study. Aparent may provide data about more than one eligible,affected child. A minimum of one parent must agree toparticipate on his/her own behalf, plus provide therequired information on the ill child throughout thestudy. In addition, all siblings age 7-18 years are invitedto participate. The age ranges were chosen because theinstruments we are using have been validated for chil-dren of those ages. Participants must speak and writeEnglish or French as data collection is only available inthe two official Canadian languages.Study RecruitmentThree hundred children and their families are beingrecruited in six cities across Canada (Vancouver, Cal-gary, Edmonton, Toronto, Ottawa, and Montreal). Siteswere chosen to maximize access to the population basedon (a) the numbers of children diagnosed annually, (b)the presence of a palliative care team member as anonsite collaborator for recruitment and ethics, and (c)the availability of a specialist clinician/team in MetabolicDiseases, and/or Genetics, and/or Neurology clinics whofollow these children and can support access to subjectsand clinic records. Prior to commencing recruitment ata participating site, institutional ethics approval wasobtained from the Research Ethics Board (REB) of thehospital, as well as from each of the universities wherethe participating co-investigators held their primary aca-demic positions.The protocol and all study materials underwent minormodifications to accommodate different requirements ateach site. These differences primarily reflect the varyingapproaches of Research Ethics Boards regarding recruit-ment. Each REB approved a different method of initialcontact between the researchers and the study partici-pants. In provinces where Health Information Protectionlegislation is strictest, the Research Assistant (RA) isprohibited from contacting families without writtenapproval from at least one of the parents. At other sites,contact information is accessible to the RA who maycall or visit with a family in clinic after an introductionSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 4 of 12Figure 1 Eligibility Criteria ChecklistSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 5 of 12from the clinician or clinic nurse. All sites approved themore passive “call back” method, where clinicians mailout invitations from the clinic to the family. Familieswho are interested call a toll-free 1-800 number formore information. The site RA provides any follow-upinformation for interested families. None of the sitesallow the researchers to recruit the families directly,especially in situations where the Site Investigator alsotends to be the child’s clinician. This non-coercive pro-cedure is intended to prevent undue pressure on thefamily to participate.When the initial recruitment met with challenges,especially where the RA requires a lengthy introductionprocess or is unable to identify eligible children due toprivacy protection laws, two alternate recruitment meth-ods were added to the protocol. In order to maximizethe scope of our enrollment, an online recruitmentmethod was proposed. The REB approved cliniciansgiving out information about our study website. Sec-ondly, disease-specific organizations such as the MPSSociety, and other organizations such as the Rare Dis-eases Foundation and the Canadian Organization forRare Disorders (CORD), are able to aid in recruitmentof eligible families by distributing information about thestudy on their website and in organizational newsletters.Each organization also has a list of parent support net-works to which appeals can be made for assistance withstudy recruitment.Accrual and AttritionThe sample size of 300 is pragmatically motivated as weanticipate that 50 participant families can be recruitedin each of the 6 sites. We are confident this sample sizeis ample for descriptive purposes, e.g., it will enable usto estimate simple proportions with a standard error notexceeding.03. Across the collaborating sites, approxi-mately 300 children are diagnosed annually with theeligible rare, progressive conditions and another 750 chil-dren are followed in the clinics. Therefore, about 1650families would be eligible or become eligible over the 36month accrual period. Based on previous work investi-gating recruitment and retention in a longitudinal pallia-tive care study, typically 80-90% of individuals areexpected to be receptive to research [34], so a samplesize of 300 is feasible. As with any longitudinal study,attrition will likely occur over time, but parents inpediatric palliative care often participate in research as away of helping others, even when they find it challen-ging practically (e.g., time) or emotionally (e.g., relivingmemories) [11].We anticipate minimizing attrition through employinga number of strategies highlighted in the literature[35-38]. RAs develop a solid relationship with familiesthrough an initial face-to-face visit, telephone contact atprescribed intervals, and letters to thank families fortheir participation. Continuity of RAs is expected tocontribute to the trusting relationship that is needed tohelp participants feel more connected to and interestedin the study over time. Efforts are made to respectfamilies’ time and recognize the value of their contribu-tion. RAs schedule data collection at the family’s conve-nience and regularly express verbal and writtenappreciation for their participation in the study. In addi-tion, along with the blank questionnaire package at each6-month data collection point, including at baseline, andregardless of how many family members participate,families are given a cheque for $40 as a token of appre-ciation. We expect that some parents may use themoney to help pay for respite while they complete thequestionnaires, but there are no restrictions on how par-ents can spend the token of appreciation.Data CollectionData collection is taking place along two parallel time-lines: one recording the child’s clinical symptomsmonthly and the other examining bio-psychosocial-spiri-tual aspects of the experience for family members every6 months. Instruments being used in the study aredetailed in Table 2 with information about who com-pletes each instrument and how frequently it is com-pleted. Data are also collected through chart reviews onentry into the study and at the end of the study or atthe time of the child’s death. Data collection will con-tinue for a minimum of 18 months, depending on howearly a family enrols in the study, providing a minimumof 4 data collection points. The method and frequencyof data collection were chosen based on longitudinalstudies with seriously ill adults that indicate trends/changes should be detectable with this timeline, whileminimizing burden as much as possible on individualswho already have significant burdens placed upon themdue to the nature of their caregiving experience [37,39].The questionnaire package and the timing of data col-lection were previously reviewed and discussed with par-ents of children with a life-threatening condition whohad at least one child enrolled on a hospice program.These parents agreed the study was feasible and theburden on families would not be too great.We prefer that baseline data, including writteninformed consent in accordance with institutional ethicsguidelines, are collected in person in order to establish arelationship between the RA and the family from thebeginning of the study. However, occasionally a familymay be unable to participate in a face-to-face meetingand so we have developed a telephone process forexplaining the study and arranging for families to sub-mit written consent and completed questionnaires with-out actually meeting with the RA. QuestionnaireSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 6 of 12packages are mailed to these families for initial and sub-sequent data collection. For the newly diagnosed family,baseline data ideally is obtained before changes occur,so within 4-6 weeks of diagnosis, but families where thechild has an established diagnosis may be recruited atany stage in the disease process. Assent/consent (thedistinction being based on age) is obtained from allchild participants who are cognitively able to assent/consent for themselves.No further consent forms will be signed during thestudy. Completed questionnaires signify ongoing con-sent. At each data collection point, families arereminded in the preamble to the questionnaire of theirright to refuse participation at any time or to not answercertain questions. To ensure privacy and confidentialityfor returns from multiple members of a family, separateenvelopes are included for each participating subject toseal their questionnaires before placing them in thelarger pre-paid, self-addressed return envelope.Clinical symptoms streamData about the ill child’s clinical symptoms are collectedmonthly using an online instrument designed by theresearch team in consultation with other experiencedCanadian clinicians, families, and a psychometrician.The instrument is a modification of the PediQUESTsymptom recording tool and the revised MemorialSymptom Assessment Scale (7-12), developed for symp-toms in children with cancer [40-43]. Symptoms arebeing tracked for timing of onset (symptom latency)[44], frequency, and distress. Assessed symptoms includedifficulties with breathing or respiration, feeding issues,pain, alertness and interaction, sleep issues, seizures,and constipation. Parents of children who receivedpalliative care services from the Canuck Place Children’sHospice reviewed the instrument and affirmed that itincludes the most common and/or troublesome symp-toms. The instrument takes 6 to 10 minutes to completeand parents may choose either an online or telephonemethod of completion. If the parent chooses the onlinemethod, s/he receives an email every month with areminder to visit the secure website and complete a websurvey. If the parent chooses the telephone method, theRA calls at monthly intervals to administer the instru-ment and enter the scores manually into the onlineTable 2 Instruments, Participant Who Completes, and Timing of Data CollectionInstrument Who Completes TimingDemographicInformationDemographic Sheet Completed by parent Baseline and updated every 6 monthsFamily LevelDataFamily Adaptability andCohesion Evaluation Scale(FACES III)[61]Completed separately by each parent who agrees toparticipate in studyBaseline and every 6 monthsCouple LevelDataNorton Quality of MarriageIndex[62]Completed separately by each parent who agrees toparticipate in study, when currently in spousal/common-law relationshipBaseline and every 6 monthsIndividual LevelData: Parent• SF-12[63]• State-Trait AnxietyInventory[64]• Center for EpidemiologicStudies Depression Scale(CES-D)[65]• Perceived Stress Scale[66]• Burden Scale[67]• Post-Traumatic GrowthInventory (PTGI)[68]• Spiritual Involvement andBeliefs Scales (SIBS)[69]• Grief Scale• Impact of ParticipationCompleted separately by each parent who agrees toparticipate in studyAll at baseline and every 6 months,except for Impact of Participation (after 1year and at end of study)Individual LevelData: AffectedChild• Clinical Symptoms • Completed by parent • Baseline and once a month• Pediatric Evaluation ofDisability Inventory (PEDI©)[45-47]• Completed by RA through observation or parentreport• Baseline and annuallyIndividual LevelData: Sibling• Kidcope[70] • Younger version completed by siblings age 7 to 12years; older version for 13 to 18 yearsAll at baseline and every 6 months• Child Behavior Checklist(CBCL)[71]• Completed by parent for siblings age 7 to18 years• Youth Self Report (YSR)[72] • Completed by siblings age 11 to18 years and able tocomplete by selfSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 7 of 12system while the parent reports on the child’s symp-toms. Parents were given the choice of administrationmethod for the symptoms’ instrument to allow flexibilityand accommodate any families lacking Internet access.With assistance from the RA, the parent assesses theill child for cognitive and motor ability on enrolmentinto the study and annually using the Pediatric Evalua-tion of Disability Inventory (PEDI) [45-47]. In additionto measuring functional abilities, the PEDI evaluates theamount of Caregiver Assistance and Modificationsrequired in caring for the child. Data are collected usingthis instrument from the time the family enrolls in thestudy until the time of the child’s death or the end ofthe data collection period, whichever comes first. RAscomplete the Caregiver Assistance and Modificationssection with the designated parent. To minimize poten-tial error, all RAs involved with this study were trainedto complete the PEDI by an occupational therapist.Further, to assess whether there is consistency acrossthe RAs’ ratings, inter-rater reliability testing was com-pleted. Analysis of the reliability involved calculating theIntra-class Correlation Coefficients (ICC) for the RAscores on a sample case from the manual. Excellent cor-relation among the RAs was found for Caregiver Assis-tance, with an ICC value of 0.959 overall (Self-Care:0.865; Mobility: 0.976; Social Function: 0.760). Testingon the Modifications scale showed an ICC value of0.651 overall (Self-Care: 0.550; Mobility: 0.674; SocialFunction: 0.400). Reliability was high for the CaregiverAssistance scale, and moderate-to-low for the Modifica-tion scale. RAs received feedback about ways to improvetheir administration of the tool in order to maintainongoing reliability.Health records are reviewed by the RA at baseline todocument the circumstances surrounding the diagnosisand the period leading up to the diagnosis, as well asthe prevalence and incidence of symptoms recordedsince diagnosis. If the child dies during the course ofthe study, a chart review is conducted to documentdetails of the care provided just prior to the death andthe circumstances of the death. Chart reviews also willbe conducted for living children living at the conclusionof the study.Bio-psychosocial-spiritual streamData about the bio-psychosocial-spiritual experiences offamily members are collected at 6 month intervals, fromthe time the family enrolls in the study until 6 monthsprior to the end of the study (to allow for final analysesand write-up), even if the child dies beforehand. Theoutcomes being measured in the study include: familyfunctioning; marital satisfaction; parent health, anxiety,depression, stress, burden, spirituality, grief, and growth;and sibling health and coping. Most of the measureshave demonstrated reliability and validity and have beenwidely used in previous research with similar popula-tions. The exception is the instrument used to measuregrief, which was designed by the research team in con-sultation with other experienced Canadian researchers.The instrument is a modification of the Inventory ofSocial Support (ISS), a 5-item self-report questionnaireabout what helps or makes it harder to cope with grief[48]. The questionnaire package can be completed inabout one hour, as estimated by parents who pilot-tested the instruments.Unlike the clinical symptom stream where data arecollected online or by telephone, the bio-psychosocial-spiritual instruments are completed at home and mailedto the main site. This method of data collection allowsfamily members to complete questionnaires in their ownhome, at their own pace, rather than having to committo a potentially lengthy interview time. At baseline, theRA obtains permission to meet with the family during aroutine clinic visit or at another more convenient loca-tion such as the family home, whichever is more amen-able to the family. Once the baseline visit is complete,no further face-to-face meetings with the family arerequired. If the timing is appropriate and participantswant to complete subsequent questionnaires face-to-facewith the RA, then they may do so at the clinic visit.Some of the children will likely die during the courseof the study; indeed, we already have faced this outcomewith one family. Clinicians involved with the child andfamily notify the site RA when a child dies. The RAimmediately mails a hand-written card of condolence tothe family. The RA also conducts a chart review todocument the circumstances of the death. Other datacollection is suspended for the family until 6 monthsafter the child’s death. After that time, the RA contactsthe family by telephone to express condolences to thefamily and obtain verbal agreement for continued parti-cipation in the study. Data collection in the bio-psycho-social-spiritual stream then continues at 6 monthintervals until the end of the study. Demographics areupdated at 6 month intervals throughout the study andinto the bereavement period.Analysis PlanRegardless of data collection method (in-person, on-line,telephone, or mail) all data from the multiple sites areentered into Daciforms, a single web-based database(Dacima Software, Inc., Montreal, QC). Daciformsallows researchers at multiple locations to enter andreview data online. Each study staff member is assigneda unique password and Site ID that allows secure accessto the centralized data. From Daciforms, data areexported into SPSS (IBM, Chicago) for descriptive analy-sis. Once we have sufficient data points, advanced dataanalysis and modeling will be performed using theSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 8 of 12open-source R statistical package (GNU General PublicLicense). Analysis for the clinical symptoms streaminvolves describing the frequency and severity of symp-toms based on the clinical symptom instrument. Follow-ing the examination of simple descriptive tables, we willfit longitudinal ordinal regression models including vari-ables representing condition type (neurological, meta-bolic, or chromosomal), time from diagnosis, age, andsex. We will apply both hierarchical random effect [49]and GEE (generalized estimating equation) [50] models.Akaike’s Information Criterion (AIC) [51] will be usedto select terms (including interactions) in random-effectmodels; resulting models will be re-fit using GEE to pro-vide population-level estimates.The symptom instrument includes items on changerelative to previous questionnaire administration basedon the expectation that ceiling effects will be modulatedby symptom progression. To capture this phenomenon,we are defining a “symptom breakthrough” as occurringif a symptom’s severity is at ceiling at time t butreported to have worsened at time t+1. We will applylongitudinal logistic regression models following thegeneral strategy outlined previously to describe patternsof incidence.Bio-psychosocial-spiritual measures will be analyzed ina similar manner with descriptive statistics and longitu-dinal regression models, and we will incorporate ran-dom effects to allow for correlation within respondentsover time and between respondents within families.Relationships between symptom progression and bio-psychosocial-spiritual measures will be investigated inan exploratory fashion. Due to the complex nature ofthe data analysis, it was important to involve a statisti-cian (RB) from the outset.Ethical IssuesAs part of designing the study, and in order to preemp-tively address potential ethical concerns, we consultedwith parents of children who received pediatric palliativecare at Canuck Place Children’s Hospice in Vancouver.These parents provided advice on timelines and fre-quency of data collection. Parents highlighted twoissues: (1) the crucial need for this type of research and(2) the potential need for emotional support to families.RAs are sensitive to this potential need and have beentrained in how to communicate with families and toascertain whether support is needed. In addition, adetailed list of institutional and community resources tosupport families is available for each site and is given tofamilies on admission to the study. Families also arereminded at each data collection point and in a semi-annual newsletter that the list of resources is available.The lists of local resources are updated semi-annuallyand posted on the study website.LimitationsOne limitation that arose early on was the challenge ofdefining a theoretical group of children with Quadrant 3conditions using a rigorous “Inclusion/ExclusionCriteria” checklist. Initially, clinicians were unsure whatQuadrant to categorize a diagnosis under and which chil-dren could participate. However, the evolving EligibleDisease List that was built from the ground up hasinvolved the clinicians in determining eligibility and hasencouraged their participation in refining the eventualcriteria. Rather than dictate the eligibility, the list hasbeen strengthened by ongoing discussion and iterativereview. While the current study focuses on families ofchildren with Quadrant 3-type life-threatening condi-tions, it is anticipated that the method may be applied toother groups of diseases. A similar process could be usedto identify eligibility in other studies. Researchers infuture studies could identify similarities and differencesamongst the Quadrants and build a comprehensive pic-ture of important strategies within pediatric palliativecare to ensure optimal care for all affected families.Another potential limitation inherent in the currentstudy design results from using multiple modalities ofdata collection. We chose to use multiple modalities ofdata collection (online, phone, written, and in-person)throughout the study in order to provide the most flex-ibility for participating families. There is some concernin the literature that people respond differently to ques-tions, particularly sensitive ones, based on the methodused to answer questions [52]. However, we believe thatit is most important for families to have some choice inhow they take part in the study and to choose what willfit best with their schedule, lifestyle, and familiarity withtechnology. This flexibility is important in minimizingfamily burden related to the study and attrition offamilies from the research. Our final data analysis willreveal any differences in mode of data collection and itspossible impact on the research findings.Lastly, instruments used in the study design areentirely quantitative. The published instruments demon-strate strong reliability and validity, therefore they werethe first choice for initial measurement of this unchartedpopulation. However we recognize the need for andimportance of also collecting qualitative data fromfamilies. We have already had strong feedback from par-ents about how important it is to “sit and talk” with thefamilies in order to better understand their full experi-ence. Our hope is to obtain future funding, so that wecan expand on quantitative findings of our studythrough interviews.DiscussionCharting the Territory is a distinctive study because ofthe focus on childhood conditions without cure orSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 9 of 12life-prolonging treatment; use of a prospective, longitu-dinal design; and simultaneous attention to the affectedchild, siblings, and parents. There is some reluctance toconduct research with this population because of theperceived negative impact on vulnerable families, how-ever there is mounting evidence to suggest that partici-pation in research during the illness experience andafter a child’s death is a positive experience for partici-pants and should be conducted. Some studies have high-lighted parents’ eagerness to share the story of theirchild’s illness and death and to provide input to helpother families [53-55]. While parents report that discus-sions of their child’s diagnosis and/or death are at timesdifficult, the vast majority of parents deny any negativeimpact or distress caused by participating in research[56-60]. However, very few studies have included a sys-tematic evaluation of the impact of participating in thistype of research, and none of the published studies eval-uated a longitudinal study design.To add to the small body of existing research and toguide the study team in development of future longitu-dinal studies with similar populations, we have incorpo-rated a component to evaluate the impact on parents ofparticipating in the study. This evaluation will be com-pleted by all participating parents through a written sur-vey after one year of enrolment in the study and at theend of the study. As well, at the end of the study theRA will contact the designated parent by telephone todebrief the experience and formally end the relationshipwith the family. Any suggestions for how the process orprocedures of the study could be improved upon will besought formally at that time, but families also areencouraged to provide feedback throughout the study. Ifany other family members wish to speak directly withthe RA at the end of the study to provide feedback orsay goodbye, this conversation will be arranged. A finalpersonalized thank-you and good-bye letter will be sentby the RA on behalf of the research team to the familyafter this closure call.We expect that this research will advance knowledge inthe fields of family caregiving, subspecialty pediatrics,pediatric palliative care, and bereavement by providingsome of the first-ever detailed descriptions of the clinicalsymptom trajectory and bio-psychosocial-spiritual aspectsfor these conditions. We will close gaps in knowledge andcontribute to the limited, existing body of knowledge spe-cific to Quadrant 3-type conditions in the emerging areaof pediatric palliative care. Extending existing researchwill enable policy makers and practitioners to betterunderstand the realities of families where a child has aprogressive, life-threatening condition. Baseline informa-tion about critical periods for symptom management andpsychosocial support will enable the design of appropriateintervention and support strategies.Specifically, the study will provide information tofamilies about what they might expect as the child’s ill-ness progresses; assist with the development of symptomassessment and evaluation tools, especially in non-verbalchildren; provide critical information to pediatricians,metabolic, genetics, and neurology specialists, family andchild health professionals, and pediatric palliative careclinicians that will assist them to better support childrenand families; provide a cohort and data to support inter-ventional research in symptom management and care offamilies; and lay the groundwork for future studies. Asnoted by the parents, this study will help them learnabout expected trajectories; they will then use thisknowledge in decision-making and in advocating.Currently, without this knowledge parents and healthprofessionals continue to ‘navigate uncharted territory.’In this study the map needed to anticipate outcomesand to guide informed decision-making throughout theirjourney will be developed.AcknowledgementsWe wish to acknowledge funding from the Canadian Institutes of HealthResearch (CIHR) for the New Emerging Team award (PET-69769), whichallowed us to develop the proposal for the current study. The current studyis funded as MOP-89984. Open access is a requirement of the fundingagency and was a consideration in the selection of BMC Pediatrics forpublication of this protocol. We also wish to thank the Site LeadCollaborators who liaise with specialist clinicians to facilitate access toresearch participants and guide the study through institutional ethics review,as well as monitor study progress and provide timely updates at theirrespective institutions; located in Calgary (Alberta Children’s Hospital - Dr.Sharron Spicer), Edmonton (Stollery Children’s Hospital - Dr. Dawn Davies),Toronto (The Hospital for Sick Children - Dr. Adam Rapoport), Ottawa(Children’s Hospital of Eastern Ontario - Dr. Christina Vadeboncoeur), andMontreal (Montreal Children’s Hospital - Dr. Stephen Liben), in addition tothe research assistants at the participating sites: Lauren Campbell, MarilynGordon, Jennifer MacInnis, Maryam Noghondarian, Rosa Alicia Paradelo, SilviaRegina-Zarow, Natalia Rincon, Megan Sloan and Edmund Tan.Author details1Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.2School of Nursing, York University, Toronto, ON, Canada. 3Child & FamilyResearch Institute, University of British Columbia, Vancouver, BC, Canada.4Faculty of Social Work, Wilfrid Laurier University, Kitchener, ON, Canada.5School of Nursing, University of Victoria, Victoria, BC, Canada. 6Faculty ofNursing, University of Toronto, Toronto, ON, Canada.Authors’ contributionsAll authors made substantive intellectual contributions to conception anddesign of this study and manuscript. HS and RS were the lead authorsresponsible for initial drafting of the manuscript. All others, especially KWand GA in the early revision stages, revised it critically for importantintellectual content. RB ensured the accuracy of the statistical information.All authors read and approved the final manuscript.Authors’ informationDr. Harold Siden, MD, MHSc, FRCPC Clinical Associate Professor, Faculty ofMedicine, Department of Pediatrics, University of British ColumbiaDevelopmental Neurosciences & Child Health, University of British Columbia4480 Oak Street, Room F612A Vancouver, BC V6H 3V4 Canada Tel: (604) 875-2776 Fax: 604-875-2384 E-mail: hsiden@cw.bc.caDr. Rose Steele, RN, PhD Professor, School of Nursing Room 342 HNESBuilding York University 4700 Keele Street Toronto, ON M3J 1P3 Canada Tel:(416) 736-2100 ext. 40556 (work) Fax: (416) 736-5714 E-mail: rsteele@yorku.caSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 10 of 12Dr. Rollin Brant, PhD Professor, Department of Statistics University of BritishColumbia Child and Family Research Institute 4480 Oak Street, L408Vancouver, BC, V6H 3V4 Canada Tel: 604-875-2000 x5389 Tel: 604-875-3570(main office) Fax: 604-875-3569 E-mail: rollin@stat.ubc.caDr. Susan Cadell, PhD, MSW Associate Professor Director, Manulife Centre forHealthy Living Lyle S. Hallman Faculty of Social Work Wilfrid LaurierUniversity 120 Duke St. West Kitchener, ON N2H 3W8 Canada Tel: (519) 884-0710 Ext. 5252 (office) Fax: (519) 888-9732 E-mail: scadell@wlu.caDr. Betty Davies, RN, PhD, FAAN Professor Emerita, School of NursingUniversity of California San Francisco Professor and Senior Scholar, School ofNursing University of Victoria PO Box 1700 STN CSC Victoria, BC V8W 2Y2Canada Tel: (250) 721-6467 Fax: (250) 721-6231 E-mail: betty.davies@nursing.ucsf.eduDr. Lynn Straatman, MD, FRCPC Clinical Assistant Professor, Faculty ofMedicine, Department of Cardiology, University of British Columbia c/oCanuck Place Children’s Hospice 1690 Matthews Ave. Vancouver, BC V6J 2T2Canada Tel: (604) 806-9356 (office) Fax: (604) 806-8763 E-mail: Lynn.Straatman@vch.caKimberley Widger RN PhD(c) CHPCN(C) Lawrence S. Bloomberg Faculty ofNursing University of Toronto 155 College Street, Suite 130 Toronto, ON,M5T 1P8 Canada Tel: 416-946-3928 Fax: 416-978-8222 E-mail: kim.widger@utoronto.caGail S Andrews, MEd Developmental Neurosciences & Child Health Universityof British Columbia 4480 Oak St., Room F615 Vancouver, BC V6H 3V4 CanadaTel: (604) 875-2000 Ext. 5345 Fax: 604-875-2384 E-mail: gandrews@cw.bc.caCompeting interestsThe authors declare that they have no competing interests.Received: 24 June 2010 Accepted: 20 September 2010Published: 20 September 2010References1. Statistics Canada: Mortality, summary list of causes. Ottawa 2003 [http://www.statcan.gc.ca/pub/84f0209x/84f0209x2003000-eng.pdf].2. Public Health Agency of Canada: Economic burden of illness in Canada,1998. Ottawa 1998 [http://www.phac-aspc.gc.ca/publicat/ebic-femc98/pdf/ebic1998.pdf].3. American Academy of Pediatrics. Committee on Bioethics and Committeeon Hospital Care: Palliative care for children. Pediatrics 2000, 106:351-357.4. 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Spirito A, Stark LJ, Williams C: Development of a brief coping checklist foruse with pediatric populations. J Pediatr Psychol 1988, 13:555-574.71. Achenbach T: Manual for the Child Behavior Checklist/4-18 and 1991 ProfileBurlington, VT: University of Vermont Department of Psychiatry 1991.72. Achenbach T: Manual for the Youth Self-Report and 1991 Profile Burlington,VT: University of Vermont Department of Psychiatry 1991.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/10/67/prepubdoi:10.1186/1471-2431-10-67Cite this article as: Siden et al.: Designing and implementing alongitudinal study of children with neurological, genetic or metabolicconditions: charting the territory. BMC Pediatrics 2010 10:67.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitSiden et al. BMC Pediatrics 2010, 10:67http://www.biomedcentral.com/1471-2431/10/67Page 12 of 12


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