Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

School Sampling Frame = QED National Longitudinal Study of HS Adolescent to Adult Health HS HS HHS HS Feeder Feeder Feeder Feeder Feeder

Sampling Frame of Adolescents and Parents N = 100,000+ (100 to 4,000 per pair of schools)

Ethnic High Educ Samples National Academy of Sciences Workshop Black Disabled Sample February 10-11, 2014 Saturation Puerto Rican Samples from 16 Schools Chinese Guidelines for Returning Individual Results from Genome Research Using Population- Main Sample 200/Community Based Banked Specimens Genetic CubanCuban Samples Carolyn Tucker Halpern

University of North Carolina at Chapel Hill Unrelated Pairs Identical Fraternal Twins Full Sibs Half Sibs in Same HH

Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

In-School In-Home Administration Administration Race and Ethnic Diversity in Add Health

Wave I School Adolescents Race/Ethnicity N Unwtd. % Students Parent 1994-1995 Admin in grades 7-12 90,118 17,670 Mexico 1,767 8.5 (79%) 144 20,745 Cuba 508 2.5 Wave II School Adolescents Central-South America 647 3.1 1996 Admin in grades 8-12 Puerto Rico 570 2.8 (88.6%) 128 14,738 China 341 1.7 Wave III Young Adults Philippines 643 3.1 Partners 2001-2002 Aged 18-26 1,507 Other Asia 601 2.9 (77.4%) 15,197 Black (Africa/Afro-Caribbean) 4,601 22.2

Wave IV Adults Non-Hispanic White (Eur/Canada) 10,760 52.0 IIV Study 2007-08 Aged 24-32 Native American (non-Hispanic) 248 1.2 ~ 100 (80.3%) 15,701 Total N 20,686 100.0

Adults Missing on race/ethnicity=59 Wave V Aged 31-42 2015-18 Target: 19,831

1 Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Biomarkers in Add Health Biological Data across Waves Transition to Adolescence Young Adulthood Adulthood Adulthood Wave I-II (Ages 12-20) Wave III (Ages 18-26) Wave IV (Ages 24-32) Wave V (Ages 31-42)

Embedded genetic sample of ~3,000 pairs

Physical development

Height, weight Height, weight Height, weight, waist Height, weight, waist

STI tests (urine) Metabolic Metabolic

HIV test (saliva) Immune function Immune function

Genetic Inflammation Inflammation (buccal cell DNA)

Cardiovascular Cardiovascular

Genetic Genetic (buccal cell DNA) (whole blood)

Medications Medications Kidney

Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Non-Genetic Biospecimen Participation Genetic Biospecimen Participation

• 99% Height, weight, waist (all Waves) • Wave II – Saliva: determine zygosity • 95% Saliva (Wave III; HIV) – Same-sex pairs in genetic sample – 66% participation • 92% Urine (Wave III; STIs) • Wave III • 99% Blood pressure (Wave IV) – Buccal cells: candidate – Full sibs, twins in genetic sample • 94% Blood Spots (Wave IV; Metabolic, immune, – 83% participation inflammation; 76% archived) • Wave IV – Buccal cells: candidate genes and genome-wide analysis – Entire Add Health sample – 96% participation for candidate markers – 78% archived for GWAS

2 Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Evolving Content of DNA-Related Consent Wave III Candidate Markers

• DAT1: Dopamine transporter 40 base pair (bp) Variable Number • Wave II zygosity test (1 page) Tandem Repeat (VNTR) in the 3’ untranslated region of the – “Receive results in about 6 weeks……all biological • DRD4: 48 bp VNTR in the third exon of the dopamine D4 receptor samples will be destroyed” gene • 5HTTLPR: 43 bp addition/deletion in the 5’ regulatory region of the • Wave III (1 page) serotonin transporter gene • MAOA: 30 bp VNTR in the promoter region of the monoamine • Wave IV (5 pages) oxidase A gene – “Understand how variations in genetic make-up, in • DRD2: TaqIA single nucleotide (SNP) in the dopamine D2 receptor combination with environment and life experiences, • CYP2A6*2: T→A substitution in exon 3 (rs1801272) of the may contribute to long term health” cytochrome P450-2A6*2 gene – “Storage for future research studies…also related to • COMT: val158met SNP (rs4680) in the catechol O- long term health, but would not be diagnostic tests to methyltransferase gene detect disease.”

Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Wave IV Candidate Markers Status of Genome-wide Genotyping

• VNTR and STR Genotyping • 12,216 specimens were archived – Monoamine Oxidase A Upstream VNTR – Dopamine D4 Receptor Exon 3 VNTR • To date, ~9,500 specimens processed – Dopamine Transporter (SLC6A3) 3’-Untranslated Region VNTR – Serotonin Transporter-Linked Polymorphic Region – Analysis of genetic pairs (~2000) complete – “Triallelic” HTTLPR (LALGS; TRI) • ~2,500 additional specimens being processed – Dopamine D5 Receptor Dinucleotide Repeat in the 5’ Region – Monoamine Oxidase A Dinucleotide Repeat • Illumina HumanOmni1-Quad v1.0 and 2.5 Chips • SNP Genotyping – Dopamine D2 Receptor TaqIA SNP rs1800497 in the 3’ UTR • Near completion: Quality Control paper on pairs – Catechol O-Methyltransferase (COMT) val158met SNP rs4680 (RS4680) • Preparing to deposit pairs GWAS data into dbGaP – Serotonin Transporter (5HTT, Symbol SLC6A4) rs12945042 (RS12945042)

3 Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Return of Biomarker Information to Add Issues Regarding Return of Genetic Data Health Respondents in Research Studies • Wave II • Associations, not diagnostic – Parents of twins received Zygosity information • Experimental methods • Wave III (Rs all 18+ years) • Imprecision, inconsistency, risk of false positives – HIV – Gonorrhea and Chlamydia • Few markers are “clinically actionable” • Wave IV • Could do more harm than good – Blood pressure (& recommendations for follow-up) – Raise irrelevant concerns BUT – Research needed: benefits/harm from returning – No blood spot result data – tests considered results experimental – No genetic data

Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Issues Regarding Return of Genetic Data Add Health Project Team in Research Studies • Diverse, multi-racial/ethnic, genetically admixed • Kathleen Mullan Harris, PI & Director populations • Carolyn Tucker Halpern, Co-I & Deputy Director – Strength of association may vary substantially among • Eric Whitsel, Co-PI Project subpopulations – How to decide what is “important” for whom? • Nancy Dole, Co-PI Biology Project • Lack of resources to • Jon Hussey, Co-investigator – Return results to participants • Joyce Tabor, Add Health Data Manager – Answer questions that then arise • Ley Killeya-Jones, Add Health Project Manager – Provide tailored, professional counseling • Sarah Dean, Assistant Project Manager

4 Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Add Health Co-Funders • Eunice Kennedy Shriver National Institute of Child Health and Human Development* Add Health Web Page • National Cancer Institute* • National Center for Health Statistics, Centers for Disease Control and Prevention, DHHS • National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, DHHS* • National Center for Minority Health and Health Disparities* http://www.cpc.unc.edu/projects/addhealth • National Institute of Allergy and Infectious Diseases* • National Institute of Deafness and Other Communication Disorders* • Online code books • National Institute of General Medical Sciences • National Institute of Mental Health • National Institute of Nursing Research* • User guides to inform data analysis • National Institute on Aging* • National Institute on Alcohol Abuse and Alcoholism* • Bibliography of Add Health publications • National Institute on Drug Abuse* • National Science Foundation* • Office of AIDS Research, NIH* • Information about the bi-annual Add Health • Office of the Assistant Secretary for Planning and Evaluation, DHHS* • Office of Behavioral and Social Sciences Research, NIH* Users Conference in Washington DC, June 2014 • Office of the Director, NIH • Office of Minority Health, Centers for Disease Control and Prevention, DHHS • Information about public-use and restricted-use • Office of Minority Health, Office of Public Health and Science, DHHS • Office of Population Affairs, DHHS* data access • Office of Research on Women's Health, NIH* Data made available to more than 4 .*Wave 4 co-funders

Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Extra slides Pairs of Individuals in Embedded Genetic Sample, Add Health Sibling Type N Twin 784 Monozygotic 307 Dizygotic 452 Undetermined 25 Full Sibling 1251 Half Sibling 442 Non-related 662 Adopted (single individuals) 560

5 Social, Behavioral, and Biological Linkages Across the Life Course Social, Behavioral, and Biological Linkages Across the Life Course

Add Health Choice of Biological Data Wave IV Consent for DNA Collection by race/ethnicity n (%)* • Biological states that are reasonably prevalent in the general population of youth & young adults Race/Ethnicity To Collection To Archive Hispanic 2,393 (96%) 1,883 (75%) • Biological states and processes theoretically and/or Black, Non-Hispanic 3,348 (96%) 2,523 (72%) empirically linked to future health White, Non-Hispanic 8,051 (97%) 6,822 (82%) • Measures that can characterize those processes Other, Non-Hispanic† 1,335 (95%) 997 (71%) • Feasible for a large scale, national field study All 15,140 (96%)‡ 12,234 (78%)‡ • Valid and reliable *Unweighted number and percentage, excluding four incarcerated respondents for whom saliva collection was prohibited. • Appropriate for longitudinal designs †Asian, American Indian, or other. ‡13 respondents with missing Wave I race are included in the Consent to Collection totals; 9 respondents • Non-invasive, cost-efficient, practical missing Wave I race are included in the Consent to Archive totals.

Social, Behavioral, and Biological Linkages Across the Life Course

Behavioral, Social, Contextual Content Across Waves Waves I, II Wave III Wave IV Demographic Demographic Demographic Family, siblings, friends Family, siblings, friends Family, siblings, friends Education, work Education, work, military Educ, work, military (records) Physical and mental health Physical and mental health Physical and mental health Daily activities and sleep Daily activities and sleep Daily activities and sleep Relationships Relationships Relationships Sexual, & fertility histories Sexual, & fertility histories Sexual, & fertility histories Substance use Substance use Substance use and abuse Delinquency and violence Involvmt w/criminal justice sys Involvmt w/criminal justice sys Attitudes, religion Attitudes, religion Work attitudes and chars, relig Economics, expectations Economics, expectations Economics, expectations Psychological, personality Psychological, personality Big 5 Personality, stressors Children and parenting Children and parenting Civic participation Civic participation Gambling Cognitive function Mentoring Psychosocial factors

6 HRS exists to serve the needs of research on aging

• Created by US NIA(NIH) in 1992 in response to Health and Retirement Study a review of research needs in late 1980s • Congressional mandate to NIA to create it • Michigan won a competitive bid to conduct it • A cooperative agreement with NIA David R. Weir Principal Investigator

HRS Co‐Investigators HRS and NHANES

 Nationally representative sample

Charles C. Eileen M. Michael D. Sharon Kenneth Helen G. John J.  Rapid public data release Brown Crimmins Hurd L.R. Kardia M. Langa Levy McArdle  + Multi‐disciplinary content  ‐ Population 50 and older  Longitudinal study

Kathleen Olivia S. Mary Beth Jacqui Robert B. David R. Robert J.  Under Michigan IRB, not PRA/OMB McGarry Mitchell Ofstedal Smith Wallace Weir Willis  Confused about what results to report

•1 Impact: Number of New Peer‐Reviewed Size Journal Articles per Year Using HRS

• From 1992 through 2012: 160 • Over 37,000 people were interviewed at least 140 120

once 100 • 200,000 interviews were completed 80 • 8,000 workers retired 60 40

• 13,000 people have died 20 – 10,500 interviews with their survivors 0

Some key innovations HRS philosophy: measure many things pretty well • Highly structured CAPI/CATI – Over 5,000 possible questions • Average interview gets about 400 • We don’t aim to replace other national • Administrative linkages to Social Security surveys on specific topics (earnings histories and benefits) and Medicare (health care) • We do match them pretty closely • Biomarkers starting in 2006 – Blood spots, physical performance • data on ~20,000 people

•2 Systolic blood pressure: HRS Mortality by Cohort Compared with Life HRS vs NHANES Tables

100% 1 90% 0.9 level 80% hrs us 70% 0.8 hrs indicated

60% Hypertension coda us 50% NHANES 2005‐08 0.7 above HRS 2006 coda BP 40% 0.6 HRS 2008 wb us

with 30% wb 20% 0.5 ahd us Percent 10% ahd 0.4 0% 90 100 110 120 130 140 150 160 170 180 190 200 mmHg 0.3 1993 1995 1997 1999 2001 2003 2005 2007

Median Wealth of Households 55 and Genetics in HRS Older—SCF and HRS (2008 dollars) • Began collecting DNA in 2006 250,000 • Oragene (saliva) • Stored in repository, no funding or definite plans 200,000 for wide‐scale use • GWAS model identified as most appealing for HRS 150,000 SCF – Broad coverage of genome permits exploratory work HRS in a wide range of health and behavioral phenotypes 100,000 • Esp. longitudinally defined phenotypes – Rich genetic data for use in social science models 50,000 • Instrumental variables, Mendelian randomization, etc – Preferable to do centrally, general access 0 1996 1998 2000 2002 2004 2006 2008 2010 2012 – Preserve samples in repository for future use

•3 ARRA

• NIA RC2 AG036495 • NIA RC4 AG039029 (Common Fund)

• samples collected in 2006, 2008, Health and Retirement Study (HRS)

2010, and 2012 ~ 20,000 total dbGaP Study Accession: phs000428.v1.p1 • Illumina 2.5m SNP chip There are 76 authorized requests associated with this study. • + exome chip • CIDR for genotyping, U Washington for QC – And imputation to 1000 genomes 22 m SNPs

HRS Policy on Reporting Results from HRS Approach to Confidentiality Non‐Genetic Data • Careful evaluation of risk • Public data –low risk of re‐identification, low to • Separate signed consents for performance moderate sensitivity measures, blood spots, and DNA (saliva) – Register on website, check box not to identify • Sensitive data –low risk of re‐identification, moderate • We report blood pressure, HbA1c, total and to high sensitivity HDL cholesterol (relatively quickly) – e.g., cholesterol level, detailed Rx meds – Signed and countersigned agreement not to identify • We do not report CRP or cystatin‐C • Restricted data –no direct identifiers but moderate risk • Things that are well understood and of re‐identification – E.g., de‐identified Medicare records, de‐identified GWAS commonly used in clinical practice are – Onerous requirements reported

•4 Consent Rates of New Respondents, Consent and Reporting for DNA by Race/Ethnicity (HRS 2010)

• HRS adopted a broad general‐use release 86 • DNA specimen collected separately, consented separately, no confusion about what biospecimen 84 will be used for what purpose 82 • No return of genetic results is promised 80 DBS DNA • UM IRB determined that dbGaP represented a 78 significant departure from information given to respondents in earlier consent 76 – Revised consent for later years 74 – Re‐informed early participants, offered opt‐out White A‐AHispanic – About 100, fewer than 1% opted out

Questions • Clinical value of information contained in samples given at one point in time increases as time moves THANK YOU forward – How far back does obligation to report extend? • Genome is heritable http://hrsonline.isr.umich.edu/ – Obligation to later generations vs privacy of participants? • Population research studies don’t advise people on their risks or how to manage them – How much genetic counseling to provide with results? • No‐return consent is an agreement, so criteria to violate that agreement should be higher than just some possible small benefit – How do we set a standard for compelling need to return?

•5 Agenda

• Quick introduction to the WLS – Design and Data • Genetic data Wisconsin Longitudinal Study • Consent procedures Center for the Demography of Health and Aging • Disclosure issues University of Wisconsin-Madison with support from the National Institute on Aging since 1991

what the WLS offers The “Happy Days” cohort •publiclongitudinal survey data following a cohort of 10,000+ Wisconsin high school graduates from ages ~18 to ~74 (and beyond?) • survey data from multiple participants • diverse administrative record data • information about many domains of respondent lives, and those of other family members • high response rates • however: WLS respondents are all high school graduates and almost all whites (rather like 2/3 of Americans of their cohort, but not like everyone)

1 The “Happy Days” cohort high school parents friends

1957 sibling graduate

wife or wife or husband husband children children

relational structure of data in the WLS

where are WLS graduates?

# # # # # # # # # # # # # ## ##### ## #### Survey Operations ### ###### # ##### # ### ##### # ##### # #### # # # ### # # # # ## # # # ## ## # ## # ## # # # # # # # # # # # # # # # # # # # # # # # ### ## # ## # # ## ######## # # # ######### # # # #### # # # # # # # # # # # # # # # # # # # # # # # # # # # # ## # # # # # # # # ## # # # ### # # # # # # ## # # # # # # # # # # ## # #### ## # # # # ### # # # ###### # # # # # # # ## ##### # # ## # # # # # # # # # ##### #### # # ### # ## ## # # # # ## ## # # # # # # # # # # # # # # # # # # # # # # # # # # ## # # # # # # #### ###### # # # # # # ### # # # ## ## ##### # ####### # # ## # # # # # #### ## # # ## # # # ### # ## # ### # # # # # # ######### # # ## # # # # # ## ####### # ## # # # ## # # # ########## #### # # # ## ## ## ## ## ## # # ##### # ## ## # # # # # ## # ## # ## ### # ###### # # ## # # ### ## # ### ### ### ## # • 1957 school survey # # ########## ## ##### # ## ### ### # # # ## # # # # # # ## # # # ## # ## # # ### #### # ## # ##### #### # # # ##### ## # # # # ###### ######### ## ##### ##### # # ## ## ##### ## ###### ### # ####### #### #### # # # # ### ## ## # # # # ##### # ######### # # # # ### ############ ##### # ### # ## ### # # # # # # # # # # # ############### ### # # ######## ### ########################### # # ############### ##### # # # # # # # # ##################### #### ###### #### ### ##### ##### ###### #### ## ######## # # # # # # # ################ ###### ## # ############ ##### ###### ### ## # ###### # ###### ######### # # # ### # # ####### ### # # # ##### ## ###################### ## ##### ########################## # # ####### # # # ### # ### #### ## ### ##### ### # #### ################## ###################### # # # # # ## ## # # # # # # # # # ## # # ## # ## ############ # ################### ## ##### # # # # # # ## # ### # # # # # # # # # # # ### #### ### # ######## ####################### ##### ############### ## # # # # # # ##### ### # # ### ## # # ### ## # # ################# ######## ### # # # # ### # ## ### # # # # # # ## # # ####################### ##### ##### # # ### # # ## # # # # ### ###### ## # ### #### # ## ######## ######### # # # # # # # # # ##### # # ### ############ ##### ##### # ## ##################################### ### # # # # # # # # # ####### # # ########### ## ## ## ####################### # # # # # # # # # ######## # # ###### ##### ### # ################### # # # # # # # # # # # ########### ######### ######### ############## # # # # # # # # # # # # # # # ######### ######### ################# ############ # # ## # # # ## # # # # # ### ####### ## ####################### # # # # # # # # # ######### ##### ######################## # ## # # # # # # ## # # # ## # ### ########################################################### # ## # # ## ### # # # # # # # # # # # # # # ### #### ############################### ##################################### # #### # ##### # # # ## ### # # # ## ##### # # #################### #################### # ## ## ## # # # # ## # ### ##### ######## ## ### ########## #################### # # ### # ## ## # # ## ## ###### ## #################### ##################### # ### # # # # # • 1964 parent post-card # # ## ### ### # # ############# ########### #################### # # # # # # ### # # ###### # ### # # ####### # # # ## # # ## # # # ## # # ### # ####### ### ## ### ####### # ###### ## # # #### # # # ## # # # ### # # ### # ##### ########## # # ## # ## # # # # # # ### # ### ########## # # # # ## # # # # # # # # # # ######## ### #### # # # # # # # # # # ############ # # # # ## # # # ## # # # # ## # # # # # # ############## # ## # # # ## # # ## ## ## # # # # ## ### # ############ # ## # # # # ## # # # ## # # # # # # # ## # ### # ## ## ## # # # # # ## # # # # # #### # # # # # # # ## ##### # # # # # # ### # # # # # # ## ## ## # ## # ### # # #### # # # # # # # # # # ### # # # # ### # # #### # # # # # # ## # # # # ### # #### # #### ## # # # # # ## # # # # # ## ## ### ## ## # # # # # # # # # # # # # # # ## # ## # # ## # # # # #### # # # # # # # # ### # ## # # ### ### # ## # ## # ## # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # ## # ## # # #### # # ## # ## ## # # ## ## # # ## # # # # # ## # ## # ### # ## ###### ## # # # # ## # # ## # # # ## ## ## ## ## ## ## ## # # # # # ####### ### # # ## # # # ## # # # # # ### ### # ## ## ### ## # # #### # # ## # ### # # ## # ######## # ## # ## # # # ##### #### ###### # • 1975 graduate telephone survey ##### # # #### # # ###### # # # # ## ## #### #### # ######## # # # # ## # # # # ## # # ### # ##### ## # # # # # # # # # # # # # # # # ####### # ## # # ## # ## ## # # # ## ## # # # # # # # ## ## # # # # # ## # # # ## # # # # # # # # # # # # # # # # # # # # # ### # ### # # # # # # # ### # # # ## # # # # #### # # # ## # # # ## # # ###### # # ## # # # ## ### # ## # # # # ##### # # # # ### # ### # # ## ### # # # # ## ### # # # # # # ## # # ### # # ## # # # # # # # # # # # # # # # # ## # # # # # # # # # ### # # # # # # ##### # ## # # # #### # # • 1977 sibling telephone survey # ## # # # # ## # # # # # # # # # # # # ### # # ## ## # # # # # # # # # # ## # # # # # # #### # # # # # ## # # # # # # # # # # # # ## # # ## # # # # # # # #### # # # # # ###### #### ## # # # # # ## # # ### # # ## #### ## # ## # ### ## ## # # ## # # # # ### # # ## ########## # # # # # # # # # ## # # # # # #### ######### # # # # # # # # ## # # ### ## # ## ## # # # # # ## # ## # ##### ############ # ## # ## ## # # ## # # # # # # # ####### # # # # # # # # # ## # #### ## # ### # # # # # ## ### # # # # ##### # # # ## # ## ### # # # ## ### # # ## # # # # # # # # # # # # # # # # # # # # # # # # ## # # ## # # # # # # # ## # # # # # # # # # ## # # ## # # # #### ## # # # # • 1992-94 grad and sib telephone and mail ## ####### # # # # ## # # # ##### ######## # # ## # # ## # # ## # # ####### # ## # # # ######## # ########## # # # # ###### # # ##### # # ### # # # # ## # # # ## # # ## ## # # # # # ## # # # # # # # # # # # # # # # # # # # # # # # # # # # # # ### # # # # #### # ## # ## ### # # # # # # # # ## ##### # # # # ### ## # # # # ## # ##### # # # # # ### ## # ## # ## ### # # # # # # # # # # # # # # ## # # # ## • 2004-06 grad, sib, and spouse telephone and # ## # # ## # # # # # ## # # # # # # # # # # # # # # # # # # # ## # # # # # # # # # ## # # # ## # # # # ## # # # # # ## # # # ## # # # # ## # # # ## # # # # # # # # ### # # ## # ### # # # ## # # ## mail # ##### # # # ## # ## # #### # # # # ###### # # # # ##### # #### ### # ## # ### # # ###### # ######## # ##### ## # # # ## # # # # # # #### ## ## # # # # # # # # # # #### #### # ### ## ### ## ##### # # ##### ## # # # # ## ## # # ## ## # ## ## ## # ## # # # # # # # # ### # ## # ### ### ### #### • 2007 onward – saliva collection # ##### ### # # ## # # # ### ### ## #

## ## # # # # • 2010-12 grad, sib home interviews and mail # ## ##

# #

#

#

2 some domains where WLS data plus: much non-survey data: are especially strong • high school standardized test scores (Henmon-Nelson Test in freshman and junior years) social/family • high school class rank physical/mental health • parents’ occupation and income (tax records), 1957-60 background income and wealth • college and employer characteristics • links to National Death Index educational history retirement and pensions • geocodes of addresses • elementary and high school resources (from state archives) employment history cognitive performance • high school yearbooks (for ~83% of all graduates) job characteristics • State disability claims leisure time activities • DNA from Oragene for graduates and siblings (N = 9000+) marital history • And soon, Social Security earning and benefit histories and stressful life events Medicare records children

methodological features biomarkers, and …

• interviews by random replicates • several measures of BMI • bracketing amounts with random anchors • facial characteristics: attractiveness, smiles, and facial mass (from high school yearbooks) • selecting special children (supplemental • DNA collection with Oragene saliva kits from interview and survey) grads (and siblings) • cognitive measurement • experience with Medicare D • health vignettes (WHS) • home interviews of graduates and siblings with • recording interviews anthropometric and performance measures in the new round, 2010-11 (age 71-72)

3 WLS 2010-11 Consent for Saliva Collection Leave Behind SAQ • Repeat of previous measures • One of three signed consent forms • Economic Literacy –Medicare • Economic Games –Saliva – Subset of cases play for real-stakes – Social Security earnings •Elder abuse • Medication Inventory • Unrestricted use for group analyses • Labs not qualified for medical diagnostics • No competence to provide medical advice • No information feedback, ever

Analyses of DNA availability/access of wls data • Currently have 9000 samples from graduates, including ~2000 from sibling • commitment to easy public availability of pairs all permissible data • Successful assays for graduates and siblings • many tools on the web to facilitate use of • 95 SNPs for candidate genes related to AD, WLS data and access to publications breast cancer, cognition, depression, • longitudinal data with a large sampling diabetes, impulsivity, fertility, longevity, fraction provides particular challenges obesity, etc. for maintaining confidentiality • Separate assays for FMR1 (Fragile X • Genomic (and some other restricted) syndrome) data may only be analyzed within a • Application underway for GWAS secure data enclave, whether at Madison or elsewhere

4 Disclosure Issues Mortality by general health in 1993 40 • Suicidal ideation

•Child abuse 30 •Elder abuse • Lake fish consumption 20 • End of life planning •Symptoms 10 Mortality by 2004 • Anesthesia 0 • General health VERY POOR FAIR EXCELLENT POOR GOOD • Genetic information General Health in 1993

WLS internet resources (use Google) • questions? write to [email protected] • public data users – http://www.ssc.wisc.edu/wlsresearch/ – documentation – bibliography and publications – variable search aids – downloadable data • small grant program – http://www.ssc.wisc.edu/wlsresearch/pilot/ •private web – proposals, instruments, manuscripts • respondent web – http://wisls.org

5 Wisconsin Longitudinal Study Center for the Demography of Health and Aging University of Wisconsin-Madison Currently funded by National Institute on Aging

6 National Children’s Study

• The National Children’s Study is a national longit itdiludinal stdtudy of env ironmen tltal iflinfluences National Children’s Study Presentation on children’s health and development for the authorized by the Children’s Health Act of 2000 National Academy of Sciences Workshop on • “Environmental influences” broadly defined to Guidelines for Returning Individual Results from Genome include physical, chemical, biological, and Research Using Population-Based Banked Specimens psychosocial • A data acquisition resource and not a Jack Moye, Jr., MD conventional study U.S. Department of Health and Human Services National Institutes of Health Centers for Disease Control and Prevention • Majority of biospecimens and data intended to U.S. Environmental Protection Agency be analyzed in future February 10-11, 2014

NCS Structure and Status Comparison of NCS with NHANES

•Current major components of the NCS NCS NHANES •Vanguard Study: pilot phase - runs for 21 years - Legislation Children’s Health Act National Health began accrual 2009 - ~5,000 families in 40 of 2000 Survey Act of 1956 locations throughout the U.S. currently enrolled Design Longitudinal Cross sectional •Main Study: exposure-response phase - runs for 21 Sample size 100,000 10,000’s years, several years time shifted from Vanguard Entry age Prenatal/newborn Infant through adult Study Stored sample types Multiple Serum, plasma, urine •Substudies: studies within studies (e.g., recruitment, sampling) Stored DNA/co nse nt All participants Participants aged ≥20 for genetic testing years •Formative Research and Supplemental Repository linkage Methodological Studies: short term, limited studies Unlinked Linked focused on methods development to support and Pregnant participants Many Few inform the Vanguard and Main Studies Child participants Many Few

1 Current NCS Return of Results Return of results continuum Strategy: Informed Consent

Sisters, BioVUNCS, NHANES PGP • NCS consent process is designed to tell the participant None Some All “Research use only” How to choose? Equal partners • what we would like to collect and why, (RUO) Who decides? • how we would collect it, how we would protect it, What can be done? • results we can share with them at the time of a given visit, and What should be done? • when and under what circumstances we may Who should decide? contact participants to ask if they would like to receive individual research results

What you should know about What you should know about joining the National Children’s joining the National Children’s Study Vanguard Study Study Vanguard Study

• How can I find out about the results of the • How can I find out about the results of the Study? Study? • “…We will share what we learn from the Study as a • “…We plan to test most of your samples in the whole. We will keep in touch through newsletters, future

on our Web site, and in other ways.  At this time, we do not know when these tests will be done, which tests will be done, and when information • “…We will share some information we learn about from the tests will be available you and your child with you when it is available A committee of doctors, scientists and community • “f“…If we k now th e resul lfts from tests we d ddo during a members (the iSMOC) will adv ise the StdStudy on whic h visit, we will share them with you then. For tests may provide information about participants’ example, we will tell you information about your health height, weight, and blood pressure…” When test results related to your health and your child’s health are available, we may ask you if you want to learn about them…”

2 National Children’s Study: Vanguard Considerations Informing the NCS Study Informed Consent for Pregnant Women’s Study Participation Approach to Return of Results

• Personal health information may be important to • “…I…I understand that these samples may be partici pant s even if test s are cond uct ed someti me i n used for a variety of tests in the future, the future including genetic tests. • Some tests for the evaluation of samples are known • “…I understand that I will not routinely get at the time of collection; others are not yet determined results back from tests done on the samples I give to the study • Some tests require delayed or future laboratory analysis, others can be reported immediately • “…I give my permission for the Study to use my biological samples to obtain my genetic • Some tests could inform current medical care; others information…” have unknown implications • Availability and salience of testing can change over time

Current NCS Return of Results Individual Research Result Strategy Considerations Health Impact Categories

• Current NCS return strategy is informed by: Health Impact Examples • Identification of analyses to be conducted with Study Descriptive health information Height, weight samples (what will be tested for) Clinically non-significant Routine genomic DNA copy • Characteristics (certification, accreditation) of analysis number variation (e.g., AMY1) source (how will testing be done) • Applicable clinical and regulatory standards and current Clinically significant practice • Medical actionable Elevated BP, blood Pb; APC or BRCA gene • Timeframe in which analysis can be completed and • Not medically actionable Alzheimer’s, spinocerebellar research results made available for potential reporting ataxia • Potential health impact of research result based on Unknown clinical significance Environmental chemicals with clinical significance and medical actionability no agreed upon critical values

3 Advice and Oversight for NCS Ongoing Development Process for Strategy on Return of Results NCS Return of Results Strategy

• Consultation with NCS Federal Advisory Committee and independent Study Monitoring and Oversight • The independent Study Monitoring and Oversight Committee Committee (iSMOC) (iSMOC) de term ines w hic h, how, an d w hen fin dings w ill be reported (including individuals, groups, communities) • Return warranted if “clinically significant and medically actionable” • When iSMOC identifies an analysis, a standard, and determines if results are clinically actionable, a recommendation is made to • Procedure: Recall/consent  repeat  refer the Study Director • Current experience limited to environmental • The Study Director, in consultation with others, determines if and contaminants and clinical chemistries – e.g., how the recommendation should be implemented elevated blood metals, water contaminants • This may include returning results to participants, consulting with exceeding EPA maximum contaminant level and reporting to oversight bodies, revising the study protocol • Further input sought for planned future analyses • If the NCS Return of Results policy is revised, this information is incorporated into Study materials

National Children’s Study NCS Repository Sample Receipt Information

Visit the NCS Website • http://www.nationalchildrensstudy.gov/

Contact us via email • mailto:[email protected]

4 Genomes are big 3.1 Billion base positions

Returning data to participants: 2.9 billion positions Understand Your Genome Symposium called 3.3 million variants Tina Hambuch, PhD, dABMG 10 February 2014, NHANES 1.5 million variants in genes 21,000 coding 9,600 NS 73 Stop

© 2013 Illumina, Inc. All rights reserved. Illumina, IlluminaDx, BaseSpace, BeadArray, BeadXpress, cBot, CSPro, DASL, DesignStudio, Eco, GAIIx, Genetic Energy, Genome Analyzer, GenomeStudio, GoldenGate, HiScan, HiSeq, Infinium, iSelect, MiSeq, Nextera, NuPCR, SeqMonitor, Solexa, TruSeq, TruSight, VeraCode, the pumpkin orange color, and the Genetic Energy streaming bases design are trademarks or registered trademarks of Illumina, Inc. All other brands and names contained herein are the property of their respective owners. 2

Monogenic diseases Genomes are complex Majority of disease risk by single gene Genomes are here Epigenetic disease(>1 gene + environment)

Consumer

11% of the genes in the genome are tested for clinically today Cancer Human Tay Sachs (100%) 100% Cystic Fibrosis (100%) Genetics

Reproductive Forensics Health

Cardiomyopathy (55%) Breast Cancer (40-80%) 50% Agriculture Infectious Disease

Type 2 Diabetes (25% to 33%) - 1.35 fold increase

Research Biopharm Alzheimer’s Disease (10%) 0% - 2-10 fold increase

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1 Genomes are being sequenced at the population level Goals of Understand Your Genome

Informed conversation on Identify opportunities and efficiencies opportunities and challenges Identify concerns and challenges associated with genomic medicine Identify policies and guidelines needs Experience physician-mediated personal genome sequencing Enable a network of stakeholders in genomic medicine

Physicians Administrators Genetic Counselors Entrepreneurs Laboratory Directors Investors Policy Makers Ethicists

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Genomes in Healthcare Require an informed community and robust processes Accuracy, Interpretation and Reporting

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 physician/patient Physician-Illumina Sample blood Sequencing at Variants Physician-patient consent process Clinical Geneticist collection Illumina’s CLIA- interpreted and discussion consultation as certified, CAP- reported to regarding results needed accredited lab physician and next steps in medical management

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2 Analytical Validity in ICL Could this Variant Be Responsible for Disease?

Genome Exome 30% 30%

25% 25%

20% 20%

15% 15% % calls % % calls % Genetic Disease A Genetic Variant 10% 10% How does it happen What kind of variant is this? 5% 5% – Autosomal dominant, What is known about this 0% 0% autosomal recessive, x- variant? 10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90

100 linked, other? >100 >100 How common is this variant? depth of coverage depth of coverage – Early onset, late onset, Are there other genes or variants Depth of coverage Sensitivity Specificity that could also be responsible? How common is it? 30x >99.9% >99.99% Is this variant the criminal or an 20x 99.5% >99.99% accessory to the crime? 10x 98.0% 99.99% 5x N/A 99.99%

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Variants 5,343 Have we interpreted this variant already? Policies YES 5,243 In clinical publications database ? NO 100

97 NO 3 YES Autoscore tool •Frequency of variant >>Incidence of disease?

Manual review •Frequency of variant •Case reports •Biological effects •Case control •Other evidence? NO 5 92 YES •Functional studies

Variant classification

Interpretation database Report: •Summaries of evidence and rationale •Combinations of variants •Reporting language •Clinical context

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3 Reporting policy decisions The power of numbers

Secondary findings Control populations

No Predisposition/Carrier screenings available for minors Identification of artifacts

Clinical report includes pathogenic, likely pathogenic and VUS that are Ethnic/population diversity suspicious for pathogenicity

Appendix includes all annotated calls that passed quality, plus interpretations Higher quality calls

Updates on interpretations Improve efficiency for interpretation

Mitigate cost of entry

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Patient/Participant requests Policies that are needed

Explore data using other Evaluate additional tools and software genes/biomarkers • Research tools • Services that offer Printed clinical report only, or data passing quality metrics too? • Assessment of parameter additional/alternative types of changes in algorithms assessment (ancestry, traits) • Annotation/interpretation New consents for every use case? software

Do receivers of genomes require IRBs, and if so, how do participants navigate that process? Share with other Donate for further individuals research • Specific individuals in • Hospitals, such as Medical community College of Wisconsin •PGP

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4 Acknowledgements

Illumina Clinical Services Laboratory Team: Support Team:

Tina Hambuch, PhD, dABMG Francisco Garcia Erica Ramos, MS, CGC Phil Podlevsky Carri-Lyn Mead, PhD Debora Thompson Michelle Hogue, LCGC Sophie Coon Jennifer Sardina, MS Stephanie Pond, PhD Amirah Khouzam, MS, MA Melissa Won, PhD Phil Cotter, PhD, FACMG, Tobias Mann, PhD FFSc(RCPA) Morten Kalberg, PhD Marc Laurent, MBA David Bentley, PhD Subramanian Shankar Ajay, PhD Mark Ross, PhD Vani Rajan Debora Thompson, MS Suneer Jain, CGMBS Trang Dahlen, MS Yelena Lyan, CGMBS Ken Sherman, MS Laura Wachtmann, MS Dawn Barry, MS Jameson Hurless, BS, CGMBS Matt Posard Meghan Hugel, MS

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