Research Program On Genes, Environment, And Health Research Articles

Multiple Stakeholder Views on Data Sharing in a Biobank in an Integrated Healthcare Delivery System: Implications for Biobank Governance

Background: Beginning in 2005, researchers at Kaiser Permanente Northern California (KPNC) Division of Research developed the Research Program on Genes, Environment, and Health (RPGEH), a research resource of linked biospecimens, health surveys, and electronic health records on more than 200,000 adult KPNC members. This study examined multiple stakeholders’ values and preferences regarding protection of participants’ privacy and wide sharing of participant data by RPGEH. Methods: We conducted 45 semi-structured interviews in person or via phone and two focus groups with seven stakeholder groups, including RPGEH participants and decliners who are KPNC members, KPNC research scientists, external scientists, leadership, Human Subjects Research Protection Program staff, and RPGEH Community Advisory Panel members. Results: Three major themes emerged related to: (1) perceived individual and social harms associated with data sharing; (2) concerns to address when governing access to RPGEH data; and (3) impact of a blurred boundary between research and clinical care in the context of biobanking. Conclusions: The study results were considered in the development of RPGEH data governance and motivated the inclusion of KPNC Community Advisory Panel members and ELSI experts on committees that evaluate data access proposals. Our findings can help inform other biobanks going through similar processes developing data sharing and access policies.

Abstract PR13: External validation of a risk prediction model for lung cancer among smokers

Abstract Early detection strategies for lung cancer may be improved by using valid risk prediction models to identify persons at highest risk for the disease. However, external validation of lung cancer risk prediction models has been limited. We sought to externally validate the PLCOM2012 model, which predicts the probability of lung cancer within six years on the basis of age, race, education, body mass index, chronic obstructive pulmonary disease, personal history of cancer, family history of lung cancer, and smoking status, quantity, duration, and quit years, in the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment, and Health (RPGEH) cohort. To increase comparability to the populations of smokers used to initially develop and validate the PLCOM2012 model, we restricted our analysis to the 28,757 ever smokers ages 55 to 74 with no history of lung cancer, no history of other non-melanoma skin cancers in the prior five years, and complete data on all model predictors. For each person, the predicted probability of lung cancer risk was estimated with data ascertained from the RPGEH survey on all predictors except quit years, which was ascertained from electronic health records. Using KPNC Cancer Registry data, we identified 672 diagnosed with lung cancer within six years post-survey. Both calibration and discrimination were examined to assess model performance. Calibration was assessed by determining the mean absolute difference in observed and predicted probabilities of lung cancer for each decile of predicted risk. Discrimination was assessed by estimating the area under curve (AUC). The absolute difference in observed and predicted probabilities of lung cancer risk was generally small: <0.010 and <0.035 in half and 90% of the analytic cohort, respectively. Although the mean absolute difference in observed and predicted probabilities of lung cancer risk was smallest for the lowest decile (0.003; observed probability: 0.003) and largest for the highest decile (0.049; observed probability: 0.08), it did not increase monotonically with each increasing decile of predicted risk. Discrimination was modest with an AUC of 0.73 (95% confidence interval: 0.71, 0.75). In a large, independent population of smokers, we found the PLCOM2012 model did not perform as well as demonstrated previously. Citation Format: Lori C. Sakoda, Laurel A. Habel, Khanh K. Thai, Charles P. Quesenberry, Jr. External validation of a risk prediction model for lung cancer among smokers. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR13.

The Kaiser Permanente Northern California research program on genes, environment, and health (RPGEH) pregnancy cohort: study design, methodology and baseline characteristics.

BackgroundExposures during the prenatal period may have lasting effects on maternal and child health outcomes. To better understand the effects of the in utero environment on children’s short- and long-term health, large representative pregnancy cohorts with comprehensive information on a broad range of environmental influences (including biological and behavioral) and the ability to link to prenatal, child and maternal health outcomes are needed. The Research Program on Genes, Environment and Health (RPGEH) pregnancy cohort at Kaiser Permanente Northern California (KPNC) was established to create a resource for conducting research to better understand factors influencing women’s and children’s health. Recruitment is integrated into routine clinical prenatal care at KPNC, an integrated health care delivery system. We detail the study design, data collection, and methodologies for establishing this cohort. We also describe the baseline characteristics and the cohort’s representativeness of the underlying pregnant population in KPNC.MethodsWhile recruitment is ongoing, as of October 2014, the RPGEH pregnancy cohort included 16,977 pregnancies (53 % from racial and ethnic minorities). RPGEH pregnancy cohort participants consented to have blood samples obtained in the first trimester (mean gestational age 9.1 weeks ± 4.2 SD) and second trimester (mean gestational age 18.1 weeks ± 5.5 SD) to be stored for future use. Women were invited to complete a questionnaire on health history and lifestyle. Information on women’s clinical and health assessments before, during and after pregnancy and women and children’s health outcomes are available in the health system’s electronic health records, which also allows long-term follow-up.DiscussionThis large, racially- and ethnically-diverse cohort of pregnancies with prenatal biospecimens and clinical data is a valuable resource for future studies on in utero environmental exposures and maternal and child perinatal and long term health outcomes. The baseline characteristics of RPGEH Pregnancy Cohort demonstrate that it is highly representative of the underlying population living in the broader community in Northern California.Electronic supplementary materialThe online version of this article (doi:10.1186/s12884-016-1150-2) contains supplementary material, which is available to authorized users.

Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.

Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.

Abstract P255: Genetic Variation in Chromosome 8p23 is Associated With Sedentary Behavior in Humans

Sedentary behavior, usually quantified as sitting time, has been shown to be associated with several adverse health outcomes, even among individuals who meet the current recommendations for physical activity. Both twin and family studies have shown that sedentary behavior aggregates in families and is a heritable trait. However, little is known about genes and DNA sequence variants that contribute to propensity to be sedentary. The purpose of our study was to conduct a genome-wide association study to identify genomic regions and DNA sequence variants associated with sedentary time. A total of 67,530 Caucasians (56% female, mean age 62.1 years [SD 12.5]) from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) cohort were used for the discovery analyses. Other RPGEH ethnicities (African-Americans: N=2,500; East Asians: N=6,300; Hispanics: N=8,800) were used for replication studies. Information on daily sitting time outside of work was obtained by a questionnaire. A custom panel of 657,184 autosomal single nucleotide polymorphisms (SNPs) was genotyped using Affymetrix platform. Associations between sedentary time (dichotomized; cases 3 hours or more, controls less than 3 hours per day) and the SNPs were tested with PLINK logistic model using age, sex, BMI and admixture principal components as covariates. The strongest evidence of association was detected on chromosome 8p23.1. A total of 24 SNPs within a 1.34 Mb region were associated with sedentary time at genome-wide significance level (p<5x10 -8 ), with SNP rs11774552 showing the peak association (OR=0.924, p= 1.7x10 -12 ). Sex-specific analyses confirmed that the associations were present both in men and women. The same SNPs were not associated with sedentary time in other ethnicities. However, SNP rs28754712, which is located in the immediate vicinity (+456 bp) of rs11774552, showed a significant association with sedentary time (OR=0.795, p=1.2x10 -3 ) in African-Americans. In summary, our results provide the first evidence of genomic region and DNA sequence variants associated with sedentary behavior in humans. If confirmed in additional replication studies, these findings will advance our understanding of biological mechanisms contributing to propensity to be sedentary.

PS3-16: Access and Collaboration with the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)

Background/Aims The Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment, and Health (RPGEH) provides a research resource to support investigations of environmental and genetic factors in the development of a wide variety of conditions. While the resource is still evolving with new data collection, it consists of data from surveys and electronic medical records on over 400,000 adult members of KPNC; biospecimens collected and stored on ~200,000 of these individuals; and data from genome-wide and telomere-length assays on ~110,000 of those who have contributed biospecimens; and linkage of these members to environmental, area-level databases.

PS3-13: Re-Identification Risk Associated with Sharing Linked Genomic and Phenotypic Data from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH)

Background/Aims It is now understood that conventional de-identification methods such as the HIPAA Safe Harbor standard do not guarantee anonymity of patient records, which may be vulnerable to a variety of attacks aimed at re-identifying confidential information. We present an analytic framework for evaluating these risks quantitatively in order to be able to explicitly balance privacy and scientific utility. As a concrete example, we examine implications for patient privacy of plans to deposit over 70,000 full-genome genotypes and associated clinical data in the dbGaP federally-managed data repository, as a component of a NIH-funded study conducted by the Research Program on Genes, Environment, and Health (RPGEH) at the Kaiser Permanente Northern California Division of Research (KPNC DOR). Risks are examined from multiple perspectives and risk reduction strategies discussed.

B4-1: An Overview of Kaiser Permanente's Research Program on Genes, Environment, and Health

Background/Aims The Research Program on Genes, Environment, and Health (RPGEH) is a large, population-based resource for genetic epidemiology developed by scientists at the Kaiser Permanente (KP) Northern California Division of Research. The goal of this program is to link research data for 500,000 broadly consented health plan members, including longitudinal electronic medical records (EMR), genomic data from biospecimens, and environmental exposure data from surveys and geographic information system (GIS) databases in order to support research on many different health conditions.

B4-4: Genome-Wide Association Study of Macular Degeneration: Early Results from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)

Background/Aims Age-related macular degeneration (AMD) is the most common cause of vision loss in individuals over the age of 50 in the United States. Genetic factors explain a large portion of the risk of developing AMD, and genetic variants at the CFH, HTRA1/ARMS2, C2/CFB, and C3 gene loci have previously been associated with the disease.

PS3-15: Genome-Wide Association Study of Anxiety Disorders: Early Results from Kaiser Permanente's Research Program on Genes, Environment, and Health (RPGEH)

Background/Aims The Kaiser Permanente/UCSF Genetic Epidemiology Research Study on Adult Health and Aging (GERA) cohort includes 110,266 individuals with comprehensive longitudinal medical records along with genome-wide genotype data. As such, it provides an unprecedented opportunity to conduct a number of genome-wide association studies (GWAS) of psychiatric disorders. Post-traumatic stress disorder (PTSD) and panic disorder (PD) are prevalent, persistent, disabling and heritable anxiety disorders. Numerous candidate gene studies have been published with inconsistent findings. We conducted the GWAS of PTSD and the GWAS of panic disorder among non-Hispanic white GERA cohorts to detect the underlying heterogeneous genetic architecture.

B4-3: Demographic and Behavioral Influences on Telomere Length and Relationship with All-Cause Mortality: Early Results from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)

Background/Aims Telomere shortening is a biomarker of aging, but it is still unclear whether it directly influences aging-related health changes and mortality, or largely reflects the accumulating influences of environmental influences and declining health. Prior studies have reported associations between short telomeres and many health conditions. Mendelian syndromes and heritability studies demonstrate the biological underpinnings of telomere length (TL), yet other studies show that environmental and behavioral factors also influence telomere lengths.

B4-5: Neighborhood Deprivation and Telomere Length: Preliminary Findings from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)

Background/Aims Shortened telomeres have been associated with numerous adverse health outcomes. In addition, a number of environmental or external exposures, including smoking, air pollution and stress, have been reported to be associated with short telomeres. We sought to examine how neighborhood quality of participants in the RPGEH Genetic Epidemiology Research Study on Adult Health and Aging (GERA) cohort affected telomere length.

C-A3-04: The Kaiser Permanente Research Program on Genes, Environment and Health: A Resource for Genetic Epidemiology in Adult Health and Aging

Aims The Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) is designed as a resource for epidemiologic studies of genetic and environmental influences on health and disease. The resource links together clinical data from electronic health records (EHR), demographic and behavioral data from participant surveys, and data on the social and physical environments in participants’ neighborhoods, with saliva and/or blood samples for deriving genetic and other data. When completed in 2013, the RPGEH is planned to include 500,000 members of Kaiser Permanente in Northern California (KPNC). Participants provide informed consent for a broad spectrum of health research and sharing of data with collaborating investigators from many institutions.

Next generation genome-wide association tool: Design and coverage of a high-throughput European-optimized SNP array

The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.