Lawrence Walter

Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian–European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent–child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent–child pairs was largely due to intermarriage. The parent–child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.

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.

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.

Effects of Psychological Intervention on Panic Attack Patients in the Emergency Department

For patients initially seen in the emergency department (ED) for panic attack, this study evaluated the effect of two brief psychological interventions in the ED on later utilization of emergency, psychiatric, and nonpsychiatric medical department services. Each of the two intervention groups received usual ED care, a brochure on panic disorder, and a referral to treatment at the psychiatry department; one of the two groups also received 20-30 minutes of contact with a representative from the psychiatry department. Both intervention groups were compared with a historical control group. The contact condition reduced ED use after the initial visit to the ED, although all three groups had more visits to the psychiatry department and to all nonpsychiatric departments. This decrease was statistically significant (P = 0.0017) when compared with the brochure condition but not when compared with the historical control group (P = 0.0672). The decrease seen in ED use is an important therapeutic and economic finding.

Medicaid patients in a private health maintenance organization: patterns of chemical dependency treatment.

Although many Medicaid beneficiaries receive health care through commercial health maintenance organizations (HMOs), the impact of private managed care on low-income individuals seeking treatment for substance abuse has rarely been studied. This study examined treatment patterns of 234 Medicaid recipients who presented for care at an HMO between 1995 and 1997. After adjustment for demographic factors and duration of health plan membership, the Medicaid patients returned to start treatment after intake less often (odds ratio = 0.60) and dropped out of treatment sooner (median = 14 versus 28 days) than non-Medicaid patients. While many Medicaid patients received significant amounts of substance abuse treatment, further research is needed to explain the observed treatment gap and to identify areas where HMOs can improve services for some of their most vulnerable members.

Medicaid chemical dependency patients in a commercial health plan

A cohort of 197 Medicaid-insured patients presenting for treatment in Kaiser Permanentes out-patient chemical dependency treatment program were observed the year prior to their program intake visit and followed for 3 years afterwards, to compare their medical costs and utilization to demographically matched commercially insured patients entering the same programs. The Medicaid-insured patients on average incurred medical costs 60% higher than non-Medicaid patients during the 12-month preintake period (

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

5402 vs

The Depression-Arkansas scale: A validation study of a new brief depression scale in an HMO.

3277). During the 3 years subsequently, however, both groups of chemical dependency patients displayed significant declines in medical costs, averaging 30% from the baseline period to the third year of follow-up. Cost trends reflected declines in use of hospital days, emergency department visits, and nonemergent outpatient visits. These results may help address concerns among Medicaid managed care providers and payers by giving a more realistic account of the long-term costs of this group of high-utilizing enrollees.

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

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. Methods The GERA cohort is a multi-ethnic cohort (average age = 63 years) of over 100,000 individuals with linked electronic medical records and questionnaire data. Telomere length was determined from a saliva sample in the Blackburn Laboratory using the novel Automated Telomere Length Analysis System (ATLAS) to handle the required high throughput processing of samples. Each sample was assayed six times using qPCR. Relative telomere length (T/S) was obtained from the initial concentrations of the sample telomere (T) with the corresponding sample reference gene (S). The distribution of (T/S) was found to be positively skewed and a log transformation was used to normalize the distribution. The final telomere length end point was the difference in adjusted means of telomere length per standard deviation unit by accounting for age and gender. The NDI is a standardized composite score of neighborhood quality derived from eight 2000 US Census data variables related to poverty/income, occupation, family structure, education and unemployment and normalized to a 100-point scale at the block-group level. Results A higher NDI indicates greater neighborhood deprivation. The NDI was linked with residential address at time of sample collection. We observed a pattern of shorter telomere length with increasing level of neighborhood deprivation. The pattern persisted even after accounting for age, gender, race/ethnicity, smoking, BMI, and the presence of cardiovascular disease, diabetes and other comorbidity. Conclusions Our results suggest that neighborhood can adversely impact telomere length. Future plans will be discussed.