Marianne Sadler

Statin use and risk of prostate cancer in the California Men's Health Study cohort.

Statins have known anticarcinogenic effects, however, evidence for long-term statin use as effective chemoprevention for prostate cancer is inconsistent. We examined the association between statin use and risk of prostate cancer among 69,047 eligible participants in the California Mens Health Study, a prospective cohort of Northern and Southern California Kaiser Permanente (KP) members, ages 45 to 69 years, initiated in 2002. Prostate cancer cases were identified by linkage to the KP California Cancer Registries. Statin exposure, estimated from automated KP outpatient pharmacy records (available since 1991 in Southern California and since 1994 in Northern California), was treated as time-varying and defined as the cumulative days dispensed of any statin from the first dispensing until a prostate cancer diagnosis, radical prostatectomy, termination of membership, or end of study (December 31, 2004). Cox proportional hazards models with age as the time scale were used to estimate rate ratios, while controlling for confounding variables. During follow-up, 888 prostate cancer cases, including 131 advanced cases, were identified. There was no association between ever statin use or <5 years use and prostate cancer. Conversely, ≥5 years use was associated with a 28% lower risk for prostate cancer compared with nonuse (adjusted rate ratio, 0.72; 95% confidence interval, 0.53-0.99). This association did not differ markedly for advanced disease. However, the association did seem to be restricted to those who regularly take nonsteroidal anti-inflammatory drugs. Our findings suggest that long-term statin use might be associated with a reduced risk of prostate cancer but perhaps only among regular nonsteroidal anti-inflammatory drug users. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2218–25)

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.

Low total serum cholesterol and intracerebral hemorrhagic stroke : Is the association confined to elderly men : The kaiser permanente medical care program

BACKGROUND AND PURPOSE Epidemiological studies indicate a higher incidence of intracerebral (but not subarachnoid) hemorrhagic stroke among persons with low total serum cholesterol levels. This report further examines the prospective relationship of total serum cholesterol with subsequent intracerebral hemorrhage in a large, well-defined population. METHODS The cohort included 61756 enrollees in a health plan from the San Francisco-Oakland metropolitan area (46% men, 63% white), aged 40 to 89 years and free of cardiovascular disease at baseline. Sixteen-year incidence of combined nonfatal and fatal intracerebral hemorrhagic stroke (International Classification of Diseases [ICD], 8th revision, code 431, or ICD, 9th revision, codes 431 and 432) was investigated in relation to serum cholesterol measured in multiphasic health checkups made in 1977 through 1985. Intracerebral hemorrhagic events were ascertained using hospital discharge records and as underlying cause of death by the California Mortality Linkage Information System. RESULTS From 1978 through 1993 (average of 10.7 years), there were 386 events (201 in men, 29% fatal; 185 in women, 42% fatal). By multivariate proportional hazards life-table regression analysis, serum cholesterol level below the sex-specific 10th percentile (< 4.62 mmol/L [178 mg/dL] in men), compared with higher cholesterol level, was associated with a significantly increased risk of intracerebral hemorrhage in men aged 65 years or older (relative risk, 2.7; 95% confidence interval, 1.4 to 5.0). An excess risk was also observed among elderly women at the lowest cholesterol range, but a chance finding could not be ruled out. No relationship was seen among men or women aged 40 to 64, and no statistical interaction of low serum cholesterol with hypertension was found in either sex. CONCLUSIONS In these data, the association between low serum cholesterol level and intracerebral hemorrhage was confined to elderly men.

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.

Risk factors for surgically treatedbenign prostatic hyperplasia in a prepaid health care plan

The relationship of age, medical history, personal habits, and urologic symptoms to the incidence of surgically treated benign prostatic hyperplasia (BPH) was studied in a cohort of 16,219 men, aged forty years and over, who received multiphasic health checkups (MHCs) during 1971 and 1972 in Oakland or San Francisco while members of the Northern California Kaiser Permanente Medical Care Program, a large prepaid health care program. Follow-up was carried out for surgically treated BPH from the date of the MHC to the date of the earliest of the following: surgery for BPH (n = 1,027); incidence of prostate cancer (n = 329), bladder cancer (n = 119), or both (n = 10); other prostate surgery (n = 5); death (n = 2,525); membership termination (n = 4,235); or December 31, 1987 (n = 7,969). The mean length of follow-up was twelve years. In multivariate analysis utilizing the Cox proportional hazards model, the following characteristics were positively associated (p less than 0.05) with risk of surgically treated BPH: age, low body mass index, nonsmoking (vs. current smoking), urine pH greater than 5, history of kidney x-ray and of tuberculosis, and each of five urologic symptoms (dysuria, loss of bladder control, trouble starting urination, nocturia, slow urine stream). The risk of BPH associated with obstructive urologic symptoms decreased markedly with age. Some of these findings are consistent with those from other studies (age, nonsmoking), while others (high urine pH, history of tuberculosis) are new and should be examined in other study populations.

Seven-Year Changes in Physical Fitness, Physical Activity, and Lipid Profile in the CARDIA Study

PURPOSE To relate seven year changes in physical fitness and physical activity in the young adult population to changes in the plasma lipid profile and to examine the influence of weight change on those relationships. METHODS The participants in this observational study were the 1777 black and white men and women, ages 18-30 at entry into the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, who completed a symptom-limited graded treadmill exercise test and had an overnight fasting blood draw at both the Baseline (1985-86) and Year 7 (1992-93) exams. CARDIA, a longitudinal study of the relationships of lifestyle and physiological variables to the development of coronary heart disease risk factors, consists of population-based cohorts in Birmingham, Alabama, Minneapolis, Minnesota and Chicago, Illinois and a cohort recruited from the membership of a large, pre-paid health care plan, broadly representative of the population, in Oakland, California. RESULTS All race/gender groups experienced mean decreases in physical fitness and self-reported physical activity and increases in weight. Decreased fitness was associated with decreased high density lipoprotein-cholesterol (HDL-C), and conversely, increased fitness was associated with increased HDL-C. The correlation coefficients of change in fitness with change in HDL-C ranged from 0.17 in white men and black women to 0.24 in white women (P < 0.001 for all race/gender groups). Change in fitness was minimally correlated with change in low density lipoprotein-cholesterol (LDL-C) in all groups (r ranged from -0.09 in black women to -0.20 in white women), triglycerides (TG) in men and white women (r ranged from -0.10 to -0.15), and total cholesterol (TC) in white men and women (r = -0.11 and -0.15, respectively). The magnitude of these correlations was further reduced with adjustment for weight change. Correlations between change in activity and change in lipid and lipoprotein values were generally weak or nonexistent, except for the suggestion of a small, direct relationship with change in HDL-C in black and white women (r = 0.14 and r = 0.11, respectively). All of the weight change adjusted correlations were essentially unaffected by further adjustment for baseline fitness or activity and other covariates. CONCLUSIONS Decreased fitness during young adulthood is associated with unfavorable changes in lipid profile, explained mostly by increased weight. Lack of association between change in activity and change in lipid profile observed in this study may be due, in part, to imprecision of activity measurement.

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.

California Men's Health Study (CMHS): a multiethnic cohort in a managed care setting

BackgroundWe established a male, multiethnic cohort primarily to study prostate cancer etiology and secondarily to study the etiologies of other cancer and non-cancer conditions.Methods/DesignEligible participants were 45-to-69 year old males who were members of a large, prepaid health plan in California. Participants completed two surveys on-line or on paper in 2002 – 2003. Survey content included demographics; family, medical, and cancer screening history; sexuality and sexual development; lifestyle (diet, physical activity, and smoking); prescription and non-prescription drugs; and herbal supplements. We linked study data with clinical data, including laboratory, hospitalization, and cancer data, from electronic health plan files.We recruited 84,170 participants, approximately 40% from minority populations and over 5,000 who identified themselves as other than heterosexual. We observed a wide range of education (53% completed less than college) and income. PSA testing rates (75% overall) were highest among black participants. Body mass index (BMI) (median 27.2) was highest for blacks and Latinos and lowest for Asians, and showed 80.6% agreement with BMI from clinical data sources. The sensitivity and specificity can be assessed by comparing self-reported data, such as PSA testing, diabetes, and history of cancer, to health plan data. We anticipate that nearly 1,500 prostate cancer diagnoses will occur within five years of cohort inception.DiscussionA wide variety of epidemiologic, health services, and outcomes research utilizing a rich array of electronic, biological, and clinical resources is possible within this multiethnic cohort. The California Mens Health Study and other cohorts nested within comprehensive health delivery systems can make important contributions in the area of mens health.

Vasectomy and the risk of prostate cancer in a cohort of multiphasic health-checkup examinees: second report.

The relationship of vasectomy to prostate cancer was studied in 5,119 men with a self-reported history of vasectomy, identified at multiphasic health checkups undergone during 1977–82 while members of the Northern California Kaiser Permanente Medical Care Program. Three unvasectomized comparison subjects were identified for each vasectomized man, matched for age, race, marital status, and date and location of the examination. Follow-up for incident prostate cancer was conducted for a mean length of 6.8 years. The relative risk of prostate cancer associated with vasectomy was 1.0 (95% confidence interval = 0.7–1.6); the relative risk was approximately one, regardless of length of interval (less than 10 years, 10–20 years, more than 20 years) between vasectomy and multiphasic health checkup or the age at vasectomy (less than 40 years vs more than 40 years). These data support earlier findings reported in this study group of the lack of an association of vasectomy with subsequent risk of prostate cancer.

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.