The question associated with efficacy and longevity of SARS-CoV-2 protection post-vaccination is paramount. The cPass surrogate virus neutralization test (sVNT) has gained popularity globally as a ...dual application assay for: 1. Accurate SARS-CoV-2 population surveillance (seroprevalence) analysis and 2. Revealing the presence of antibodies that block and effectively neutralize the interaction between the SARS-CoV-2 receptor binding domain and the host cell ACE2 receptor in recovered or vaccinated individuals. This study describes an approach for accurate quantification of neutralizing antibodies using the cPass sVNT with an automated workflow on the Tecan EVO and Dynex Agility platforms that is applicable to other liquid handling systems. This methodology was used to assess the stability of SARS-CoV-2 neutralizing antibodies between freeze/thaw and refrigerated sample storage conditions. Furthermore, a subset of twenty-five samples from SARS-CoV-2 infected/recovered individuals revealed a 600-fold difference in the neutralizing antibody response where low titers were represented in about half of the samples. Finally, pre- and post-vaccination samples were tested for neutralizing antibodies using the qualitative and semi-quantitative cPass sVNT protocols revealing undetectable or relatively low levels after the first vaccine dose and a decline in levels longitudinally over the months following the second dose. This wide range in neutralizing (blocking) antibodies from both natural infection and vaccination supports a differential immune response that may be attributed to several physiological and genetic factors underlining the potential for measuring SARS-CoV-2 neutralizing antibody titer levels post-vaccination to help ensure robust and prolonged immunity.
Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The ...array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.
► European, East Asian, African American and Latino race/ethnicity optimized arrays. ► High density genotyping arrays for large-scale genome-wide association studies. ► Novel design alternates rounds of pairwise SNP selection and imputation coverage. ► Increased SNP density achieved by reduced redundancy of high performing SNPs.
The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed ...a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions.
Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included.
As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort.
The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort's diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities.
We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ...ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.
To assess excess maternal transmission of type 2 diabetes in a multiethnic cohort. Previous studies have reported higher prevalence of diabetes among mothers of probands with type 2 diabetes than ...among fathers. This analysis is vulnerable to biases, and this pattern has not been observed in all populations or races.
We assessed evidence for excess maternal transmission among 42,533 survey respondents with type 2 diabetes (probands) by calculating the prevalence of diabetes in their siblings and offspring. To assess data quality, we evaluated completeness of family history data provided. Accuracy of family information reported by probands was also evaluated by comparing survey responses in a subsample of 206 probands with family histories modified after further interviews with relatives.
Siblings (n = 60,532) of probands with affected mothers had a greater prevalence of diabetes (20%) than those with affected fathers (17%) (P < 0.001 for adjusted odds ratios). Prevalence of diabetes was higher among the offspring (n = 72,087) of female (3.4%) versus male (2.2%) probands (P < 0.001 for adjusted odds ratios). These patterns were evident in all races and both sexes; however, the effect size was clinically insignificant in African-Americans and male offspring. In general, probands provided more complete data about diabetes status for the maternal arm of the pedigree than the paternal arm. Completeness of knowledge was not related to proband sex, but was related to education and race, and inversely to age. Accuracy of proband-reported family history was consistently good (kappa statistics generally > 0.70).
Excess maternal transmission was observed in all races and both sexes, although the size of the excess was negligible in African-Americans and male offspring. Potential reporting and censoring biases are discussed.
We established a male, multiethnic cohort primarily to study prostate cancer etiology and secondarily to study the etiologies of other cancer and non-cancer conditions.
Eligible 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.
A 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 Men's Health Study and other cohorts nested within comprehensive health delivery systems can make important contributions in the area of men's health.
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.
Background/AimsShortened 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.MethodsThe 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.ResultsA 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.ConclusionsOur results suggest that neighborhood can adversely impact telomere length. Future plans will be discussed.
Background/AimsTelomere 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.MethodsAs part of the RPGEH, the Genetic Epidemiology Research Study on Adult Health and Aging (GERA), a multi-ethnic cohort (average age = 63 years) has measured TL from saliva samples on over 100,000 individuals with linked electronic medical records. A survey of demographic and behavioral factors was conducted 2 years prior to saliva collection. With these data, we examined demographic relationships with TL, behavioral influences, and relationship of TL with all-cause mortality following sample collection.ResultsAs expected, TL is inversely correlated with age, and women have longer telomeres than men except as young adults. All analyses controlled for age and gender. As seen in other studies, we find significantly longer TL among African Americans than other groups. TL is positively correlated with education and body mass index (BMI), and negatively correlated with cigarette smoking and alcohol consumption. We found no relationship with major depression or stress-related disorders, even when limited to recent episodes. We found that short TL was prospectively associated with mortality, although only those with the shortest TL were at increased risk; the association suggested a critical threshold of short TL determines effects on mortality. The association persisted even after adjustment of the demographic and behavioral factors such as age, sex, race, education, BMI, smoking, and alcohol consumption.ConclusionsWhile this could indicate a direct effect of TL on health, it will also be important to examine the extent of pre-existing morbidities in these individuals to understand their possible role in the pathway between TL and longevity.
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