@article {12923, title = {Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.}, journal = {PNAS}, volume = {120}, year = {2023}, pages = {e2215840120}, abstract = {

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using "second and third generation clocks," PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

}, keywords = {Acceleration, Aging, Biomarkers, Cross-Sectional Studies, DNA Methylation, Epigenesis, genetic}, issn = {1091-6490}, doi = {10.1073/pnas.2215840120}, author = {Jessica Faul and Jung K Kim and Levine, Morgan E and Bharat Thyagarajan and David R Weir and Eileen M. Crimmins} } @article {10.1001/jamaneurol.2022.3543, title = {Estimating the Prevalence of Dementia and Mild Cognitive Impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project}, journal = {JAMA Neurology}, volume = {79}, year = {2022}, pages = {1242-1249}, abstract = {Nationally representative data are critical for understanding the causes, costs, and outcomes associated with dementia and mild cognitive impairment (MCI) in the US and can inform policies aimed at reducing the impact of these conditions on patients, families, and public programs. The nationally representative Health and Retirement Study (HRS) is an essential resource for such data, but the HRS substudy providing dementia diagnostic information was fielded more than 20 years ago and more recent data are needed.The Harmonized Cognitive Assessment Protocol (HCAP) was developed to update national estimates of the prevalence of MCI and dementia in the US and examine differences by age, race, ethnicity, and sex.HRS is an ongoing longitudinal nationally representative study of people 51 years and older with staggered entry dates from 1992 to 2022 and follow-up ranging from 4 to 30 years. HCAP is a cross-sectional random sample of individuals in HRS who were 65 years or older in 2016. Of 9972 age-eligible HRS participants, 4425 were randomly selected for HCAP, and 3496 completed a comprehensive neuropsychological test battery and informant interview, none of whom were excluded. Dementia and MCI were classified using an algorithm based on standard diagnostic criteria and comparing test performance to a robust normative sample.Groups were stratified by age, sex, education, race, and ethnicity.National prevalence estimates using population weights.The mean (SD) age of the study population sample (N = 3496) was 76.4 (7.6) years, and 2095 participants (60\%) were female. There were 551 participants who self-identified as Black and not Hispanic (16\%), 382 who self-identified as Hispanic regardless of race (16\%), 2483 who self-identified as White and not Hispanic (71\%), and 80 who self-identified as another race (2\%), including American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, or another self-described race. A total of 393 individuals (10\%; 95\% CI, 9-11) were classified as having dementia and 804 (22\%; 95\% CI, 20-24) as having MCI. Every 5-year increase in age was associated with higher risk of dementia (weighted odds ratio [OR], 1.95 per 5-year age difference; 95\%, CI, 1.77-2.14) and MCI (OR, 1.17 per 5-year age difference, 95\% CI, 1.09-1.26). Each additional year of education was associated with a decrease in risk of dementia (OR, 0.93 per year of school, 95\% CI, 0.89-0.97) and MCI (OR, 0.94, 95\% CI, 0.91-0.97). Dementia was more common among non-Hispanic Black individuals (OR, 1.81; 95\% CI, 1.20-2.75) and MCI in Hispanic individuals (OR, 1.42; 95\% CI, 1.03-1.96) compared with non-Hispanic White individuals. Other group comparisons by race and ethnicity were not possible owing to small numbers. No differences in prevalence were found between female individuals and male individuals.Using a comprehensive neuropsychological test battery and large sample, the national prevalence of dementia and MCI in 2016 found in this cross-sectional study was similar to that of other US-based studies, indicating a disproportionate burden of dementia and MCI among older Black and Hispanic adults and those with lower education.}, keywords = {Dementia, HCAP, mild cognitive impairment}, issn = {2168-6149}, doi = {10.1001/jamaneurol.2022.3543}, author = {Jennifer J Manly and Richard N Jones and Kenneth M. Langa and Ryan, Lindsay H. and Levine, Deborah A. and McCammon, Ryan and Heeringa, Steven G. and David R Weir} } @article {13496, title = {Exome Array Analysis of 9721 Ischemic Stroke Cases from the SiGN Consortium.}, journal = {Genes }, volume = {14}, year = {2022}, pages = {61}, abstract = {

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., < 4.7 {\texttimes} 10), including two common SNPs in that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare in European Caucasians (MAF < 0.1\%) and the associations were driven by African American samples. There was no evidence for replication of these associations in either TOPMed Stroke samples ( = 5613 cases) or UK Biobank ( = 5874 stroke cases), although power to replicate was very low given the low allele frequencies of the associated variants and a shortage of samples from diverse ancestries. Our study highlights the need for acquiring large, well-powered diverse cohorts to study rare variants, and the technical challenges using array-based genotyping technologies for rare variant genotyping.

}, keywords = {Exome, Gene Frequency, Genome-Wide Association Study, Ischemic stroke, Stroke}, issn = {2073-4425}, doi = {10.3390/genes14010061}, author = {Xu, Huichun and Nguyen, Kevin and Gaynor, Brady J and Ling, Hua and Zhao, Wei and McArdle, Patrick F and O{\textquoteright}Connor, Timothy D and Stine, O Colin and Ryan, Kathleen A and Lynch, Megan and Smith, Jennifer A and Jessica Faul and Hu, Yao and Haessler, Jeffrey W and Fornage, Myriam and Kooperberg, Charles and Perry, James A and Hong, Charles C and Cole, John W and Pugh, Elizabeth and Doheny, Kimberly and Sharon L R Kardia and David R Weir and Kittner, Steven J and Mitchell, Braxton D} } @article {12125, title = {Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol~Use.}, journal = {Biological Psychiatry}, volume = {85}, year = {2019}, pages = {946-955}, abstract = {

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.

METHODS: We analyzed \~{}250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.

RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1\% to 2.2\% of phenotypic variance, reflecting 11\% to 18\% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95\% credible intervals.

CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

}, keywords = {Alcohol Drinking, Databases, Genetic, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Smoking}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2018.11.024}, author = {Brazel, David M and Jiang, Yu and Hughey, Jordan M and Turcot, Val{\'e}rie and Zhan, Xiaowei and Gong, Jian and Batini, Chiara and Weissenkampen, J Dylan and Liu, Mengzhen and Barnes, Daniel R and Bertelsen, Sarah and Chou, Yi-Ling and Erzurumluoglu, A Mesut and Jessica Faul and Jeffrey Haessler and Anke R Hammerschlag and Hsu, Chris and Kapoor, Manav and Lai, Dongbing and Le, Nhung and Christiaan de Leeuw and Loukola, Anu and Mangino, Massimo and Melbourne, Carl A and Pistis, Giorgio and Qaiser, Beenish and Rohde, Rebecca and Shao, Yaming and Heather M Stringham and Wetherill, Leah and Zhao, Wei and Agrawal, Arpana and Laura Bierut and Chen, Chu and Charles B Eaton and Goate, Alison and Christopher A Haiman and Andrew C Heath and Iacono, William G and Nicholas G Martin and Tinca J Polderman and Reiner, Alex and Rice, John and Schlessinger, David and H Steven Scholte and Smith, Jennifer A and Tardif, Jean-Claude and Hilary A Tindle and Van Der Leij, Andries R and Boehnke, Michael and Chang-Claude, Jenny and Francesco Cucca and David, Sean P and Tatiana Foroud and Howson, Joanna M M and Sharon L R Kardia and Charles Kooperberg and Laakso, Markku and Lettre, Guillaume and Pamela A F Madden and McGue, Matt and Kari E North and Posthuma, Danielle and Timothy Spector and Stram, Daniel and Tobin, Martin D and David R Weir and Kaprio, Jaakko and Gon{\c c}alo R Abecasis and Liu, Dajiang J and Scott Vrieze} } @article {11949, title = {Effect of delayed cell processing and cryopreservation on immunophenotyping in multicenter population studies.}, journal = {Journal of Immunological Methods}, volume = {463}, year = {2018}, pages = {61-70}, abstract = {

Variability induced by delayed cell processing and cell cryopreservation presents unique challenges for immunophenotyping in large population studies. We conducted a pilot study to evaluate the effect of delayed cell processing and cryopreservation on cell percentages obtained by immunophenotyping. We collected blood from 20 volunteers and compared the effect of (a) delayed cell processing up to 72 h (b) cryopreservation and (c) the combined effect of delayed cell processing and cryopreservation on immunophenotyping of 31 cell subsets that included several subsets of T, B, Natural Killer (NK) cells, monocytes and dendritic cells using both whole blood collected in EDTA tubes and peripheral blood mononuclear cells collected in CPT tubes. We found the delayed cell processing up to 72 h or cryopreservation alone did not significantly affect the percentages T cells, dendritic cells or monocytes but significantly increased the percentage of B cells and NK cells (p for trend <=0.01) but. However combination of delayed cell processing up to 72 h and cryopreservation significantly increased the percentage of T cells as compared to cells processed immediately (p for trend <0.0001) while a delayed cell processing followed by cryopreservation decreased the percentage of NK cells (p for trend <0.0001). Total B-cells increased significantly with a 24-48 h delay in cell processing and cryopreservation but not at 72 h. The percentages of monocytes and dendritic cells remained unaffected by the combination of delayed cell processing and cryopreservation. These findings suggest that immunophenotyping of several immune cell subsets can be successfully implemented in large population studies as long as blood is processed within 48 h of biospecimen collection though some cell subsets may be more susceptible to a combination of delayed cell processing and cryopreservation.

}, keywords = {Cell Separation, Cryopreservation, Immunophenotyping, Leukocytes, Time Factors}, issn = {1872-7905}, doi = {10.1016/j.jim.2018.09.007}, author = {Bharat Thyagarajan and Barcelo, Helene and Eileen M. Crimmins and David R Weir and Minnerath, Sharon and Vivek, Sithara and Jessica Faul} } @article {9314, title = {Evaluating Strategies for Reducing Field Costs in a Longitudinal Study}, year = {2016}, month = {06/2017}, pages = {1-8}, institution = {Institute for Social Research, University of Michigan}, address = {Ann Arbor, MI}, author = {David R Weir and Mary Beth Ofstedal} } @article {8926, title = {Economic development and gender inequality in cognition: a comparison of China and India, and of SAGE and the HRS sister studies.}, journal = {Journal of Economics of Ageing}, volume = {4}, year = {2014}, month = {2014 Dec 01}, pages = {114-125}, abstract = {

This paper examines cognition measures by age and gender from two types of studies in China and India. It finds that despite some notable differences in samples and measures, a general strong association of cognition in older ages with education emerges as a potential explanation for gender gaps and cohort differences. Female disadvantage in cognition is greater in India, both before and after controlling for education. The process of rural-urban migration draws more cognitively able women to cities in China but not in India. The advent of modern longitudinal studies of aging in these developing countries holds great promise for future work.

}, keywords = {CHARLS, Economics, Gender Differences, LASI, Older Adults, SAGE, Sister studies}, issn = {2212-828X}, doi = {10.1016/j.jeoa.2014.08.002}, author = {David R Weir and Margaret Lay and Kenneth M. Langa} } @inbook {5219, title = {Elastic Powers: The Integration of Biomarkers into the Health and Retirement Study}, booktitle = {Bio-Social Surveys: Current insight and future promise}, year = {2007}, note = {ProCite field 6 : In ProCite field 8 : eds}, pages = {78-95}, publisher = {The National Academies Press}, organization = {The National Academies Press}, address = {Washington, DC}, keywords = {Methodology}, url = {https://www.ncbi.nlm.nih.gov/books/NBK62437/}, author = {David R Weir}, editor = {Weinstein, Maxine and James W Vaupel and Kenneth W. Wachter} } @article {6961, title = {The Economic Consequences of a Husband{\textquoteright}s Death: Evidence from the HRS and AHEAD}, journal = {Social Security Bulletin}, volume = {65}, year = {2004}, pages = {31-44}, publisher = {65}, abstract = {This article examines the economic status of older widowed women in the 1990s using the Health and Retirement Study. Widowhood remains an important risk factor for transition into poverty, although somewhat less so than 20 years ago. Despite increased labor force participation rates among women and Employee Retirement Income Security Act (ERISA) reforms, widows live with lower household earnings, pension income, and wealth than do married women. Women widowed at younger ages are at greatest risk for economic hardship after widowhood and their situation declines with the duration of widowhood. We also find that women in households that are least prepared financially for widowhood are at greatest risk of husband{\textquoteright}s death, because of the strong relationship between mortality and wealth.}, keywords = {Net Worth and Assets}, url = {https://www.ssa.gov/policy/docs/ssb/v65n3/v65n3p31.html}, author = {Purvi Sevak and David R Weir and Robert J. Willis} }