Genetic Modulations of Morbidity Compression: A Population-Based Study



 DESCRIPTION (provided by applicant): Human longevity steadily increased over the past century. There is great uncertainty, however, regarding the extent to which this was accompanied by the compression of morbidity. Given current dramatic increases in health care costs, especially costs during the last 6 months of life, this question is of profound importance t society. The National Long Term Care Survey (NLTCS) is a Medicare-based sample of the U.S. population aged 65+ initiated in 1982 with longitudinal follow-up in 1984, 1989, 1994, 1999, and 2004, with complete linkage to Medicare claims and vital statistics data for 1982-2009, and for eligible participants to Medicaid files (i.e., the 2004-2007 MAX files), supplemented with the 1999-2009 MDS and OASIS files. The 1982-1994 NLTCS produced the first reported major improvements of functional health as assessed by Activities of Daily Living (ADL) and Instrumental ADL (IADL) scores within the NLTCS population. The 1999 NLTCS substantially expanded its scope by selecting 1,877 participants and 869 siblings for supplemental data collection in 2000- 2002, yielding 639 blood (participants only) and 2,078 buccal swab (participants and siblings) samples for genetic studies. Moreover, of the 1,808 NLTCS participants contributing to the biospecimen sample, 1,345 were alive at the 2004 NLTCS and 1,183 were re-assessed. A total of 1,031 participants were age 85+ initially (429) or attained age 85 during the 2000-2010 follow-up period (602), with a total of 717 still alive as of the cutof date in 2010. The biospecimen sample currently provides 13,303 person-years of follow-up data, with 5,098 person-years above age 85. We propose to utilize this unique population-based sample, its associated functional data, linked Medicare/Medicaid claims data, and DNA samples, to quantitate variable degrees of the compression of morbidity and to test the hypothesis that constitutional genetic factors contribute to the modulation of these differential ratios of healthspans/lifespans. We will first address the connections between longevity, co-morbidity, functional health (ADL/IADL), and declines of physiological and cognitive functions (Aim 1). We will then conduct SNP array analysis of 639 blood and 2,078 buccal swab samples to obtain and assess a wide range of genetic information (Aim 2). We will assess associations of phenotypes of long healthy life with candidate polymorphisms within two highly relevant coupled gene networks-Insulin/IGF1 signaling (incl. FOXO3A and IGFR) and mTOR pathways-linked to aging and longevity across different species (Aim 3). Then, given published associations of genome-wide heterozygosity with cardiovascular health (Campbell et al., 2007), we will seek such associations with degrees of morbidity compression (Aim 4). Also, given the scientific value of the project data, we will release additional years of de-identified CMS data (Aim 5) and de- identified versions of the genotypic/phenotypic data derived from our SNP array analysis (Aim 6), using CMS, NIA, and Duke IRB approved protocols. We will replicate/validate our results using data from the Health and Retirement Study (HRS), employing comparable phenotypic and genotypic measures and linked CMS data.