Biostatistics Core leadership and staff continue to provide expertise in data collection, study design, and statistical analysis to high priority research on frailty – in studies sponsored by OAIC cores, and selected funded research projects. This activity occurs through direct collaboration, the provision of database and computing infrastructure, mentorship, and leadership. Among specific highlights for the past five years:
Core-Supported Pilot Projects:
(1) Heart rate variability and frailty (Paulo Chaves, MD, PhD; Year 1) – This study investigated the role of dysregulation of cardiovascular dynamics, as assessed by measures of heart rate variability and complexity, in frailty and disability.
(2) Genetics determinants of muscle weakness (Jeremy Walston, MD; Year 2) – This project utilized WHAS I and II data to identify IL-6 gene variants associated with elevations of serum IL-6, and to determine the relationship between these genotypes, skeletal muscle strength, and the syndrome of frailty. The results have been published in Experimental Gerontology, 40:344-352.
(3) Cholesterol and cognition in late life (Michelle Mielke, PhD; Year 3) – The aim of this study was to describe the relationship between brain-derived and peripheral cholesterol levels and various domains of cognition, including speed of processing, executive functioning, memory and global cognition. The results have been published in J Gerontol A Biol Sci Med Sci. 2008; 63(6):619-24.
(4) Selenium supplementation trial (Richard Semba, MD, Jeremy Walston, MD; Year 4) – This study aimed to study (i) the effects of oral selenium supplementation on the inflammatory response in older adults with an increased IL-6 level and low normal selenium levels over a two month intervention period; (ii) the effects of selenium supplementation on the activity of the selenium- dependent antioxidant enzyme glutathione peroxidase, and on altered protein production in older adults with increased serum IL-6 and low normal levels of selenium; and (iii) the effect of selenium supplementation on hemoglobin.
(5) The Effect of High-Intensity Volunteering on the Risk of Frailty (Erwin Tan, MD; Year 5) –the Experience Corps Baltimore trial is a community-based health promotion trial to evaluate a senior volunteer program which places people 60 and older in meaningful roles in public elementary schools designed to have high impact on children’s' outcomes and intend to increase social, cognitive and physical activity of EC volunteers. This study investigates potential multi-physiologic system effects of Experience Corps program participation on increasing physical and cognitive activity
Core-Supported Pilot Projects:
(1) Hemoglobin and mortality in disabled older women (Paulo Chaves, MD, PhD; Year 1) – This study examined the associations between hemoglobin concentration and 5-year all-cause mortality and serum erythropoietin as the basis for the identification of date-driven thresholds and to assess the clinical relevance of mildly low Hb. The results from this study have been published in The Journal of the American Geriatrics Society, 52:1-6.
(2) Hospitalization and ADL dependence in older women (Cynthia Boyd, MD; Years 1-2) –Changes in self-reported function in older adults are known to occur in the 2 weeks prior to, during, and in the first few months after hospitalization. The long-term outcome of hospitalization on functional status in disabled older adults is not known. The objective of this study was to determine whether hospitalization predicts long-term Activities of Daily Living (ADL) dependence in previously ADL independent, although disabled, older women. The results from this study have been published in J Gerontol A Biol Sci Med Sci.;60(7):888-93.
(3) Contributions of serum IL-6 level and total/differential WBC to frailty (Sean Leng, MD, PhD; Year 3) – To help to advance understanding of the involvement of WBC and IL-6 as two distinct components of the inflammation system underlying the geriatric syndrome of frailty, this study conducted a cross-sectional analysis of data from the WHAS cohorts to evaluate independent and potentially synergistic associations between prevalent frailty and WBC counts and IL-6 levels. The results from this study have been published in The Journal of the American Geriatrics Society, 55(6):864-71.
(4) Modeling multiple physiological systems and the social context of frailty (Chris Seplaki, PhD; Years 4-5) – This project aims: 1) To test the hypothesis that the aggregate number of physiologic systems not functioning normally is an independent determinant of the presence and extent of the frailty syndrome; 2) Develop a theory of the relationship between frailty and stress-related physiological dysregulation, and to evaluate the theorized associations and their independent or aggregate effects; 3) To develop evidence as to the life course development of frailty and whether the onset of either physiotype or phenotype is occurring later in the life span with successive birth cohorts.
Core-Supported External Research Projects:
(1) Characterization, onset, and outcomes of frailty (Women’s Health and Aging Study; Linda Fried, MD; Years 1-3) – Research augmenting the original study hypotheses to the investigation of frailty was completed along two lines: (a) We evaluated evidence for the association of multiple physiological systems and frailty, applying advanced methods such as cluster and latent class analyses; (b) As an RC1-funded project, our Core Director evaluated evidence for progressive development of a frailty syndrome, which may become a cycle. These studies laid important groundwork for identifying threshold relationships of multisystem physiologic dysregulations with frailty. The results of this study have been published by J Gerontol A Biol Sci Med Sci. 63(9):
(2) Groundwork for delineating the implications of disordered sleep for frailty in older adults (Early Identification and Treatment of Sleep Disordered Breathing and Sleep Heart Health Study; Naresh Punjabi, MD; Years 1-2) – We collaborated with Dr. Punjabi to design and implement innovative multi-stage modeling analyses of transitions through sleep stages, using night-long polysomnography data. These analyses lay the groundwork to better delineate sleep architecture, and determine its role quality in frailty and subsequent outcomes.
(3) Frailty ramifications for post-surgical outcomes (Jahnigan Career Development Award, Martin A. Makary, MD; Year 3). Dr. Makary’s parent project is investigating surgical decision making in older patients. In December, 2005, he responded to an RC1 support solicitation, requesting assistance in augmenting his study to evaluate the utility of frailty status as a predictor of adverse surgical outcomes, net of standard surgical risk indices. Frail status was found to strongly predict complications, length of hospital stay, and discharge to institution, independently of standard surgical risk scores, and with high predictive accuracy.
(4) Genetic determinants of cognitive decline (Cognitive Pathways Study, Michelle Carlson, Ph.D.; Year 3-present) – This study aims to identify gene variants associated with trajectories of cognitive frailty and decline in the WHAS cohort. It benefits from the participation of Marilyn Albert, Ph.D; Professor of Neurology and an internationally recognized expert in the study of Alzheimer’s disease. The Genetics, Genomics, and Molecular Core has collaborated with Drs. Albert and Carlson on selection of genes associated with cognitive decline and genotyping of these new SNPs. In collaboration, our core developed an analysis plan to assess the relationship between the measures of cognition and the sets of genotypes and is collaborating in implementing it.
Methods Development Projects:
Beyond supporting the science of this OAIC, our Core is optimally positioned to lead in answering important unresolved methodological questions for research on frailty and its amelioration. Here are two examples:
(1) Methodology for Producing Frailty Phenotypes – “Frailty” has been usefully conceptualized and measured from a number of perspectives. Our group conceptualizes frailty as a syndrome of decreased resiliency. In 2001, investigators who would lead this OAIC published a “phenotype” (henceforth, “CHS”) for frailty underlain by the aforementioned theory. While this work was a major advance, gaps remained at the initiation of this OAIC. Construct validation was lacking. A paradigm for accomplishing such validation, and then producing measures, was needed. We saw a need to advance beyond clinical assessment, and define “physiotypes” more closely tied to the defining biology. This project advanced toward filling each gap. We modeled frailty as a “latent” variable. As accomplishment #1, it supplied internal construct validation of the CHS phenotype vis à vis hypothesis of frailty as a clinical syndrome. As accomplishment #2, it advanced statistical methods for deriving phenotypic summary measures from latent variable models. As accomplishment #3, it applied its overarching paradigm to characterize generalized pro-inflammation in the InCHIANTI study — an important first step toward the development of frailty “physiotypes.”
(2) Methods to improve accuracy of findings subject to loss of information – Such loss is frequent for data on frailty. This may well relate to frailty severity, thus substantially bias causal associations, lose statistical power, and limit generalizability of research findings. This project advanced capability for handling these problems, on two fronts. First, a procedure was developed to better account for missing covariate information in studies where screening information is available for a sub-sample that is more nearly population-representative than a full study sample. Secondly, an analytic strategy employing the semi-parametric proportional subdistributional hazards model was developed to better handle competing risk of mortality — a huge challenge for the study of frailty incidence. It was applied to estimate the association between life-space constriction and cumulative incidence of frailty in the WHAS, accounting for frailty-free mortality. The results of this study have been published by Am J Epidemiol. 2008; 167(2):240-48.
Methods created through this Core’s Development Projects have significantly advanced capability for studying frailty. Building on these, we now propose to take on five new challenges for frailty research, focused on increasing our ability translate observational research into clinical treatments and practice:
(1) To improve biological specificity in characterizing frailty. We would develop mathematical, dynamical systems models making operational the theory that frailty results from mutually accelerating dysregulation in multiple homeostatically linked physiological systems.
(2) To design studies that can empirically test predictions made by competing theoretic and mathematical models for frailty.
(3) Building on i)-ii), to identify aspects of dysregulation that are rate-limiting for effective treatment, thus strategies to interrupt the spiral as a whole.
(4) To create intervention trial designs to evaluate and compare the effectiveness of (a) multi-faceted interventions that may be necessary to ameliorate multi-systemic dysregulation underlying frailty, and (b) single-faceted interventions hypothesized either to act globally or intervene on critical points.
(5) To define when a body of evidence on frailty becomes sufficient to justify new clinical practices, and what are the most parsimonious, cost-effective targets for clinical translation. We consider this a “science of translation.”