Frailty is a clinical syndrome characterized by decreased resilience to stressors, resulting from dysregulation across multiple physiological systems. Frailty is prevalent in elders and is associated with a wide range of adverse outcomes including death, disability, hip fracture, and falls. In the absence of a gold standard, there is a lack of consensus on the operational definition of frailty. Fried and colleagues developed the physical frailty phenotype (PFP) scale using gait speed, grip strength, exhaustion, physical activity, and weight loss. Since its emergence, the PFP scale has been repeatedly validated and widely used in assessing frailty. The PFP scale, however, like all other frailty assessments, has limitations. First, precision is lost in the process of dichotomizing continuous indicators (e.g., gait speed). In addition, all five frailty indicators in the PFP scale are assumed to be of equal importance in measuring frailty. Moreover, the PFP scale is very effective in identifying the frailest elders but has limited ability to differentiate persons with low levels of frailty. This dissertation had two overarching goals. The first was to create a new continuous scale for assessing frailty and to comprehensively evaluate its construct and predictive validity as well as measurement properties. The second was to explore the genetic basis of frailty. First, I demonstrated the feasibility to construct a continuous frailty scale that had high construct validity and desirable measurement properties. Second, I showed that the new continuous frailty scale had high predictive validity for adverse health outcomes including mortality, disability, hip fracture, and falls among older adults. Third, the new scale could provide additional risk stratification for adverse outcomes above and beyond the categorical PFP scale, especially at the lower to middle end of the frailty continuum. Fourth, the new frailty scale was strongly associated with recovery of and improvement in activities of daily living function among elders who were newly disabled. Fifth, older persons with higher scores on the new frailty scale were more likely to have prolonged length of hospital stay after undergoing myocardial infarction and coronary artery bypass grafting. Additionally, frailer elders had higher mortality after experiencing myocardial infarction, heart failure, pneumonia, and coronary artery bypass grafting. Lastly, several genetic variants that have biological plausibility were suggestively associated with frailty. From a methodological perspective, the new continuous frailty scale frailty is a valid continuous construct with a unidimensional factor structure robust to nuanced differences in measurements and invariant across cohorts and demographics including age and sex. In addition, the new frailty scale has high predictive validity for multiple health outcomes including death, disability, hip fracture, and falls among community-dwelling older adults. Moreover, the new frailty scale could capture elders’ ability to recover from stressors (disability, medical events, and surgeries), which is considered one of the defining features of frailty. Findings from this dissertation could also have important public health and clinical implications. First, the new continuous frailty scale could further stratify risk of outcomes among robust and prefrail persons, suggesting these two subgroups were not homogeneous. Second, the new frailty scale was able to pinpoint frailty level in the early stage, which may be valuable for identifying at-risk persons who are not frail yet and offers opportunities for interventions that prevent or slow down the progression of frailty and maintain health and function. Third, assessment of frailty may help clinicians, public health professionals, and researchers better identify at-risk elders after experiencing disability and acute diseases and provide useful information in making informed decisions about surgical procedures. Fourth, the new continuous frailty scale, due to its continuous and sensitive nature, may be suitable to evaluate the effectiveness of interventions for frailty and track trajectories of frailty over time
