DESCRIPTION (provided by applicant): The age-related loss of muscle mass and strength is an important contributor to mobility disability, poor health outcomes, and death. It is important t identify older adults in whom mobility limitation is due to low muscle mass and strength because they may be potentially amenable to treatment with novel therapies that increase muscle mass and muscle strength. Accordingly, in response to RFA-AG-15-013, we have assembled a large interdisciplinary team of experts and key opinion leaders to develop and evaluate diagnostic cut-points for low muscle mass and muscle strength that predict an increased risk of mobility-disability among older adults, defined operationally as gait speed < 0.8 meters/ sec. We will analyze pooled data from two types of studies that include large number of individuals with mobility-disability to accomplish the aims listed below: 1. Studies of community-dwelling older adults, limited to participants with mobility complaints; 2. Carefully characterized clinical populations of patients with heart failure, hip fracture, osteoarthritis, or human immune-deficiency virus (HIV)-infection at risk for mobility-disability, and participants of randomized trals of older adults with low muscle mass, muscle strength or mobility limitation. Aim 1 is to develop and assess diagnostic cut-points for low muscle mass and strength - separately for men and women - with regard to their sensitivity, specificity and positive predictive value (PPV) in identifying those at risk of prevalent and incident mobility disability in epidemiologic studies of community-dwelling older adults with higher prevalence of mobility disability than the general population. We will weigh the trade-off between sensitivity and specificity in establishing cut-points for lean mass and strength. We will evaluate various approaches to allometrically scale muscle mass, strength and physical performance measures in predicting risk of mobility disability. We will evaluate whether composite, multi-component models that include both muscle mass and strength may be more predictive of mobility-disability than separate cut-points for each. We will assess the effects of comorbid conditions on the relation between muscle mass, strength, and mobility. We will also establish cut-points for change in muscle mass and strength that best discriminate those who develop mobility disability from those who do not. Aim 2 will apply the cut-points established in aim 1 to carefully characterized clinical populations an to participants of randomized trials to evaluate their sensitivity, specificity, and PPV in these populations. Aim 3 will compare the sensitivity, specificity, and positive predictive value of new cut-points with those proposed previously by others. We have added two exploratory aims to 1. determine whether consideration of muscle quality improves the sensitivity, specificity, and PPV of cut-points, and 2. evaluate various approaches to allometrically scale adiposity in establishing the cut-points. We will convene a consensus conference of stakeholders to review the results towards the goal of securing a consensus on these evidence-based cut points. The findings of this project have important implications for clinical practice, public health and policy, and drug development.

PUBLIC HEALTH RELEVANCE Mobility disability is a major public health problem, which contributes to loss of independence and poor health outcomes; older adults in whom mobility limitation is due to low muscle mass and strength may be amenable to treatment with novel pharmacological therapies. Accordingly, this project will develop and evaluate diagnostic cut-points for low muscle mass and muscle strength that predict an increased risk of mobility disability among older adults by analyzing pooled and harmonized data from two types of studies that include the largest number of individuals with mobility disability ever assembled: 1. Studies of community-dwelling older adults, limited to participants with mobility complaints; 2. Carefully characterized clinical populations of patients with heart failure, hip fracture, knee osteoarthritis, or human immune-deficiency virus (HIV)-infection at risk for mobility disability, and randomized trials of older adlts with low muscle mass, muscle strength or mobility limitation. The findings of this project have important implications for clinical practice, public health and policy, and drug development.