A Comparison of 5 Measures of Accelerated Biological Aging and Their Association With Incident Cardiovascular Disease: The CARDIA Study.

BACKGROUND: Accelerated biological aging is an increasingly popular way to track the acceleration of biology over time that may not be captured by calendar time. Biological aging has been linked to external and internal chronic stressors and has the potential to be used clinically to understand a person's personalized functioning and predict future disease. We compared the association of different measures of biological aging and incident cardiovascular disease (CVD) overall and by race. METHODS AND RESULTS: We used multiple informants models to compare the strength of clinical marker-derived age acceleration, 5 measures of epigenetic age acceleration (intrinsic and extrinsic epigenetic age acceleration, GrimAge acceleration, and PhenoAge acceleration), and 1 established clinical predictor of future CVD, Framingham 10-year risk score, with incident CVD over an 11-year period (2007-2018). Participants were 913 self-identified Black or White (41% and 59%, respectively) female or male (51% and 49%, respectively) individuals enrolled in the US-based CARDIA (Coronary Artery Risk Development in Young Adults) cohort study. The analytic baseline for this study was the 20-year follow-up examination (2005-2006; median age 45 years). We also included race-specific analysis. We found that all measures were modestly correlated with one another. However, clinical marker-derived age acceleration and Framingham 10-year risk score were more strongly associated with incident CVD than all the epigenetic measures. Clinical marker-derived age acceleration and Framingham 10-year risk score were not significantly different than one another in their association with incident CVD. CONCLUSIONS: The type of accelerated aging measure should be taken into consideration when comparing their association with clinical outcomes. A multisystem clinical composite shows associations with incident CVD equally to a well-known clinical predictor.

Aging, Race, and Health Disparities: Recommendations from the Research Centers Collaborative Network.

Racial disparities in adverse health outcomes with aging have been well described. Yet, much of the research focuses on racial comparisons, with relatively less attention to the identification of underlying mechanisms. To address these gaps, the Research Centers Collaborative Network held a workshop on aging, race, and health disparities to identify research priorities and inform the investigation, implementation, and dissemination of strategies to mitigate disparities in healthy aging. This article provides a summary of the key recommendations and highlights the need for research that builds a strong evidence base with both clinical and policy implications. Successful execution of these recommendations will require a concerted effort to increase participation of underrepresented groups in research through community engagement and partnerships. In addition, resources to support and promote the training and development of health disparities researchers will be critical in making health equity a shared responsibility for all major stakeholders.

Self-reported experiences of discrimination and incident dementia.

INTRODUCTION: Discrimination negatively impacts health and may contribute to racial/ethnic disparities in dementia risk. METHODS: Experiences of lifetime and everyday discrimination were assessed among 6509 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We assessed the association of discrimination with incidence of dementia including adjustment for important risk factors, cohort attrition, and we assessed for effect modification by race/ethnicity. RESULTS: Prevalence of any lifetime discrimination in MESA was 42%, highest among Black adults (72%). Over a median 15.7 years of follow-up, there were 466 incident cases of dementia. Lifetime discrimination, but not everyday discrimination, was associated with incident dementia (Wald p = 0.03). Individuals reporting lifetime discrimination in ≥2 domains (compared to none) had greater risk for dementia (hazard ratio: 1.40; 95%: 1.08, 1.82) after adjustment for sociodemographic, clinical, and behavioral risk factors. Associations did not differ by race/ethnicity. CONCLUSIONS: These findings demonstrate an association of greater experiences of lifetime discrimination with incident dementia.

Relative contributions of six lifestyle- and health-related exposures to epigenetic aging: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: DNA methylation-based GrimAge acceleration (GrimAA) is associated with a wide range of age-related health outcomes including cardiovascular disease. Since DNA methylation is modifiable by external and behavioral exposures, it is important to identify which of these exposures may have the strongest contributions to differences in GrimAA, to help guide potential intervention strategies. Here, we assessed the relative contributions of lifestyle- and health-related components, as well as their collective association, to GrimAA. RESULTS: We included 744 participants (391 men and 353 women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with blood DNA methylation information at CARDIA Exam Year (Y) 20 (2005-2006, mean age 45.9 years). Six cumulative exposures by Y20 were included in the analysis: total packs of cigarettes, total alcohol consumption, education years, healthy diet score, sleep hours, and physical activity. We used quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods to assess the relative contribution of each exposure to a single overall association with GrimAA. We also assessed the collective association of the six components combined with GrimAA. Smoking showed the greatest positive contribution to GrimAA, accounting for 83.5% of overall positive associations of the six exposures with GrimAA (QGC weight = 0.835). The posterior inclusion probability (PIP) of smoking also achieved the highest score of 1.0 from BKMR analysis. Healthy diet and education years showed inverse contributions to GrimAA. We observed a U-shaped pattern in the contribution of alcohol consumption to GrimAA. While smoking was the greatest contributor across sex and race subgroups, the relative contributions of other components varied by subgroups. CONCLUSIONS: Smoking, alcohol consumption, and education showed the highest contributions to GrimAA in our study. Higher amounts of smoking and alcohol consumption were likely to contribute to greater GrimAA, whereas achieved education was likely to contribute to lower GrimAA. Identifying pertinent lifestyle- and health-related exposures in a context of collective components can provide direction for intervention strategies and suggests which components should be the primary focus for promoting younger GrimAA.

Association Between Body Mass Index and Cancer Screening Adherence Among Latinas in the United States and Puerto Rico.

Background: Research on the role of body size on cancer screening is mixed with few studies among Latinas in the United States. We evaluated the association between body size and cancer screening adherence among Latinas living in Puerto Rico and the rest of the United States. Methods: We conducted a cross-sectional study using 2012-2018 Behavioral Risk Factor Surveillance System data among Latinas 50-64 years of age (n = 16,410). Breast, cervical, and colorectal cancer screening (guideline adherent: yes/no), height and weight were self-reported. Prevalence ratios (PRs) derived from Poisson models were estimated for each cancer screening utilization for Puerto Rico versus rest of the United States by body mass index (BMI) category. Results: Nearly a quarter of women lacked adherence with breast and cervical cancer screening and 43.6% were nonadherent to colorectal cancer screening. Latinas with BMI ≥40.0 kg/m2 in both groups were more likely to lack adherence to cervical cancer screening than women with BMI 18.5-24.9 kg/m2. For those with BMI ≥40.0 kg/m2, Latinas in Puerto Rico were more likely to lack adherence to colorectal cancer screening recommendations than Latinas living in the rest of the United States (adjusted PR: 1.38; 95% confidence interval = 1.12-1.70). Conclusions: The role of body size in cancer screening utilization among Latinas differs in women living in Puerto Rico versus in the rest of the United States and varies by cancer type. Understanding Latinas' experience can inform culturally adapted interventions to promote cancer screening.

Navigating Black Aging: The Biological Consequences of Stress and Depression.

OBJECTIVES: Black persons in the United States are more likely to suffer from social inequality. Chronic stress caused by social inequality and racial discrimination results in weathering of the body that causes physiological dysregulation and biological age being higher than chronological age (accelerated aging). Depression has been linked to both racial discrimination and accelerated aging and accelerated aging has been demonstrated to be higher in Black than White persons, on average. However, we know little about accelerated aging across the life course in Black Americans. METHODS: We used mixed-effects growth models to measure biological age acceleration, measured with cardiometabolic markers, over a 20-year period in Black participants of the Coronary Artery Risk Development in Young Adults Study who were aged 27-42 years at analytic baseline. We included an interaction between depressive symptoms and time to determine whether risk of depression was associated with a faster rate of biological aging. RESULTS: We found that the rate of biological aging increased over a 20-year span and that those at risk for depression had a faster rate of biological aging than those not at risk. We also found that various social factors were associated with biological age acceleration over time. DISCUSSION: Given the known association between perceived racial discrimination and depressive symptoms, we provide a novel instance of the long-term effects of social inequality. Specifically, biological age acceleration, a marker of physiological dysregulation, is associated with time among Black persons and more strongly associated among those with depressive symptoms.

Racial differences in the association of accelerated aging with future cardiovascular events and all-cause mortality: the coronary artery risk development in young adults study, 2007-2018.

OBJECTIVE: Variability of Cardiovascular disease (CVD) risk, including racial difference, is not fully accounted for by the variability of traditional CVD risk factors. We used a multiple biomarker model as a framework to explore known racial differences in CVD burden. DESIGN: We measured associations between accelerated aging (AccA) measured by a combination of biomarkers, and cardiovascular morbidity and all-cause mortality using data from the Coronary Artery Risk Development in Young Adults study (CARDIA). AccA was defined as the difference between biological age, calculated using biomarkers with the Klemera and Doubal method, and chronological age. Using logistic regression, we assessed overall and race-specific associations between AccA, CVD, and all-cause mortality. RESULTS: Among our cohort of 2959 Black or White middle-aged adults, after adjustment, a one-year increase in AccA was associated with increased odds of CVD (Odds Ratio (OR) = 1.04; 95% CI: 1.02, 1.06), stroke (OR = 1.12; 95% CI: 1.07, 1.17), and all-cause mortality (OR = 1.05; 95% CI: 1.02, 1.08). We did not find significant overall racial differences, but we did find race by sex differences where Black men differed markedly from White men in the strength of association with CVD (OR = 1.06, 95% CI: 1.01, 1.12). CONCLUSIONS: We provide evidence that AccA is associated with future CVD.

A cross-sectional analysis of racial differences in accelerated aging and cognitive function among patients with atrial fibrillation: The SAGE-AF study: Forrester, Accelerated aging and cognitive function.

BACKGROUND: Non-Whites are more likely to suffer from cognitive impairment and complications of atrial fibrillation (AF) than Whites, though Whites are more likely to be diagnosed with AF. We examined whether non-Whites with AF are biologically older than Whites with AF and whether accelerated biological aging is associated with cognitive functioning. METHODS: We used baseline data from the ongoing Systematic Assessment of Geriatric Elements in Atrial Fibrillation prospective cohort study, collected 2016-2020 across ambulatory care practices in Massachusetts and Georgia. Of 1244 enrolled, 974 participants with full biological data were included in the present analysis. Accelerated aging (AccA) was calculated based on a combination of biomarkers associated with age and physiological "wear and tear." FINDINGS: The main outcome was score on Montreal Cognitive Assessment (MoCA). Non-Whites had 2.9 years more AccA than Whites and higher AccA was associated with a lower MoCA score among both Whites (-0.06, 95% CI: -0.10, -0.03) and non-Whites (-0.14, 95% CI: -0.27, 0.02). This association was significantly greater among non-whites (-0.11, 95% CI: -0.20, -0.01). INTERPRETATION: Non-White AF patients are functionally "older" than their White counterparts and experience a stronger deleterious association between AccA and cognition. These findings underscore the importance of taking functional age into account when treating patients with AF, particularly non-White patients, to enhance treatment and improve AF outcomes.

Allostatic Load Among Black Sexual Minority Women.

Background: Allostatic load is the physiological deterioration that accumulates as the body responds to stress, resulting in disparities in chronic disease. Although perceptions of stress vary, marginalization and social disadvantage are associated with elevated allostatic load. Allostatic load is understudied in the multiply marginalized populations of sexual minority Black women. Methods: We used data from six waves of the National Health and Nutrition Examination Survey (2001-2010, 2015-2016) to identify heterosexual (n = 78), lesbian (n = 21), and bisexual (n = 57) Black women. We quantified allostatic load using nine biomarkers, and compared mean allostatic load across the three groups, adjusting for age, educational attainment, income, and country of birth to account for possible confounding. Results: We found no significant differences in allostatic load among heterosexual, lesbian, and bisexual Black women. Conclusions: These findings suggest that sexual orientation may not contribute to within-group differences in allostatic load among Black women, a group previously noted to have elevated allostatic load.

Accelerated aging: A marker for social factors resulting in cardiovascular events?

BACKGROUND: Medicine and public health are shifting away from a purely "personal responsibility" model of cardiovascular disease (CVD) prevention towards a societal view targeting social and environmental conditions and how these result in disease. Given the strong association between social conditions and CVD outcomes, we hypothesize that accelerated aging, measuring earlier health decline associated with chronological aging through a combination of biomarkers, may be a marker for the association between social conditions and CVD. METHODS: We used data from the Coronary Artery Risk Development in Young Adults study (CARDIA). Accelerated aging was defined as the difference between biological and chronological age. Biological age was derived as a combination of 7 biomarkers (total cholesterol, HDL, glucose, BMI, CRP, FEV1/h2, MAP), representing the physiological effect of "wear and tear" usually associated with chronological aging. We studied accelerated aging measured in 2005-06 as a mediator of the association between social factors measured in 2000-01 and 1) any incident CVD event; 2) stroke; and 3) all-cause mortality occurring from 2007 through 18. RESULTS: Among 2978 middle-aged participants, mean (SD) accelerated aging was 3.6 (11.6) years, i.e., the CARDIA cohort appeared to be, on average, 3 years older than its chronological age. Accelerated aging partially mediated the association between social factors and CVD (N=219), stroke (N=36), and mortality (N=59). Accelerated aging mediated 41% of the total effects of racial discrimination on stroke after adjustment for covariates. Accelerated aging also mediated other relationships but to lesser degrees. CONCLUSION: We provide new evidence that accelerated aging based on easily measurable biomarkers may be a viable marker to partially explain how social factors can lead to cardiovascular outcomes and death.

Cancer Pain in Relation to Metropolitan Area Segregation and Nursing Home Racial and Ethnic Composition.

OBJECTIVES: To estimate pain reporting among residents with cancer in relation to metropolitan area segregation and NH racial and ethnic composition. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: 383,757 newly admitted black (B), Hispanic (H), or white (W) residents with cancer in 12,096 US NHs (2011-2013). METHODS: Using the Minimum Data Set 3.0, pain in past 5 days was determined by self-report or use of pain management. The Theil entropy index, a measure of metropolitan area segregation, was categorized [high (up to 0.20), very high (0.20-0.30), or extreme (0.30-0.53)]. RESULTS: Pain prevalence decreased across segregation level (black: high = 77%, very high = 75%, extreme = 72%; Hispanic: high = 79%, very high = 77%, extreme = 70%; white: high = 80%, very high = 77%, extreme = 74%). In extremely segregated areas, all residents were less likely to have recorded pain [adjusted prevalence ratios: blacks, 4.6% less likely, 95% confidence interval (CI) 3.1%-6.1%; Hispanics, 6.9% less likely, 95% CI 4.2%-9.6%; whites, 7.4% less likely, 95% CI 6.5%-8.2%] than in the least segregated areas. At all segregation levels, pain was recorded more frequently for residents (black or white) in predominantly white (>80%) NHs than in mostly black (>50%) NHs or residents (Hispanic or white) in predominantly white NHs than mostly Hispanic (>50%) NHs. CONCLUSIONS AND IMPLICATIONS: We observed decreased pain recording in metropolitan areas with greater racial and ethnic segregation. This may occur through the inequitable distribution of resources between NHs, resident-provider empathy, provider implicit bias, resident trust, and other factors.

Racial Segregation Across U.S. Nursing Homes: A Systematic Review of Measurement and Outcomes.

BACKGROUND AND OBJECTIVES: Nursing homes remain subjected to institutional racial segregation in the United States. However, a standardized approach to measure segregation in nursing homes does not appear to be established. A systematic review was conducted to identify all formal measurement approaches to evaluate racial segregation among nursing home facilities, and to then identify the association between segregation and quality of care in this context. RESEARCH DESIGN AND METHODS: PubMed, Scopus, and Web of Science databases were searched (January 2018) for publications relating to nursing home segregation. Following the PRISMA guidelines, studies were included that formally measured racial segregation of nursing homes residents across facilities with regional-level data. RESULTS: Eight studies met the inclusion criteria. Formal segregation measures included the Dissimilarity Index, Disparities Quality Index, Modified Thiel's Entropy Index, Gini coefficient, and adapted models. The most common data sources were the Minimum Data Set (MDS; resident-level), the Certification and Survey Provider Enhanced Reporting data (CASPER; facility-level), and the Area Resource File/ U.S. Census Data (regional-level). Most studies showed evidence of racial segregation among U.S. nursing home facilities and documented a negative impact of segregation on racial minorities and facility-level quality outcomes. DISCUSSION AND IMPLICATIONS: The measurement of racial segregation among nursing homes is heterogeneous. While there are limitations to each methodology, this review can be used as a reference when trying to determine the best approach to measure racial segregation in future studies. Moreover, racial segregation among nursing homes remains a problem and should be further evaluated.

Advances in Understanding the Causes and Consequences of Health Disparities in Aging Minorities.

PURPOSE OF REVIEW: The purpose was to discuss appropriate methods for advancing our understanding of health disparities or minority aging including life-course perspectives, biological measures, pain measurement, and generational approaches. RECENT FINDINGS: Life course perspectives provide an orientation for studying older minorities that concomitantly captures exposures and stressors that may lead to earlier onset of disease and premature mortality. The use of biological markers to study health disparities in older minorities is necessary in order to identify pathways between psychosocial factors and health outcomes. Work focusing on pain disparities should include explorations of relationships between psychosocial factors, and subjective and objective measures of pain. Studying families can provide insight into genetic associations and coping styles in older minorities. SUMMARY: Methodological approaches that take life course, biology, and social factors into account may help identify causal pathways between social determinants of health and health outcomes among older minorities. Once these causal pathways have been identified, more strategies and interventions that strive toward health equity across older adults of all race/ethnic groups can be developed.

Association between allostatic load and health behaviours: a latent class approach.

BACKGROUND: Allostatic load (AL) has been characterised in many ways throughout the literature; however, its relationship to health behaviours has only been studied in limited populations. We aimed to uncover qualitative patterns of biological indicators in AL and determine if those patterns were associated with certain health behaviours. METHODS: We conducted latent class analysis using biological indicators from a multiethnic population. We fit latent class regression of class on health behaviours (smoking, poor diet, physical activity and alcohol use) to measure the association between each latent class of AL and each health behaviour. RESULTS: Four classes, 'Metabolic+Cholesterol, 'Blood Pressure', 'Metabolic+Blood Pressure' and 'Low', were found in the sample. Latent class regression showed that physical activity and alcohol use were significantly associated with the 'Metabolic+Blood Pressure' class. CONCLUSION: Less physical activity was required to improve AL than was previously found. Low to moderate alcohol use was beneficial for lower AL. Implications of the amount of physical activity necessary to lower AL is discussed.

A Framework of Minority Stress: From Physiological Manifestations to Cognitive Outcomes.

Cognitive impairment and dementia continue to threaten the aging population. Although no one is immune, certain groups, namely black older persons, are more likely to have a diagnosis of certain dementias. Because researchers have not found a purely biological reason for this disparity, they have turned to a biopsychosocial model. Specifically, black persons in the United States are more likely to live with social conditions that affect their stress levels which in turn affect physiological regulation leading to conditions that result in higher levels of cognitive impairment or dementia. Here we discuss some of these social conditions such as discrimination, education, and socioeconomic status, and how physiological dysregulation, namely allostatic load that can lead to cognitive impairment and dementia in black persons especially.

Patterns of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Risk of Dementia.

OBJECTIVE: To identify clusters of patients with incident mild cognitive impairment (MCI) based on their neuropsychiatric symptoms (NPS) and to examine the risk of progression to dementia based on these clusters. METHODS: In this cohort study with a median of 2 years of follow-up from the National Alzheimer's Coordinating Center, 540 patients with MCI at least 60 years old with complete data and follow-up were studied. Latent class analysis was used to identify clusters of patients based on their NPS, and Cox proportional hazards models were used to examine risk of progression to dementia based on clusters. Incident MCI was defined as a participant having MCI at a current visit but having been cognitively normal at his or her previous (yearly) visit. The Neuropsychiatric Inventory Questionnaire assessed the presence of 12 neuropsychiatric behavioral domains. RESULTS: Three clusters were identified: a severe cluster (agitation, anxiety, apathy, nighttime behaviors, inhibition), an affective cluster (depression, anxiety, irritability, nighttime behaviors), and an asymptomatic cluster. The prevalence of each class was 56% for the asymptomatic class followed by the affective class (37%) and finally the severe class (7%). Compared with the asymptomatic class, the severe class had more than twice the hazard of progression to dementia (2.69; 95% CI: 1.12-2.70) and the affective class had over 1.5 times the hazard of progression to dementia (1.79; 95% CI: 1.12-2.70). CONCLUSION: Among persons with incident MCI, patterns of NPS may increase the likelihood of progression to dementia. Implications for early detection and treatment are discussed.

Latent Classes of Neuropsychiatric Symptoms in NACC Controls and Conversion to Mild Cognitive Impairment or Dementia.

BACKGROUND: A number of studies have linked neuropsychiatric symptoms to increase risk of dementia. OBJECTIVE: To determine if risk of conversion to mild cognitive impairment or dementia among healthy controls varied as a function of their pattern of neuropsychiatric symptoms. METHOD: We studied individuals in the National Alzheimer Coordinating Center dataset collected from 34 Alzheimer Disease Centers between 2005 and 2013. The analysis included 4,517 volunteers who were ≥60 years old, cognitively normal, and had complete Neuropsychiatric Inventory data at their baseline visit, and had at least one follow-up. We used latent class analysis to identify four classes based on patterns of NPI symptoms. We used a Cox proportional hazards model to determine if time to MCI or dementia varied by baseline latent class membership. RESULTS: We identified four latent classes of neuropsychiatric symptoms: irritable, depressed, complex (depression, apathy, irritability, and nighttime behaviors) and asymptomatic. 873 participants converted to MCI or dementia. Hazard ratios for conversion by class were 1.76 (95% CI: 1.34, 2.33) for the irritable class, 3.20 (95% CI: 2.24, 4.58) for the complex class, and 1.90 (95% CI: 1.49, 2.43) for the depressed class, with the asymptomatic class as the reference. CONCLUSIONS: Membership in all three symptomatic classes was associated with greater risk of conversion to MCI or dementia; the complex class had the greatest risk. Different patterns of neuropsychiatric symptoms may represent different underlying neuropathological pathways to dementia. Further work imaging and pathology research is necessary to determine if this is the case.

Latent classes of course in Alzheimer's disease and predictors: the Cache County Dementia Progression Study.

OBJECTIVE: Several longitudinal studies of Alzheimer's disease (AD) report heterogeneity in progression. We sought to identify groups (classes) of progression trajectories in the population-based Cache County Dementia Progression Study (N = 328) and to identify baseline predictors of membership for each group. METHODS: We used parallel-process growth mixture models to identify latent classes of trajectories on the basis of Mini-Mental State Exam (MMSE) and Clinical Dementia Rating sum of boxes scores over time. We then used bias-corrected multinomial logistic regression to model baseline predictors of latent class membership. We constructed receiver operating characteristic curves to demonstrate relative predictive utility of successive sets of predictors. RESULTS: We fit four latent classes; class 1 was the largest (72%) and had the slowest progression. Classes 2 (8%), 3 (11%), and 4 (8%) had more rapid worsening. In univariate analyses, longer dementia duration, presence of psychosis, and worse baseline MMSE and Clinical Dementia Rating sum of boxes were associated with membership in class 2, relative to class 1. Lower education was associated with membership in class 3. In the multivariate model, only MMSE remained a statistically significant predictor of class membership. Receiver operating characteristic areas under the curve were 0.98, 0.88, and 0.67, for classes 2, 3, and 4 relative to class 1. CONCLUSIONS: Heterogeneity in AD course can be usefully characterized using growth mixture models. The majority belonged to a class characterized by slower decline than is typically reported in clinical samples. Class membership could be predicted using baseline covariates. Further study may advance our prediction of AD course at the population level and in turn shed light on the pathophysiology of progression.

Simulating effects of biomarker enrichment on Alzheimer's disease prevention trials: conceptual framework and example.

BACKGROUND: We present a conceptual framework for simulations to determine the utility of biomarker enrichment to increase statistical power to detect a treatment effect in future Alzheimer's disease prevention trials. We include a limited set of simulation results to illustrate aspects of this framework. METHODS: We simulated data based on the Alzheimer's Disease Anti-Inflammatory Prevention Trial, and a range of sample sizes, biomarker positive predictive values, and treatment effects. We also investigated the consequences of assuming homogeneity of parameter estimates as a function of dementia outcome. RESULTS: Use of biomarkers to increase the sample fraction that would develop Alzheimer's disease in the absence of intervention from 0.5 to 0.8 would increase power from 0.35 to 0.69 with n = 200. Ignoring sample heterogeneity resulted in overestimation of power. CONCLUSION: Biomarker enrichment can increase statistical power, but estimates of the expected increase are sensitive to a variety of assumptions outlined in the framework.