Background and objective

Most methods for developing clinical prognostic models focus on identifying parsimonious and accurate models to predict a single outcome; however, patients and providers often want to predict multiple outcomes simultaneously. As an example, for older adults one is often interested in predicting nursing home admission as well as mortality. We propose and evaluate a novel predictor-selection computing method for multiple outcomes and provide the code for its implementation.

Methods

Our proposed algorithm selected the best subset of common predictors based on the minimum average normalized Bayesian Information Criterion (BIC) across outcomes: the Best Average BIC (baBIC) method. We compared the predictive accuracy (Harrell's C-statistic) and parsimony (number of predictors) of the model obtained using the baBIC method with: 1) a subset of common predictors obtained from the union of optimal models for each outcome (Union method), 2) a subset obtained from the intersection of optimal models for each outcome (Intersection method), and 3) a model with no variable selection (Full method). We used a case-study data from the Health and Retirement Study (HRS) to demonstrate our method and conducted a simulation study to investigate performance.

Results

In the case-study data and simulations, the average Harrell's C-statistics across outcomes of the models obtained with the baBIC and Union methods were comparable. Despite the similar discrimination, the baBIC method produced more parsimonious models than the Union method. In contrast, the models selected with the Intersection method were the most parsimonious, but with worst predictive accuracy, and the opposite was true in the Full method. In the simulations, the baBIC method performed well by identifying many of the predictors selected in the baBIC model of the case-study data most of the time and excluding those not selected in the majority of the simulations.

Conclusions

Our method identified a common subset of variables to predict multiple clinical outcomes with superior balance between parsimony and predictive accuracy to current methods.

Background Durable memory decline may occur in older adults after surgical (coronary artery bypass grafting [CABG]) or nonsurgical (percutaneous coronary intervention) coronary revascularization. However, it is unknown whether individual memory risk can be predicted. We reanalyzed an epidemiological cohort of older adults to predict memory decline at ≈1 year after revascularization. Methods and Results We studied Health and Retirement Study participants who underwent CABG or percutaneous coronary intervention at age ≥65 years between 1998 and 2015 and participated in ≥1 biennial postprocedure assessment. Using a memory score based on direct and proxy cognitive tests, we identified participants whose actual postprocedure memory score was 1-2 (mild) or >2 (major) SDs below expected postprocedure performance. We modeled probability of memory decline using logistic regression on preoperatively known factors and evaluated model discrimination and calibration. A total of 1390 participants (551 CABG, 839 percutaneous coronary intervention) underwent CABG/percutaneous coronary intervention at 75±6 years old; 40% were women. The cohort was 83% non-Hispanic White, 8.4% non-Hispanic Black, 6.4% Hispanic ethnicity, and 1.7% from other groups masked by the HRS (Health and Retirement Study) to preserve participant confidentiality. At a median of 1.1 (interquartile range, 0.6-1.6) years after procedure, 267 (19%) had mild memory decline and 88 (6.3%) had major memory decline. Factors predicting memory decline included older age, frailty, and off-pump CABG; obesity was protective. The optimism-corrected area under the receiver operator characteristic curve was 0.73 (95% CI, 0.71-0.77). A cutoff of 50% probability of memory decline identified 14% of the cohort as high risk, and was 94% specific and 30% sensitive for late memory decline. Conclusions Preoperative factors can be used to predict late memory decline after coronary revascularization in an epidemiological cohort with high specificity.

Background

Difficulties with daily functioning are common in middle-aged adults. However, little is known about the epidemiology or clinical course of these problems, including the extent to which they share common features with functional impairment in older adults.

Objective

To determine the epidemiology and clinical course of functional impairment and decline in middle age.

Design

Cohort study.

Setting

The Health and Retirement Study.

Participants

6874 community-dwelling adults aged 50 to 56 years who did not have functional impairment at enrollment.

Measurements

Impairment in activities of daily living (ADLs), defined as self-reported difficulty performing 1 or more ADLs, assessed every 2 years for a maximum follow-up of 20 years, and impairment in instrumental ADLs (IADLs), defined similarly. Data were analyzed by using multistate models that estimate probabilities of different outcomes.

Results

Impairment in ADLs developed in 22% of participants aged 50 to 64 years, in whom further functional transitions were common. Two years after the initial impairment, 4% (95% CI, 3% to 5%) of participants had died, 9% (CI, 8% to 11%) had further ADL decline, 50% (CI, 48% to 52%) had persistent impairment, and 37% (CI, 35% to 39%) had recovered independence. In the 10 years after the initial impairment, 16% (CI, 14% to 18%) had 1 or more episodes of functional decline and 28% (CI, 26% to 30%) recovered from their initial impairment and remained independent throughout this period. The pattern of findings was similar for IADLs.

Limitation

Functional status was self-reported.

Conclusion

Functional impairment and decline are common in middle age, as are transitions from impairment to independence and back again. Because functional decline in older adults has similar features, current interventions used for prevention in older adults may hold promise for those in middle age.

Primary funding source

National Institute on Aging and National Center for Advancing Translational Sciences through the University of California, San Francisco, Clinical and Translational Sciences Institute.

BACKGROUND: Many clinical and financial decisions for older adults depend on the future risk of disability and mortality. Prognostic tools for long-term disability risk in a general population are lacking. We aimed to create a comprehensive prognostic tool that predicts the risk of mortality, of activities of daily living (ADL) disability, and walking disability simultaneously using the same set of variables. METHODS: We conducted a longitudinal analysis of the nationally-representative Health and Retirement Study (HRS). We included community-dwelling adults aged ≥70 years who completed a core interview in the 2000 wave of HRS, with follow-up through 2018. We evaluated 40 predictors encompassing demographics, diseases, physical functioning, and instrumental ADLs. We applied novel methods to optimize three models simultaneously while prioritizing variables that take less time to ascertain during backward stepwise elimination. The death prediction model used Cox regression and both the models for walking disability and for ADL disability used Fine and Gray competing-risk regression. We examined calibration plots and generated optimism-corrected statistics of discrimination using bootstrapping. To simulate unavailable patient data, we also evaluated models excluding one or two variables from the final model. RESULTS: In 6646 HRS participants, 2662 developed walking disability, 3570 developed ADL disability, and 5689 died during a median follow-up of 9.5 years. The final prognostic tool had 16 variables. The optimism-corrected integrated area under the curve (iAUC) was 0.799 for mortality, 0.685 for walking disability, and 0.703 for ADL disability. At each percentile of predicted mortality risk, there was a substantial spread in the predicted risks of walking disability and ADL disability. Discrimination and calibration remained good even when missing one or two predictors from the model. This model is now available on ePrognosis (https://eprognosis.ucsf.edu/alexlee.php) CONCLUSIONS: Given the variability in disability risk for people with similar mortality risks, using individualized risks of disabilities may inform clinical and financial decisions for older adults.

Background

Despite concern that cardiac surgery may adversely affect cognition, little evidence is available from population-based studies using presurgery data. With the use of the Health and Retirement Study, we compared memory change after participant-reported cardiac catheterization or cardiac surgery.

Methods

Participants were community-dwelling adults aged 65 years and older who self-reported cardiac catheterization or "heart surgery" at any biennial Health and Retirement Study interview between 2000 and 2014. Participants may have undergone the index procedure any time in the preceding 2 years. We modeled preprocedure to postprocedure change in composite memory score, derived from objective memory testing, using linear mixed effects models. We modeled postprocedure subjective memory decline with logistic regression. To quantify clinical relevance, we used the predicted memory change to estimate impact on ability to manage medications and finances independently.

Results

Of 3,105 participants, 1,921 (62%) underwent catheterization and 1,184 (38%) underwent operation. In adjusted analyses, surgery participants had little difference in preprocedure to postprocedure memory change compared with participants undergoing cardiac catheterization (-0.021 memory units; 95% confidence interval: -0.046 to 0.005 memory units, p = 0.12). If the relationship were causal, the point estimate for memory decline would confer an absolute 0.26% or 0.19% decrease in ability to manage finances or medications, respectively, corresponding to 4.6 additional months of cognitive aging. Cardiac surgery was not associated with subjective memory decline (adjusted odds ratio 0.93, 95% confidence interval: 0.74 to 1.18).

Conclusions

In this large, population-based cohort, memory declines after heart surgery and cardiac catheterization were similar. These findings suggest intermediate-term population-level adverse cognitive effects of cardiac surgery, if any, are likely subtle.

Importance

Difficulty performing daily activities such as bathing and dressing ("functional impairment") affects nearly 15% of middle-aged adults. Older adults who develop such difficulties, often because of frailty and other age-related conditions, are at increased risk of acute care use, nursing home admission, and death. However, it is unknown if functional impairments that develop among middle-aged people, which may have different antecedents, have similar prognostic significance.

Objective

To determine whether middle-aged individuals who develop functional impairment are at increased risk for hospitalization, nursing home admission, and death.

Design, setting, and participants

This matched cohort study analyzed longitudinal data from the Health and Retirement Study, a nationally representative prospective cohort study of US adults. The study population included 5540 adults aged 50 to 56 years who did not have functional impairment at study entry in 1992, 1998, or 2004. Participants were followed biennially through 2014. Individuals who developed functional impairment between 50 and 64 years were matched by age, sex, and survey wave with individuals without impairment as of that age and survey wave. Statistical analysis was conducted from March 15, 2017, to December 11, 2018.

Exposures

Impairment in activities of daily living (ADLs), defined as self-reported difficulty performing 1 or more ADLs, and impairment in instrumental ADLs (IADLs), defined similarly.

Main outcomes and measures

The 3 primary outcomes were time from the first episode of functional impairment (or matched survey wave, in controls) to hospitalization, nursing home admission, and death. Follow-up assessments occurred every 2 years until 2014. Competing risks survival analysis was used to assess the association of functional impairment with hospitalization and nursing home admission and Cox proportional hazards regression analysis was used to assess the association with death.

Results

Of the 5540 study participants (2739 women and 2801 men; median age, 53.7 years [interquartile range, 52.3-55.2 years]), 1097 (19.8%) developed ADL impairment between 50 and 64 years, and 857 (15.5%) developed IADL impairment. Individuals with ADL impairment had an increased risk of each adverse outcome compared with those without impairment, including hospitalization (subhazard ratio, 1.97; 95% CI, 1.77-2.19), nursing home admission (subhazard ratio, 2.62; 95% CI, 1.99-3.45), and death (hazard ratio, 2.06; 95% CI, 1.74-2.45). After multivariable adjustment, the risks of hospitalization (subhazard ratio, 1.54; 95% CI, 1.36-1.75) and nursing home admission (subhazard ratio, 1.73; 95% CI, 1.24-2.43) remained significantly higher among individuals with ADL impairment, but the risk of death was not statistically significant (hazard ratio, 1.06; 95% CI, 0.85-1.32). Individuals with IADL impairment had an increased risk of all 3 outcomes in adjusted and unadjusted analyses.

Conclusions and relevance

Similar to older adults, middle-aged adults who develop functional impairment appear to be at increased risk for adverse outcomes. Even among relatively young people, functional impairment has important clinical implications.

Understanding the hierarchy of functional impairment in older adults has helped illuminate mechanisms of impairment and inform interventions, but little is known about whether hierarchies vary by age. We compared the pattern of new-onset impairments in activities of daily living (ADLs) and instrumental ADLs (IADLs) from middle age through older age. We conducted a cohort study using nationally representative data from 32 486 individuals enrolled in the Health and Retirement Study. The outcomes were new-onset impairment in each ADL and IADL, defined as self-reported difficulty performing each task, assessed yearly for 9 years. We used multistate models and competing risks survival analysis to estimate the cumulative incidence of impairment in each task by age group (ages 50-64, 65-74, 75-84, and 85 or older). The pattern of incident ADL impairments differed by age group. Among individuals ages 50-64 and 65-74 who were independent at baseline, over 9 years' follow-up, difficulties dressing and transferring were the most common impairments to develop. In individuals ages 75-84 and 85 or older who were independent at baseline, difficulties bathing, dressing, and walking were most common. For IADLs, the pattern of impairments was similar across age groups; difficulty shopping was most common followed by difficulty managing money and preparing meals. Complementary analyses demonstrated a similar pattern. These findings suggest that the hierarchy of ADL impairment differs by age. These findings have implications for the development of age-specific interventions to prevent or delay functional impairment.

Triglyceride (TG) storage in adipose tissue provides the major reservoir for metabolic energy in mammals. During lipolysis, fatty acids (FAs) are hydrolyzed from adipocyte TG stores and transported to other tissues for fuel. For unclear reasons, a large portion of hydrolyzed FAs in adipocytes is re-esterified to TGs in a "futile," ATP-consuming, energy dissipating cycle. Here we show that FA re-esterification during adipocyte lipolysis is mediated by DGAT1, an ER-localized DGAT enzyme. Surprisingly, this re-esterification cycle does not preserve TG mass but instead functions to protect the ER from lipotoxic stress and related consequences, such as adipose tissue inflammation. Our data reveal an important role for DGAT activity and TG synthesis generally in averting ER stress and lipotoxicity, with specifically DGAT1 performing this function during stimulated lipolysis in adipocytes.

Background

Guidelines recommend that clinicians use clinical prediction models to estimate future risk to guide decisions. For example, predicted fracture risk is a major factor in the decision to initiate bisphosphonate medications. However, current methods for developing prediction models often lead to models that are accurate but difficult to use in clinical settings.

Objective

The objective of this study was to develop and test whether a new metric that explicitly balances model accuracy with clinical usability leads to accurate, easier-to-use prediction models.

Methods

We propose a new metric called the Time-cost Information Criterion (TCIC) that will penalize potential predictor variables that take a long time to obtain in clinical settings. To demonstrate how the TCIC can be used to develop models that are easier-to-use in clinical settings, we use data from the 2000 wave of the Health and Retirement Study (n=6311) to develop and compare time to mortality prediction models using a traditional metric (Bayesian Information Criterion or BIC) and the TCIC.

Results

We found that the TCIC models utilized predictors that could be obtained more quickly than BIC models while achieving similar discrimination. For example, the TCIC identified a 7-predictor model with a total time-cost of 44 seconds, while the BIC identified a 7-predictor model with a time-cost of 119 seconds. The Harrell C-statistic of the TCIC and BIC 7-predictor models did not differ (0.7065 vs. 0.7088, P=0.11).

Conclusion

Accounting for the time-costs of potential predictor variables through the use of the TCIC led to the development of an easier-to-use mortality prediction model with similar discrimination.