Child wasting and concurrent stunting in low- and middle-income countries.

Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.

Early-childhood linear growth faltering in low- and middle-income countries.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

Causes and consequences of child growth faltering in low-resource settings.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

Automated analysis of unstructured clinical assessments improves emergency department triage performance: A retrospective deep learning analysis.

Objectives: Efficient and accurate emergency department (ED) triage is critical to prioritize the sickest patients and manage department flow. We explored the use of electronic health record data and advanced predictive analytics to improve triage performance. Methods: Using a data set of over 5 million ED encounters of patients 18 years and older across 21 EDs from 2016 to 2020, we derived triage models using deep learning to predict 2 outcomes: hospitalization (primary outcome) and fast-track eligibility (exploratory outcome), defined as ED discharge with <2 resource types used (eg, laboratory or imaging studies) and no critical events (eg, resuscitative medications use or intensive care unit [ICU] admission). We report area under the receiver operator characteristic curve (AUC) and 95% confidence intervals (CI) for models using (1) triage variables alone (demographics and vital signs), (2) triage nurse clinical assessment alone (unstructured notes), and (3) triage variables plus clinical assessment for each prediction target. Results: We found 12.7% of patients were hospitalized (n = 673,659) and 37.0% were fast-track eligible (n = 1,966,615). The AUC was lowest for models using triage variables alone: AUC 0.77 (95% CI 0.77-0.78) and 0.70 (95% CI 0.70-0.71) for hospitalization and fast-track eligibility, respectively, and highest for models incorporating clinical assessment with triage variables for both hospitalization and fast-track eligibility: AUC 0.87 (95% CI 0.87-0.87) for both prediction targets. Conclusion: Our findings highlight the potential to use advanced predictive analytics to accurately predict key ED triage outcomes. Predictive accuracy was optimized when clinical assessments were added to models using simple structured variables alone.

Human Immunodeficiency Virus Status, Tenofovir Exposure, and the Risk of Poor Coronavirus Disease 19 Outcomes: Real-World Analysis From 6 United States Cohorts Before Vaccine Rollout.

BACKGROUND: People with human immunodeficiency virus (HIV) (PWH) may be at increased risk for severe coronavirus disease 2019 (COVID-19) outcomes. We examined HIV status and COVID-19 severity, and whether tenofovir, used by PWH for HIV treatment and people without HIV (PWoH) for HIV prevention, was associated with protection. METHODS: Within 6 cohorts of PWH and PWoH in the United States, we compared the 90-day risk of any hospitalization, COVID-19 hospitalization, and mechanical ventilation or death by HIV status and by prior exposure to tenofovir, among those with severe acute respiratory syndrome coronavirus 2 infection between 1 March and 30 November 2020. Adjusted risk ratios (aRRs) were estimated by targeted maximum likelihood estimation, with adjustment for demographics, cohort, smoking, body mass index, Charlson comorbidity index, calendar period of first infection, and CD4 cell counts and HIV RNA levels (in PWH only). RESULTS: Among PWH (n = 1785), 15% were hospitalized for COVID-19 and 5% received mechanical ventilation or died, compared with 6% and 2%, respectively, for PWoH (n = 189 351). Outcome prevalence was lower for PWH and PWoH with prior tenofovir use. In adjusted analyses, PWH were at increased risk compared with PWoH for any hospitalization (aRR, 1.31 [95% confidence interval, 1.20-1.44]), COVID-19 hospitalizations (1.29 [1.15-1.45]), and mechanical ventilation or death (1.51 [1.19-1.92]). Prior tenofovir use was associated with reduced hospitalizations among PWH (aRR, 0.85 [95% confidence interval, .73-.99]) and PWoH (0.71 [.62-.81]). CONCLUSIONS: Before COVID-19 vaccine availability, PWH were at greater risk for severe outcomes than PWoH. Tenofovir was associated with a significant reduction in clinical events for both PWH and PWoH.

Development and Validation of a Diabetic Retinopathy Risk Stratification Algorithm.

OBJECTIVE: Although diabetic retinopathy is a leading cause of blindness worldwide, diabetes-related blindness can be prevented through effective screening, detection, and treatment of disease. The study goal was to develop risk stratification algorithms for the onset of retinal complications of diabetes, including proliferative diabetic retinopathy, referable retinopathy, and macular edema. RESEARCH DESIGN AND METHODS: Retrospective cohort analysis of patients from the Kaiser Permanente Northern California Diabetes Registry who had no evidence of diabetic retinopathy at a baseline diabetic retinopathy screening during 2008-2020 was performed. Machine learning and logistic regression prediction models for onset of proliferative diabetic retinopathy, diabetic macular edema, and referable retinopathy detected through routine screening were trained and internally validated. Model performance was assessed using area under the curve (AUC) metrics. RESULTS: The study cohort (N = 276,794) was 51.9% male and 42.1% White. Mean (±SD) age at baseline was 60.0 (±13.1) years. A machine learning XGBoost algorithm was effective in identifying patients who developed proliferative diabetic retinopathy (AUC 0.86; 95% CI, 0.86-0.87), diabetic macular edema (AUC 0.76; 95% CI, 0.75-0.77), and referable retinopathy (AUC 0.78; 95% CI, 0.78-0.79). Similar results were found using a simpler nine-covariate logistic regression model: proliferative diabetic retinopathy (AUC 0.82; 95% CI, 0.80-0.83), diabetic macular edema (AUC 0.73; 95% CI, 0.72-0.74), and referable retinopathy (AUC 0.75; 95% CI, 0.75-0.76). CONCLUSIONS: Relatively simple logistic regression models using nine readily available clinical variables can be used to rank order patients for onset of diabetic eye disease and thereby more efficiently prioritize and target screening for at risk patients.

Parent-focused prevention of adolescent health risk behavior: Study protocol for a multisite cluster-randomized trial implemented in pediatric primary care.

Evidence-based parenting interventions play a crucial role in the sustained reduction of adolescent behavioral health concerns. Guiding Good Choices (GGC) is a 5-session universal anticipatory guidance curriculum for parents of early adolescents that has been shown to reduce substance use, depression symptoms, and delinquent behavior. Although prior research has demonstrated the effectiveness of evidence-based parenting interventions at achieving sustained reductions in adolescent behavioral health concerns, public health impact has been limited by low rates of uptake in community and agency settings. Pediatric primary care is an ideal setting for implementing and scaling parent-focused prevention programs as these settings have a broad reach, and prevention programs implemented within them have the potential to achieve population-level impact. The current investigation, Guiding Good Choices for Health (GGC4H), tests the feasibility and effectiveness of implementing GGC in 3 geographically and socioeconomically diverse large integrated healthcare systems. This pragmatic, cluster randomized clinical trial will compare GGC parenting intervention to usual pediatric primary care practice, and will include approximately 3750 adolescents; n = 1875 GGC intervention and n = 1875 usual care. The study team hypothesizes that adolescents whose parents are randomized into the GGC intervention arm will show reductions in substance use initiation, the study's primary outcomes, and other secondary (e.g., depression symptoms, substance use prevalence) and exploratory outcomes (e.g., health services utilization, anxiety symptoms). The investigative team anticipates that the implementation of GGC within pediatric primary care clinics will successfully fill an unmet need for effective preventive parenting interventions. Trial registration: Clinicaltrials.govNCT04040153.

Complier stochastic direct effects: identification and robust estimation.

Mediation analysis is critical to understanding the mechanisms underlying exposure-outcome relationships. In this paper, we identify the instrumental variable-direct effect of the exposure on the outcome not through the mediator, using randomization of the instrument. We call this estimand the complier stochastic direct effect (CSDE). To our knowledge, such an estimand has not previously been considered or estimated. We propose and evaluate several estimators for the CSDE: a ratio of inverse-probability of treatment-weighted estimators (IPTW), a ratio of estimating equation estimators (EE), a ratio of targeted minimum loss-based estimators (TMLE), and a TMLE that targets the CSDE directly. These estimators are applicable for a variety of study designs, including randomized encouragement trials, like the Moving to Opportunity housing voucher experiment we consider as an illustrative example, treatment discontinuities, and Mendelian randomization. We found the IPTW estimator to be the most sensitive to finite sample bias, resulting in bias of over 40% even when all models were correctly specified in a sample size of N=100. In contrast, the EE estimator and TMLE that targets the CSDE directly were far less sensitive. The EE and TML estimators also have advantages in terms of efficiency and reduced reliance on correct parametric model specification.

Exploiting nonsystematic covariate monitoring to broaden the scope of evidence about the causal effects of adaptive treatment strategies.

In studies based on electronic health records (EHR), the frequency of covariate monitoring can vary by covariate type, across patients, and over time, which can limit the generalizability of inferences about the effects of adaptive treatment strategies. In addition, monitoring is a health intervention in itself with costs and benefits, and stakeholders may be interested in the effect of monitoring when adopting adaptive treatment strategies. This paper demonstrates how to exploit nonsystematic covariate monitoring in EHR-based studies to both improve the generalizability of causal inferences and to evaluate the health impact of monitoring when evaluating adaptive treatment strategies. Using a real world, EHR-based, comparative effectiveness research (CER) study of patients with type II diabetes mellitus, we illustrate how the evaluation of joint dynamic treatment and static monitoring interventions can improve CER evidence and describe two alternate estimation approaches based on inverse probability weighting (IPW). First, we demonstrate the poor performance of the standard estimator of the effects of joint treatment-monitoring interventions, due to a large decrease in data support and concerns over finite-sample bias from near-violations of the positivity assumption (PA) for the monitoring process. Second, we detail an alternate IPW estimator using a no direct effect assumption. We demonstrate that this estimator can improve efficiency but at the potential cost of increase in bias from violations of the PA for the treatment process.

Associations between spousal caregiving and health among older adults in Mexico: A targeted estimation approach.

OBJECTIVE: To evaluate associations between spousal caregiving and mental and physical health among older adults in Mexico. METHODS: Data come from the Mexican Health & Aging Study, a national population-based study of adults ≥50 years and their spouses (2001-2015). We compared outcomes for spousal caregivers to outcomes for those whose spouses had difficulty with at least one basic or instrumental activity of daily living (I/ADL) but were not providing care; the control group conventionally includes all married respondents regardless of spouse's need for care. We used targeted maximum likelihood estimation to evaluate the associations with past-week depressive symptoms, lower-body functional limitations, and chronic health conditions. RESULTS: At baseline, 846 women and 629 men had a spouse with ≥1 I/ADL. Of these, 60.9% of women and 52.6% of men were spousal caregivers. Spousal caregiving was associated with more past-week depressive symptoms for men (Marginal Risk Difference (RD): 0.27, 95% confidence internal [CI]: 0.03, 0.51) and women (RD: 0.15, 95% CI: 0.07, 0.23). We could not draw conclusions about associations with lower-body functional limitations and chronic health conditions. On average, all respondents whose spouses had caregiving needs had poorer health than the overall sample. CONCLUSION: We found evidence of an association between spousal caregiving and mental health among older Mexican adults with spouses who had need for care. However, our findings suggest that older adults who are both currently providing or at risk of providing spousal care may need targeted programs and policies to support health and long-term care needs.

Use of Machine Learning to Develop a Risk-Stratification Tool for Emergency Department Patients With Acute Heart Failure.

STUDY OBJECTIVE: We use variables from a recently derived acute heart failure risk-stratification rule (STRATIFY) as a basis to develop and optimize risk prediction using additional patient clinical data from electronic health records and machine-learning models. METHODS: Using a retrospective cohort design, we identified all emergency department (ED) visits for acute heart failure between January 1, 2017, and December 31, 2018, among adult health plan members of a large system with 21 EDs. The primary outcome was any 30-day serious adverse event, including death, cardiopulmonary resuscitation, balloon-pump insertion, intubation, new dialysis, myocardial infarction, or coronary revascularization. Starting with the 13 variables from the STRATIFY rule (base model), we tested whether predictive accuracy in a different population could be enhanced with additional electronic health record-based variables or machine-learning approaches (compared with logistic regression). We calculated our derived model area under the curve (AUC), calculated test characteristics, and assessed admission rates across risk categories. RESULTS: Among 26,189 total ED encounters, mean patient age was 74 years, 51.7% were women, and 60.7% were white. The overall 30-day serious adverse event rate was 18.8%. The base model had an AUC of 0.76 (95% confidence interval 0.74 to 0.77). Incorporating additional variables led to improved accuracy with logistic regression (AUC 0.80; 95% confidence interval 0.79 to 0.82) and machine learning (AUC 0.85; 95% confidence interval 0.83 to 0.86). We found that 11.1%, 25.7%, and 48.9% of the study population had predicted serious adverse event risk of less than or equal to 3%, less than or equal to 5%, and less than or equal to 10%, respectively, and 28% of those with less than or equal to 3% risk were admitted. CONCLUSION: Use of a machine-learning model with additional variables improved 30-day risk prediction compared with conventional approaches.

Adversarial Monte Carlo Meta-Learning of Optimal Prediction Procedures.

We frame the meta-learning of prediction procedures as a search for an optimal strategy in a two-player game. In this game, Nature selects a prior over distributions that generate labeled data consisting of features and an associated outcome, and the Predictor observes data sampled from a distribution drawn from this prior. The Predictor's objective is to learn a function that maps from a new feature to an estimate of the associated outcome. We establish that, under reasonable conditions, the Predictor has an optimal strategy that is equivariant to shifts and rescalings of the outcome and is invariant to permutations of the observations and to shifts, rescalings, and permutations of the features. We introduce a neural network architecture that satisfies these properties. The proposed strategy performs favorably compared to standard practice in both parametric and nonparametric experiments.

Assessment of Value of Neighborhood Socioeconomic Status in Models That Use Electronic Health Record Data to Predict Health Care Use Rates and Mortality.

Importance: Prediction models are widely used in health care as a way of risk stratifying populations for targeted intervention. Most risk stratification has been done using a small number of predictors from insurance claims. However, the utility of diverse nonclinical predictors, such as neighborhood socioeconomic contexts, remains unknown. Objective: To assess the value of using neighborhood socioeconomic predictors in the context of 1-year risk prediction for mortality and 6 different health care use outcomes in a large integrated care system. Design, Setting, and Participants: Diagnostic study using data from all adults age 18 years or older who had Kaiser Foundation Health Plan membership and/or use in the Kaiser Permantente Northern California: a multisite, integrated health care delivery system between January 1, 2013, and June 30, 2014. Data were recorded before the index date for each patient to predict their use and mortality in a 1-year post period using a test-train split for model training and evaluation. Analyses were conducted in fall of 2019. Main Outcomes and Measures: One-year encounter counts (doctor office, virtual, emergency department, elective hospitalizations, and nonelective), total costs, and mortality. Results: A total of 2 951 588 patients met inclusion criteria (mean [SD] age, 47.2 [17.4] years; 47.8% were female). The mean (SD) Neighborhood Deprivation Index was -0.32 (0.84). The areas under the receiver operator curve ranged from 0.71 for emergency department use (using the LASSO method and electronic health record predictors) to 0.94 for mortality (using the random forest method and electronic health record predictors). Neighborhood socioeconomic status predictors did not meaningfully increase the predictive performance of the models for any outcome. Conclusions and Relevance: In this study, neighborhood socioeconomic predictors did not improve risk estimates compared with what is obtainable using standard claims data regardless of model used.

Learning to learn from data: Using deep adversarial learning to construct optimal statistical procedures.

Traditionally, statistical procedures have been derived via analytic calculations whose validity often relies on sample size growing to infinity. We use tools from deep learning to develop a new approach, adversarial Monte Carlo meta-learning, for constructing optimal statistical procedures. Statistical problems are framed as two-player games in which Nature adversarially selects a distribution that makes it difficult for a statistician to answer the scientific question using data drawn from this distribution. The players' strategies are parameterized via neural networks, and optimal play is learned by modifying the network weights over many repetitions of the game. Given sufficient computing time, the statistician's strategy is (nearly) optimal at the finite observed sample size, rather than in the hypothetical scenario where sample size grows to infinity. In numerical experiments and data examples, this approach performs favorably compared to standard practice in point estimation, individual-level predictions, and interval estimation.

US Migration Status of Adult Children and Cognitive Decline Among Older Parents Who Remain in Mexico.

Low- and middle-income countries (LMICs) are experiencing rapid aging, a growing dementia burden, and relatively high rates of out-migration among working-age adults. Family member migration status may be a unique societal determinant of cognitive aging in LMIC settings. We aimed to evaluate the association between adult child US migration status and change in cognitive performance scores using data from the Mexican Health and Aging Study, a population-based, national-level cohort study of Mexico adults aged ≥50 years at baseline (2001), with 2-, 12-, and 14-year follow-up waves (2003, 2012, and 2015). Cognitive performance assessments were completed by 5,972 and 4,939 respondents at 11 years and 14 years of follow-up, respectively. For women, having an adult child in the United States was associated with steeper decline in verbal memory scores (e.g., for 9-year change in immediate verbal recall z score, marginal risk difference (RD) = -0.09 (95% confidence interval (CI): -0.16, -0.03); for delayed verbal recall z score, RD = -0.10 (95% CI: -0.17, -0.03)) and overall cognitive performance (for overall cognitive performance z score, RD = -0.04, 95% CI: -0.07, -0.00). There were mostly null associations for men. To our knowledge, this is the first study to have evaluated the association between family member migration status and cognitive decline; future work should be extended to other LMICs facing population aging.

Targeted learning with daily EHR data.

Electronic health records (EHR) data provide a cost- and time-effective opportunity to conduct cohort studies of the effects of multiple time-point interventions in the diverse patient population found in real-world clinical settings. Because the computational cost of analyzing EHR data at daily (or more granular) scale can be quite high, a pragmatic approach has been to partition the follow-up into coarser intervals of pre-specified length (eg, quarterly or monthly intervals). The feasibility and practical impact of analyzing EHR data at a granular scale has not been previously evaluated. We start filling these gaps by leveraging large-scale EHR data from a diabetes study to develop a scalable targeted learning approach that allows analyses with small intervals. We then study the practical effects of selecting different coarsening intervals on inferences by reanalyzing data from the same large-scale pool of patients. Specifically, we map daily EHR data into four analytic datasets using 90-, 30-, 15-, and 5-day intervals. We apply a semiparametric and doubly robust estimation approach, the longitudinal Targeted Minimum Loss-Based Estimation (TMLE), to estimate the causal effects of four dynamic treatment rules with each dataset, and compare the resulting inferences. To overcome the computational challenges presented by the size of these data, we propose a novel TMLE implementation, the "long-format TMLE," and rely on the latest advances in scalable data-adaptive machine-learning software, xgboost and h2o, for estimation of the TMLE nuisance parameters.

Having an Adult Child in the United States, Physical Functioning, and Unmet Needs for Care Among Older Mexican Adults.

BACKGROUND: Migration of adult children may impact the health of aging parents who remain in low- and middle-income countries. Prior studies have uncovered mixed associations between adult child migration status and physical functioning of older parents; none to our knowledge has examined the impact on unmet caregiving needs. METHODS: Data come from a population-based study of Mexican adults ≥50 years. We used longitudinal targeted maximum likelihood estimation to estimate associations between having an adult child US migrant and lower-body functional limitations, and both needs and unmet needs for assistance with basic or instrumental activities of daily living (ADLs/IADLs) for 11,806 respondents surveyed over an 11-year period. RESULTS: For women, having an adult child US migrant at baseline and 2-year follow-up was associated with fewer lower-body functional limitations [marginal risk difference (RD) = -0.14, 95% confidence interval (CI) = -0.26, -0.01] and ADLs/IADLs (RD = -0.08, 95% CI = -0.16, -0.001) at 2-year follow-up. Having an adult child US migrant at all waves was associated with a higher prevalence of functional limitations at 11-year follow-up (RD = 0.04, 95% CI = 0.01, 0.06). Having an adult child US migrant was associated with a higher prevalence of unmet needs for assistance at 2 (RD = 0.13, 95% CI = 0.04, 0.21) and 11-year follow-up for women (RD = 0.07, 95% CI = -0.02, 0.15) and 11-year follow-up for men (RD = 0.08, 95% CI = 0.00, 0.16). CONCLUSION: Having an adult child US migrant had mixed associations with physical functioning, but substantial adverse associations with unmet caregiving needs for a cohort of older adults in Mexico.

Comparing predictive abilities of longitudinal child growth models.

The Bill and Melinda Gates Foundation's Healthy Birth, Growth and Development knowledge integration project aims to improve the overall health and well-being of children across the world. The project aims to integrate information from multiple child growth studies to allow health professionals and policy makers to make informed decisions about interventions in lower and middle income countries. To achieve this goal, we must first understand the conditions that impact on the growth and development of children, and this requires sensible models for characterising different growth patterns. The contribution of this paper is to provide a quantitative comparison of the predictive abilities of various statistical growth modelling techniques based on a novel leave-one-out validation approach. The majority of existing studies have used raw growth data for modelling, but we show that fitting models to standardised data provide more accurate estimation and prediction. Our work is illustrated with an example from a study into child development in a middle income country in South America.