Evaluating the robustness of targeted maximum likelihood estimators via realistic simulations in nutrition intervention trials.

Several recently developed methods have the potential to harness machine learning in the pursuit of target quantities inspired by causal inference, including inverse weighting, doubly robust estimating equations and substitution estimators like targeted maximum likelihood estimation. There are even more recent augmentations of these procedures that can increase robustness, by adding a layer of cross-validation (cross-validated targeted maximum likelihood estimation and double machine learning, as applied to substitution and estimating equation approaches, respectively). While these methods have been evaluated individually on simulated and experimental data sets, a comprehensive analysis of their performance across real data based simulations have yet to be conducted. In this work, we benchmark multiple widely used methods for estimation of the average treatment effect using ten different nutrition intervention studies data. A nonparametric regression method, undersmoothed highly adaptive lasso, is used to generate the simulated distribution which preserves important features from the observed data and reproduces a set of true target parameters. For each simulated data, we apply the methods above to estimate the average treatment effects as well as their standard errors and resulting confidence intervals. Based on the analytic results, a general recommendation is put forth for use of the cross-validated variants of both substitution and estimating equation estimators. We conclude that the additional layer of cross-validation helps in avoiding unintentional over-fitting of nuisance parameter functionals and leads to more robust inferences

Evaluating the robustness of targeted maximum likelihood estimators via realistic simulations in nutrition intervention trials.

Several recently developed methods have the potential to harness machine learning in the pursuit of target quantities inspired by causal inference, including inverse weighting, doubly robust estimating equations and substitution estimators like targeted maximum likelihood estimation. There are even more recent augmentations of these procedures that can increase robustness, by adding a layer of cross-validation (cross-validated targeted maximum likelihood estimation and double machine learning, as applied to substitution and estimating equation approaches, respectively). While these methods have been evaluated individually on simulated and experimental data sets, a comprehensive analysis of their performance across real data based simulations have yet to be conducted. In this work, we benchmark multiple widely used methods for estimation of the average treatment effect using ten different nutrition intervention studies data. A nonparametric regression method, undersmoothed highly adaptive lasso, is used to generate the simulated distribution which preserves important features from the observed data and reproduces a set of true target parameters. For each simulated data, we apply the methods above to estimate the average treatment effects as well as their standard errors and resulting confidence intervals. Based on the analytic results, a general recommendation is put forth for use of the cross-validated variants of both substitution and estimating equation estimators. We conclude that the additional layer of cross-validation helps in avoiding unintentional over-fitting of nuisance parameter functionals and leads to more robust inferences

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

SummarySustainable Development Goal 2.2.2, to end malnutrition by 2030, measures progress through elimination of child wasting, defined as weight-for-length more than 2 standard deviations below international standards. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery, and persistence — key features of wasting epidemiology that could inform preventive interventions and disease burden estimates. Here, we show through an analysis of 21 longitudinal cohorts that wasting is a highly dynamic process of onset and recovery, and incidence peaks between birth and 3 months — far earlier than peak prevalence at 12-15 months. By age 24 months 29.2% of children had experienced at least one wasting episode, more than 5-fold higher than point prevalence (5.6%), demonstrating that wasting incidence is far higher than cross-sectional surveys suggest. Children wasted before 6 months were more likely to experience concurrent wasting and stunting (low height-for-age) later, increasing their risk of mortality. In diverse populations with seasonal rainfall, population average weight-for-length varied substantially (>0.5 z in some cohorts), with the lowest mean Z-scores during the rainiest months, creating potential for seasonally targeted interventions. Our results motivate a new focus on extending preventive interventions for wasting to pregnant and lactating mothers, and for preventive and therapeutic interventions to include children below age 6 months in addition to current targets of ages 6-59 months

Risk factors and impacts of child growth faltering in low- and middle-income countries

SummaryGrowth faltering (low length-for-age or weight-for length) in the first 1000 days — from conception to two years of age — influences both short and long-term health and survival. Evidence for interventions to prevent growth faltering such as nutritional supplementation during pregnancy and the postnatal period has increasingly accumulated, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. In addition, there is need to better understand age-windows and population subgroups in which to focus future preventive efforts. Here, we show using a population intervention effects analysis of 33 longitudinal cohorts (83,671 children) and 30 separate exposures that improving maternal anthropometry and child condition at birth, in particular child length-at-birth, accounted for population increases by age 24 months in length-for-age Z of 0.04 to 0.40 and weight-for-length Z by 0.02 to 0.15. Boys had consistently higher risk of all forms of growth faltering than girls, and early growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits had higher mortality rates from birth to two years than those without 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 key opportunities for new preventive interventions

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

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

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.</p