Natural Direct Effects Research Articles

The mediating role of combined lifestyle factors on the relationship between education and gastric cancer in the Stomach cancer Pooling (StoP) Project.

The causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category. The natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men. The mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

Physical activity motives have a direct effect on mental health.

Physical activity (PA) motives are associated with both moderate-to-vigorous intensity PA (MVPA) and mental health. Studies examining whether PA motives relate directly to mental health or indirectly through MVPA are lacking. This study examined the direct effect of five PA motives (i.e., enjoyment, competence, fitness, social, appearance) on mental health and their indirect effects through MVPA in adolescents. A total of 424 participants (57.1% females) ages 14-15 years from the longitudinal MATCH study were included. Mediation analyses, based on the counterfactual framework, assessed the natural direct effect of PA motives on mental health, and the natural indirect effects through MVPA. Separate models were conducted for each PA motive. Natural direct effects were observed for enjoyment ( [95%CI]=2.12 [0.34, 3.90]), competence ( [95%CI]=1.58[0.28, 2.88]), fitness ( [95%CI]=1.42[0.04, 2.80]), and social ( [95%CI]=2.32[1.03, 3.60]) motives. No natural direct effects were observed for appearance motives. A natural indirect effect through MVPA was observed for fitness motives, and no other natural indirect effects were found. Interventions and public health strategies in adolescents need to acknowledge the importance of enjoyment, competence social and fitness motives in PA to promote mental health, and integrate specific recommendations on the importance of the reasons why adolescents participate in PA.

The electrophysiological masking level difference: effects of age and mediation of hearing and cognition

Objective Evaluate the conceptual framework that age effects on the electrophysiological binaural masking level difference (MLD) are partially mediated by age-related hearing loss and/or global cognitive function via mediation analysis. Design Participants underwent a series of audiometric tests. The MLD was measured via cortical auditory evoked potentials using a speech stimulus (/ɑ/) in speech-weighted background noise. We used mediation analyses to determine the total effect, natural direct effects, and natural indirect effects, which are displayed as regression coefficients ([95% CI]; p value). Study sample Twenty-eight individuals aged 19–87 years (mean [SD]: 53.3 [25.2]), recruited from the community. Results Older age had a significant total effect on the MLD (-0.69 [95% CI: −0.96, −0.45]; p < 0.01). Neither pure tone average (-0.11 [95% CI: −0.43, 0.24; p = 0.54] nor global cognitive function (-0.02 [95% CI: −0.13, 0.02]; p = 0.55) mediated the relationship of age and the MLD and effect sizes were small. Results were insensitive to use of alternative hearing measures or inclusion of interaction terms. Conclusions The electrophysiological MLD may be an age-sensitive measure of binaural temporal processing that is minimally affected by age-related hearing loss and global cognitive function.

The primary importance of the research question: implications for understanding natural versus controlled direct effects.

The primary importance of the research question: implications for understanding natural versus controlled direct effects.

Early-life exposure to Chinese famine and stroke risk in mid- to late life: the mediating roles of cognitive function and depression

BackgroundLimited research has examined the role that famine exposure plays in adulthood stroke risk. We aim to explore the causal implications of early exposure to the Great Chinese Famine on stroke risk and determine whether these associations were mediated by cognitive function, and depression.MethodsWe sampled 12,681 individuals aged 45 years and older from the China Health and Retirement Longitudinal Study (CHARLS) and divided them into fetally exposed, childhood-exposed, adolescence/adulthood-exposed and unexposed groups. Stroke was defined by self- or proxy-reported physician diagnosis. Based on a counterfactual framework, marginal structural models were used to estimate the natural direct effect and the natural indirect effects through cognitive function and depression for causal inference.ResultsWe found that early-life exposure to Chinese famine was directly related to increased stroke risk in mid- to late life. Cognitive function and depression accounted for a greater part of the effect for childhood famine exposure, mediating 36.35% (95%CI: 14.19, 96.19%) of the overall association between famine exposure and incident stroke, than for the fetal, adolescence/adulthood famine exposure groups. However, the natural indirect effect through depression was not significant in the fetally exposed group. The results were robust in the sensitivity analysis of model specification and unobserved confounding.ConclusionsOur findings are consistent with the latency, pathway, and accumulation models, supporting the life-course theory. Early stages of life exposed to the Chinese Famine were associated with higher risk of stroke in mid- to late life. Enhanced cognitive and depression interventions may reduce stroke risk in middle-aged and older Chinese adults who exposure to famine in early life.

Associations of Body Mass Index With Pain and the Mediating Role of Inflammatory Biomarkers in People With Hand Osteoarthritis.

To examine the association of body mass index (BMI) with pain in people with hand osteoarthritis (OA), and explore whether this association, if causal, is mediated by systemic inflammatory biomarkers. In 281 Nor-Hand study participants, we estimated associations between BMI and hand pain, as measured by the Australian/Canadian Osteoarthritis Hand Index (AUSCAN; range 0-20) and Numerical Rating Scale (NRS; range 0-10); foot pain, as measured by NRS (range 0-10); knee/hip pain, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; range 0-20); painful total body joint count; and pain sensitization. We fit natural-effects models to estimate natural direct and natural indirect effects of BMI on pain through inflammatory biomarkers. Each 5-unit increase in BMI was associated with more severe hand pain (on average increased AUSCAN by 0.64 [95% confidence interval (95% CI) 0.23, 1.08]), foot pain (on average increased NRS by 0.65 [95% CI 0.36, 0.92]), knee/hip pain (on average increased WOMAC by 1.31 [95% CI 0.87, 1.73]), generalized pain, and pain sensitization. Mediation analyses suggested that the effects of BMI on hand pain and painful total body joint count were partially mediated by leptin and high-sensitivity C-reactive protein (hsCRP), respectively. Effect sizes for mediation by leptin were larger for the hands than for the lower extremities, and were statistically significant for the hands only. In people with hand OA, higher BMI is associated with greater pain severity in the hands, feet, and knees/hips. Systemic effects of obesity, measured by leptin, may play a larger mediating role for pain in the hands than in the lower extremities. Low-grade inflammation, measured by hsCRP, may contribute to generalized pain in overweight/obese individuals.

The association between pre-pregnancy body mass index and perinatal death and the role of gestational age at delivery.

The pathophysiology behind the association between obesity and perinatal death is not fully understood but may be in part due to higher rates of pregnancy complications at earlier gestation amongst obese women. We aimed to quantify the proportion of perinatal deaths amongst obese and overweight women mediated by gestational age at stillbirth or live birth. The study included all singleton births at ≥20 weeks' gestation in British Columbia, 2004-2017, and excluded pregnancy terminations. The proportion of the association between BMI and perinatal death mediated by gestational age at delivery (in weeks) was estimated using natural effect models, with adjustment for potential confounders. Sensitivity analyses for unmeasured confounding and women missing BMI were conducted. Of 392,820 included women, 20.6% were overweight and 12.8% obese. Women with higher BMI had a lower gestational age at delivery. Perinatal mortality was 0.5% (1834 pregnancies); and was elevated in overweight (adjusted odds ratio [AOR] = 1.22, 95% confidence interval [CI] 1.08-1.37) and obese women (AOR = 1.55, 95% CI 1.36-1.77). Mediation analysis showed that 63.1% of the association between obesity and perinatal death was mediated by gestational age at delivery (natural indirect effect AOR = 1.32, 95% CI 1.23-1.42, natural direct effect AOR = 1.18, 95% CI 1.05-1.32). Similar, but smaller effects were seen when comparing overweight women vs. women with a normal BMI. Estimated effects were not affected by adjustment for additional risk factors for perinatal death or sensitivity analyses for missing data. Obese pregnancies have a higher risk of perinatal death in part mediated by a lower gestational age at delivery.

Simple yet sharp sensitivity analysis for unmeasured confounding

Abstract We present a method for assessing the sensitivity of the true causal effect to unmeasured confounding. The method requires the analyst to set two intuitive parameters. Otherwise, the method is assumption free. The method returns an interval that contains the true causal effect and whose bounds are arbitrarily sharp, i.e., practically attainable. We show experimentally that our bounds can be tighter than those obtained by the method of Ding and VanderWeele, which, moreover, requires to set one more parameter than our method. Finally, we extend our method to bound the natural direct and indirect effects when there are measured mediators and unmeasured exposure–outcome confounding.

Relationships of multiple metals exposure, global DNA methylation, and urothelial carcinoma in central Taiwan

The relationship between heavy metal exposure and human health has been investigated mostly for individual metals, failing to consider their potential interactions. In this study, we assessed the joint effects of multiple metals using generalized weighted quantile sum (WQS) regression on the risk of urothelial carcinoma (UC). Also, we performed mediation analysis to evaluate the mediator %5-MedC in DNA involved in the mechanism of urothelial carcinogenesis. We conducted a hospital-based case-control study of 355 UC patients and 710 controls, where diagnosis of UC was histologically confirmed. All data were collected from face-to-face interviews and medical records. Also, we measured six metals and 8-OHdG in urine samples along with %5-MedC in peripheral blood. Ni and Pb levels increased with UC risk in single-pollutant analysis using traditional logistic regression, and similar results were obtained in multi-pollutant analysis, where all metals analyzed were considered. In WQS analysis, the weights of Ni (27%), Pb (20%), Cr (18%), and Co (16%) predominated in the metal mixture index. WQS score and UC risk showed odds ratios of 1.65 (95%CI: 1.26, 2.15) and 1.43 (95%CI: 1.00, 2.05) for a linear and non-linear relationship, respectively. Finally, we did not observe a natural indirect effect of %5-MedC in DNA; however, a marginal effect of WQS score and natural direct effect were still found after considering a natural indirect effect. In conclusion, positive associations between WQS scores and increased risk of UC were observed. Interactions of multiple metals should be considered in assessing human health risk.

Contribution of maternal cardiometabolic risk factors to racial-ethnicity disparities in preterm birth subtypes

There are recognized racial-ethnic disparities in preterm birth and in maternal cardiometabolic risk factors likely linked to systemic racism. However, it is unclear the extent to which cardiometabolic risk factors contribute to the higher rates of preterm birth among minoritized populations. This study aimed to evaluate racial-ethnic disparities in preterm birth subtypes and the role of maternal cardiometabolic risk factors as mediators of the association between maternal race-ethnicity and preterm birth subtypes. This was a retrospective cohort study of 295,210 singleton live births from 2011 to 2018. Preterm birth subtypes were defined as medically indicated and spontaneous preterm birth. Poisson regression with robust standard errors were used to provide estimates of the relative risks and 95% confidence intervals for preterm birth subtypes. Causal mediation analysis used logistic regression models to estimate the natural direct and natural indirect (mediated) effects of maternal cardiometabolic risk factors. Compared with White individuals, Black, Asian, and Hispanic individuals were at increased risk for having both medically indicated preterm birth (1.45, 1.30-1.61; 1.21, 1.12-1.31; and 1.13, 1.05-1.22, respectively) (risk ratios, 95% confidence intervals, respectively) and spontaneous preterm birth (1.20, 1.08-1.34; 1.34, 1.26-1.43; and 1.16, (1.08-1.23), independent of established risk factors. The extent to which cardiometabolic risk factors mediated the associations between race-ethnicity (each group vs White in separate analyses) and preterm birth subtypes varied by race-ethnicity. Hypertensive disorders mediated 30.1% of the association between Black race-ethnicity and medically indicated preterm birth, but it did not mediate the association for other racial-ethnic groups or for spontaneous preterm birth. Any glucose disorder in pregnancy was a mediator of medically indicated preterm birth and spontaneous preterm birth for Asian (65.8% and 13.9%, respectively) and Hispanic (17.3% and 11.9%) race-ethnicity but not for Black race-ethnicity. Overweight or obesity mediated the association between race-ethnicity and medically indicated preterm birth (15.5% among Black individuals and 25.1% among Hispanic individuals) and spontaneous preterm birth (10.7% among Hispanic individuals) but was not a mediator among Asian individuals. Black, Asian, and Hispanic individuals are at increased risk for preterm birth. Maternal cardiometabolic risk factors partially mediate the associations between race-ethnicity and preterm birth subtypes but the extent varies by race-ethnicity. These findings suggest that strategies that improve and diminish differences in cardiometabolic health between race-ethnicity populations may diminish disparities in preterm birth.

Pre-Pregnancy Body Mass Index and Risk of Macrosomia and Large for Gestational Age Births with Gestational Diabetes Mellitus as a Mediator: A Prospective Cohort Study in Central China.

This study aimed to examine the risk of macrosomia and large for gestational age (LGA) births in relation to maternal pre-pregnancy body mass index (BMI) status mediated through gestational diabetes mellitus (GDM). This prospective study included 34,104 singleton pregnancies at 8–14 weeks of gestation. The interesting outcomes were macrosomia (≥4000 g) and LGA (≥90th percentile). Mediation analyses were conducted using log-binomial regression adjusted for age, education, parity, fetal sex, and gestational weight gain. The proportion mediated was estimated based on the risk difference scale, and the E-value was utilized to assess potential confounders. Overall, 15.9% of women had GDM, and there were 4.0% macrosomia and 9.9% LGA births. The proportion mediated by GDM on macrosomia was up to 40% among obese women, and the estimate of the total effect was 6.18 (95% CI: 5.26–7.26), of the natural direct effect was 4.10 (95% CI: 3.35–4.99), and of the natural indirect effect was 1.51 (95% CI: 1.31–1.76). Likewise, among overweight women, the proportion mediated by GDM on macrosomia was up to 40%. Furthermore, consistent findings were evident for the outcome of LGA births. Pre-pregnancy overweight/obesity increased the risk of macrosomia and LGA births independently and partly mediated by GDM.

Does weight mediate the effect of smoking on coronary heart disease? Parametric mediational g-formula analysis.

In settings in which there are time-varying confounders affected by previous exposure and a time-varying mediator, natural direct and indirect effects cannot generally be estimated unbiasedly. In the present study, we estimate interventional direct effect and interventional indirect effect of cigarette smoking as a time-varying exposure on coronary heart disease while considering body weight as a time-varying mediator. To address this problem, the parametric mediational g-formula was proposed to estimate interventional direct effect and interventional indirect effect. We used data from the Multi-Ethnic Study of Atherosclerosis to estimate effect of cigarette smoking on coronary heart disease, considering body weight as time-varying mediator. Over a 11-years period, smoking 20 cigarettes per day compared to no smoking directly (not through weight) increased risk of coronary heart disease by an absolute difference of 1.91% (95% CI: 0.49%, 4.14%), and indirectly decreased coronary heart disease risk by -0.02% (95% CI: -0.05%, 0.04%) via change in weight. The total effect was estimated as an absolute 1.89% increase (95% CI: 0.49%, 4.13%). The overall absolute impact of smoking to incident coronary heart disease is modest, and we did not discern any important contribution to this effect relayed through changes to bodyweight. In fact, changes in weight because of smoking have no meaningful mediating effect on CHD risk.

Bayesian kernel machine regression-causal mediation analysis.

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.

Multifoetal gestations mediate the effect of in vitro fertilisation (IVF) on ischaemic placental disease in autologous oocyte IVF more than donor oocyte IVF.

Ischaemic placental disease (IPD) affects 16%-23% of pregnancies in the United States. In vitro fertilisation (IVF) is a risk factor for IPD, and the magnitude of increase in risk differs for individuals using donor oocytes (donor IVF) versus their own oocytes (autologous IVF). In addition, multifoetal gestations, which are more common in IVF than non-IVF pregnancies, also are a risk factor for IPD. To quantify the contribution of multifoetal gestations to the association between IVF and IPD. We conducted a retrospective cohort study at a tertiary hospital from 1January, 2000 to 1 August 2018 using electronic medical records and state vital statistics data. IPD was defined as preeclampsia, placental abruption, small for gestational age (SGA) birth or an intrauterine foetal demise due to placental insufficiency. We used mediation analysis to decompose the total effect of IVF on IPD into a natural direct effect and an indirect effect through multifoetal gestations. We repeated the analyses separately for donor and autologous IVF. All models were adjusted for maternal age, race, parity, insurance, year of delivery and account for multiple pregnancies per person. We identified 86,514 deliveries, of which 281 resulted from donor IVF and 4173 resulted from autologous IVF. IVF pregnancies had 1.99 (95% CI 1.88, 2.10) times the risk of IPD compared to non-IVF pregnancies, and 75.5% of this increased risk was mediated by multifoetal gestations. Autologous IVF pregnancies had 1.95 (95% CI 1.84, 2.07) times the risk of IPD compared to non-IVF pregnancies, and the per cent mediated was 78.8%. Donor IVF pregnancies had 2.50 (95% CI 2.09, 2.92) times the risk of IPD, but the per cent mediated was 37.5%. The majority of the association between autologous IVF and IPD was mediated through multifoetal gestations; however, this was not the case for donor IVF pregnancies.

Causal Mediation for Survival Data: A Unifying Approach via GLM

Mediation analysis has been receiving much attention from the scientific community in the last years, mainly due to its ability to disentangle causal pathways from exposures to outcomes. Particularly, causal mediation analysis for time-to-event outcomes has been widely discussed using accelerated failures times, Cox and Aalen models, with continuous or binary mediator. We derive general expressions for the Natural Direct Effect and Natural Indirect Effect for the time-to-event outcome when the mediator is modeled using generalized linear models, which includes existing procedures as particular cases. We also define a responsiveness measure to assess the variations in continuous exposures in the presence of ediation. We consider a community-based prospective cohort study that investigates the mediation of hepatitis B in the relationship between hepatitis C and liver cancer. We fit different models as well as distinct distributions and link functions associated to the mediator. We also notice that estimation of NDE and NIE using different models leads to non-contradictory conclusions despite their effect scales. The survival models provide a compelling framework that is appropriate to answer many research questions involving causal mediation analysis. The extensions through GLMs for the mediator may encompassa broad field of medical research, allowing the often necessary control for confounding.

Are sex differences in the outcome of peritoneal dialysis explained by nurse assistance? A cohort study with data from the Registre de Dialyse Péritonéale de Langue Française.

We aimed to evaluate sex differences in peritoneal dialysis (PD) outcomes and to explore direct and indirect effects of nurse-assisted PD on outcomes. This was a retrospective study using data from the Registre de Dialyse Péritonéale de Langue Française of incident PD patients between 2005 and 2016. Cox proportional hazards modelling was used to analyse transfer to haemodialysis (HD), death, PD failure, peritonitis and renal transplantation. Mediation analyses with a counterfactual approach were carried out to evaluate natural direct and indirect effects of sex on transfer to HD and peritonitis, with nurse-assisted PD as a mediator a priori. Of the 14 659 patients included, there were 5970 females (41%) and 8689 males (59%). Women were more frequently treated by nurse-assisted PD than men [2926/5970 (49.1%) versus 3357/8689 (38.7%)]. In the multivariable analysis, women had a lower risk of transfer to HD [cause-specific hazard ratio {cs-HR} 0.82 {95% confidence interval (CI) 0.77-0.88}], death [cs-HR 0.90 (95% CI 0.85-0.95)], peritonitis [cs-HR 0.82 (95% CI 0.78-0.87)], PD failure [cs-HR 0.86 (95% CI 0.83-0.90)] and a lower chance of undergoing transplant [cs-HR 0.83 (95% CI 0.77-0.90)] than men. There was a direct effect of sex on the risk of transfer to HD [cs-HR 0.82 (95% CI 0.82-0.83)], with an indirect effect of nurse-assisted PD [cs-HR 0.97 (95% CI 0.96-0.99)]. Nurse-assisted PD had no indirect effect on the risk of peritonitis. Our results suggest that compared with men, women have a lower risk of both transfer to HD and peritonitis. Mediation analysis showed that nurse assistance was a potential mediator in the causal pathway between sex and transfer to HD.

Causal inference with a mediated proportional hazards regression model

The natural direct and indirect effects in causal mediation analysis with survival data having one mediator is addressed by VanderWeele. He derived an approach for (1) an accelerated failure time regression model in general cases and (2) a proportional hazards regression model when the time-to-event outcome is rare. If the outcome is not rare, then VanderWeele did not derive a simple closed-form expression for the log-natural direct and log-natural indirect effects for the proportional hazards regression model because the baseline cumulative hazard function does not approach zero. We develop two approaches to extend VanderWeele’s approach, in which the assumption of a rare outcome is not required. We obtain the natural direct and indirect effects for specific time points through numerical integration after we calculate the cumulative baseline hazard by (1) applying the Breslow method in the Cox proportional hazards regression model to estimate the unspecified cumulative baseline hazard; (2) assuming a piecewise constant baseline hazard model, yielding a parametric model, to estimate the baseline hazard and cumulative baseline hazard. We conduct simulation studies to compare our two approaches with other methods and illustrate our two approaches by applying them to data from the ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Consortium.

Sensitivity analysis for unobserved confounding in causal mediation analysis allowing for effect modification, censoring and truncation

Causal mediation analysis is used to decompose the total effect of an exposure on an outcome into an indirect effect, taking the path through an intermediate variable, and a direct effect. To estimate these effects, strong assumptions are made about unconfoundedness of the relationships between the exposure, mediator and outcome. These assumptions are difficult to verify in a given situation and therefore a mediation analysis should be complemented with a sensitivity analysis to assess the possible impact of violations. In this paper we present a method for sensitivity analysis to not only unobserved mediator-outcome confounding, which has largely been the focus of previous literature, but also unobserved confounding involving the exposure. The setting is estimation of natural direct and indirect effects based on parametric regression models. We present results for combinations of binary and continuous mediators and outcomes and extend the sensitivity analysis for mediator-outcome confounding to cases where the continuous outcome variable is censored or truncated. The proposed methods perform well also in the presence of interactions between the exposure, mediator and observed confounders, allowing for modeling flexibility as well as exploration of effect modification. The performance of the method is illustrated through simulations and an empirical example.

Identification, Semiparametric Efficiency, and Quadruply Robust Estimation in Mediation Analysis with Treatment-Induced Confounding

Natural mediation effects are often of interest when the goal is to understand a causal mechanism. However, most existing methods and their identification assumptions preclude treatment-induced confounders often present in practice. To address this fundamental limitation, we provide a set of assumptions that identify the natural direct effect in the presence of treatment-induced confounders. Even when some of those assumptions are violated, the estimand still has an interventional direct effect interpretation. We derive the semiparametric efficiency bound for the estimand, which unlike usual expressions, contains conditional densities that are variational dependent. We consider a reparameterization and propose a quadruply robust estimator that remains consistent under four types of possible misspecification and is also locally semiparametric efficient. We use simulation studies to demonstrate the proposed method and study an application to the 2017 Natality data to investigate the effect of prenatal care on preterm birth mediated by preeclampsia with smoking status during pregnancy being a potential treatment-induced confounder.

Aerobic fitness mediates the intervention effects of a school-based physical activity intervention on academic performance. The school in Motion study – A cluster randomized controlled trial

Little information exists on the mechanism of how physical activity interventions effects academic performance. We examined whether the effects of a school-based physical activity intervention on academic performance were mediated by aerobic fitness. The School in Motion study was a nine-month cluster randomized controlled trial between September 2017 and June 2018. Students from 30 Norwegian lower secondary schools (N = 2,084, mean age [SD] = 14 [0.3] years) were randomly assigned into three groups: the Physically Active Learning (PAL) intervention (n = 10), the Don’t Worry—Be Happy (DWBH) intervention (n = 10), or control (n = 10). Aerobic fitness was assessed by the Andersen test and academic performance by national tests in reading and numeracy. Mediation was assessed according to the causal steps approach using linear mixed models. In the PAL intervention, aerobic fitness partially mediated the intervention effect on numeracy by 28% from a total effect of 1.73 points (95% CI: 1.13 to 2.33) to a natural direct effect of 1.24 points (95% CI: 0.58 to 1.91), and fully mediated the intervention effect on reading, with the total effect of 0.89 points (95% CI: 0.15 to 1.62) reduced to the natural direct effect of 0.40 points (95% CI: −0.48 to 1.28). Aerobic fitness did not mediate the effects on academic performance in the DWBH intervention. As aerobic fitness mediated the intervention effect on academic performance in one intervention, physical activity of an intensity that increases aerobic fitness is one strategy to improve academic performance among adolescents.