Effect of missed clinic visits on treatment outcomes among people with tuberculosis: a quasi-experimental study utilizing instrumental variable analysis.

Objectives: Missed clinic visits disrupt the continuity of care and potentially impact tuberculosis (TB) treatment outcomes negatively. We evaluated the effect of missed clinic visits on mortality and treatment success among people with bacteriologically confirmed pulmonary TB in rural eastern Uganda. Methods: Using routine TB clinic data, we designed a quasi-experimental study and used instrumental variable analysis to estimate a cause-effect. The exposure was one or more missed clinic visit(s), the instrumental variable was patient residence in the same sub-county as the TB clinic, and the outcomes were mortality and treatment success. We performed a two-stage least squares logistic regression for causal analysis and reported the odds ratio (OR) and 95% confidence interval (CI). Results: Of 762 participants with similar baseline characteristics, 186 (24.4%) missed ≥1 clinic visit(s), 342 (44.9%) resided in the same sub-county as the TB clinic, 61 (8.0%) had died, and 687 (90.2%) were successfully treated for TB. Missed clinic visits increased mortality (OR 2.88, 95% CI 1.36-6.13) and reduced TB treatment success (OR 0.41, 95% CI 0.20-0.82). Conclusions: Missed clinic visits increase mortality and negatively impact treatment success among people with TB. The reasons for missed clinic visits should be identified and tackled through context-specific measures.

Using genetics to explore complement C5 as a druggable protein in periodontitis.

Aim: An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis. Method: In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1ß (IL-1ß), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1ß, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. Results: In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers. Conclusions: The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease.

Impact of being taken into out-of-home care: a longitudinal cohort study of First Nations and other child welfare agencies in Manitoba, Canada.

Background: Across Canada, Child Protection Services (CPS) disrupt Indigenous families by apprehending their children at alarmingly high rates. The harms borne by children in out-of-home care (OoHC) have been extensively documented. We examined the impact of OoHC on Manitoba children's health and legal system outcomes to provide rigorous evidence on how discretionary decision-making by CPS agencies can affect these outcomes. Methods: In partnership with First Nations researchers, we used linked administrative data to identify Manitoba children (born 2007-2018) served by First Nations and other Manitoba CPS agencies. We compared those taken into OoHC (n = 19,324) with those never in care but with an open CPS file due to child protection concerns (n = 27,290). We used instrumental variable analysis (CPS agency rates of OoHC as the instrument) to obtain odds ratios (aOR) and 95% confidence intervals adjusted for child, maternal, and family factors. Findings: Mean age (yrs ± standard deviation) at first CPS contact for children taken into OoHC was 2.8 ± 3.7 (First Nations) and 3.0 ± 3.8 (other), and for children never in care was 4.5 ± 4.5 (First Nations) and 5.1 ± 4.7 (other). Among children served by a First Nations agency, males made up 50.6% (n = 5496) in OoHC and 51.0% (n = 6579) never in care. Among children served by other agencies, males made up 51.0% (n = 4324) in OoHC and 51.0% (n = 7428) never in care. Odds of teen pregnancy (First Nations aOR 3.69, 1.40-9.77; other aOR 5.10, 1.83-14.25), teen birth (First Nations aOR 3.23, 1.10-9.49; other aOR 5.06, 1.70-15.03), and sexually transmitted infections (other aOR 7.21, 3.63-14.32) were higher for children in care than children never in care, as were odds of being accused (other aOR 2.71, 1.27-5.75), a victim (other aOR 1.68, 1.10-2.56), charged with a crime (other aOR 2.68, 1.21-5.96), or incarcerated (First Nations aOR 3.64, 1.95-6.80; other aOR 1.19, 1.19-8.04). Interpretation: Being in OoHC worsened children's health and legal system outcomes. The importance of reducing the number of children taken into care was emphasized in briefings to provincial and First Nations governments. The government response will be monitored. Funding: Social Sciences and Humanities Research Council (no. 890-2018-0029).

Hierarchical joint analysis of marginal summary statistics-Part II: High-dimensional instrumental analysis of omics data.

Instrumental variable (IV) analysis has been widely applied in epidemiology to infer causal relationships using observational data. Genetic variants can also be viewed as valid IVs in Mendelian randomization and transcriptome-wide association studies. However, most multivariate IV approaches cannot scale to high-throughput experimental data. Here, we leverage the flexibility of our previous work, a hierarchical model that jointly analyzes marginal summary statistics (hJAM), to a scalable framework (SHA-JAM) that can be applied to a large number of intermediates and a large number of correlated genetic variants-situations often encountered in modern experiments leveraging omic technologies. SHA-JAM aims to estimate the conditional effect for high-dimensional risk factors on an outcome by incorporating estimates from association analyses of single-nucleotide polymorphism (SNP)-intermediate or SNP-gene expression as prior information in a hierarchical model. Results from extensive simulation studies demonstrate that SHA-JAM yields a higher area under the receiver operating characteristics curve (AUC), a lower mean-squared error of the estimates, and a much faster computation speed, compared to an existing approach for similar analyses. In two applied examples for prostate cancer, we investigated metabolite and transcriptome associations, respectively, using summary statistics from a GWAS for prostate cancer with more than 140,000 men and high dimensional publicly available summary data for metabolites and transcriptomes.

The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study.

BACKGROUND: Metabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI, kg/m2). OBJECTIVES: In this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal. METHODS: A liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample Mendelian randomization (MR) analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial, and response (or change in abundance) states. RESULTS: We observed 473 associations with BMI (175 fasting, 188 postprandial, and 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, and 3 response) to be associated with BMI. MR associations included the glucogenic amino acid alanine, which was inversely associated with BMI in the response state (ß: -0.081; SE: 0.023; P = 5.91 × 10-4), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. CONCLUSIONS: Overall, this study showed that MR estimates were strongly correlated with observational effect estimates, suggesting that the broad associations seen between BMI and metabolite variation has a causal underpinning. Specific effects in previously unassessed postprandial and response states are detected, and these may likely mark novel life course risk exposures driven by regular nutrition.

Effect of supplementary private health insurance on out-of-pocket inpatient medical expenditure: evidence from Malaysia.

The vital role of healthcare financing in achieving universal health coverage is indisputable. However, most countries, including Malaysia, face challenges in establishing an equitable and sustainable healthcare financing system due to escalating healthcare costs, an ageing population and a growing disease burden. With desirable pre-payment and risk pooling features, private health insurance (PHI) is considered an alternative financing option to reduce out-of-pocket (OOP) medical expenditure. However, ongoing theoretical and empirical debates persist regarding the adequacy of financial risk protection provided by PHI largely because it depends on its role, the benefit design and the regulations in place. Our study aimed to investigate the effect of supplementary PHI on OOP inpatient medical expenditure in Malaysia. Secondary data analysis was conducted using the Malaysian National Health and Morbidity Survey 2019 dataset. A total of 983 respondents with a history of inpatient hospitalization in the past 12 months were included in the study. Instrumental variable analysis using a two-stage residual inclusion was performed to address endogeneity bias, with wealth status and education level as the instrumental variables. Tobit regression model was used in the second stage considering the censored distribution of the outcome variable. Missing data were handled using multiple imputation. About one-fifth of the respondents had PHI. In this study, we found that having PHI significantly increased OOP inpatient medical expenditure in all three marginal effects. Additionally, age, residential location, ethnicity (citizenship), being covered by government guarantee letter, government funding and employer-sponsored health insurance were other significant factors associated with OOP inpatient medical expenditure. Our findings undermine a key justification to advocate PHI uptake among the population, with a need for the Malaysian government to reassess the role of PHI in healthcare financing and reconsider PHI subsidization policy. Regulations should also be strengthened to enhance the financial risk protection provided by PHI.

Does cycle commuting reduce the risk of mental ill-health? An instrumental variable analysis using distance to nearest cycle path.

BACKGROUND: Previous studies have linked cycling with improved mental wellbeing but these studies tend to use cross-sectional survey data that have small sample sizes and self-reported health measures, and are potentially susceptible to omitted-variable bias and reverse causation. We use an instrumental variable approach and an objective measure of mental ill-health taken from linked administrative data to ask: 'Does cycle commuting reduce the risk of mental ill-health?' METHODS: Our study links data on commuting in Edinburgh and Glasgow from the Scottish population census with mental health prescriptions from the National Health Service Prescribing Information System records. We use road distance from home to nearest cycle path as an instrumental variable for cycle commuting. RESULTS: In total, 378 253 people aged 16-74 years living and working in the City of Edinburgh and Glasgow City council areas at the 2011 census were included in our study; 1.85% of commuters in Glasgow and 4.8% of commuters in Edinburgh cycled to work. Amongst cyclists, 9% had a prescription for mental health compared with 14% amongst non-cyclists. Using a bivariate probit model, we estimate a mean average reduction in prescriptions for antidepressants and/or anxiolytics in the 5 years following the census of -15.1% (95% CI: -15.3% to -15.0%) amongst cycle commuters compared with those who use any other mode to commute. CONCLUSIONS: This work suggests that cycle commuting is causally related to reduced mental ill-health and provides further evidence in support of the promotion of active travel to encourage commuters travelling shorter distances to shift to cycle commutes.

Alcohol-related morbidity and mortality by fathers' parental leave: A quasi-experimental study in Sweden.

BACKGROUND AND AIMS: Fathers' parental leave has been associated with decreased risks of alcohol-related hospitalizations and mortality. Whether this is attributable to the health protections of parental leave itself (through stress reduction or behavioral changes) or to selection into leave uptake remains unclear, given that fathers are more likely to use leave if they are in better health. Using the quasi-experimental variation of a reform incentivizing fathers' leave uptake (the 1995 Father's quota reform), this study aimed to assess whether fathers' parental leave influences alcohol-related morbidity and mortality. DESIGN: Quasi-experimental interrupted time series and instrumental variable analyses. SETTING: Sweden. PARTICIPANTS: Fathers of singleton children born from January 1992 to December 1997 (n = 220 412). MEASUREMENTS: Exposure was indicated by the child's birthdate before or after the reform and used to instrument fathers' 2- and 8-year parental leave uptake. Outcomes included fathers' hospitalization rates for acute alcohol-related (intoxication; mental and behavioral disorders) and chronic alcohol-related diagnoses (cardiovascular, stomach and other diseases; liver diseases), as well as alcohol-related mortality, up to 2, 8 and 18 years after the first child's birthdate. FINDINGS: In interrupted time series analyses, fathers of children born after the reform exhibited immediate decreases in alcohol-related hospitalization rates up to 2 (incidence rate ratio [IRR] = 0.66, 95% confidence interval [CI] = 0.51-0.87), 8 (IRR = 0.74, 95% CI = 0.57-0.96) and 18 years after birth (IRR = 0.72, 95% CI = 0.54-0.96), particularly in acute alcohol-related hospitalization rates, compared with those with children born before. No changes were found for alcohol-related mortality. Instrumental variable results suggest that alcohol-related hospitalization decreases were driven by fathers' parental leave uptake (e.g. 2-year hospitalizations: IRR = 0.16, 95% CI = 0.03-0.84). CONCLUSIONS: In Sweden, a father's parental leave eligibility and uptake may protect against alcohol-related morbidity.

Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study.

Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]). Interpretation: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. Funding: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.

The causal effects of education on adult health, mortality and income: evidence from Mendelian randomization and the raising of the school leaving age.

BACKGROUND: On average, educated people are healthier, wealthier and have higher life expectancy than those with less education. Numerous studies have attempted to determine whether education causes differences in later health outcomes or whether another factor ultimately causes differences in education and subsequent outcomes. Previous studies have used a range of natural experiments to provide causal evidence. Here we compare two natural experiments: a policy reform, raising the school leaving age in the UK in 1972; and Mendelian randomization. METHODS: We used data from 334 974 participants of the UK Biobank, sampled between 2006 and 2010. We estimated the effect of an additional year of education on 25 outcomes, including mortality, measures of morbidity and health, ageing and income, using multivariable adjustment, the policy reform and Mendelian randomization. We used a range of sensitivity analyses and specification tests to assess the plausibility of each method's assumptions. RESULTS: The three different estimates of the effects of educational attainment were largely consistent in direction for diabetes, stroke and heart attack, mortality, smoking, income, grip strength, height, body mass index (BMI), intelligence, alcohol consumption and sedentary behaviour. However, there was evidence that education reduced rates of moderate exercise and increased alcohol consumption. Our sensitivity analyses suggest that confounding by genotypic or phenotypic confounders or specific forms of pleiotropy are unlikely to explain our results. CONCLUSIONS: Previous studies have suggested that the differences in outcomes associated with education may be due to confounding. However, the two independent sources of exogenous variation we exploit largely imply consistent causal effects of education on outcomes later in life.

Instrumental Variable Analysis of Racial Discrimination and Blood Pressure in a Sample of Young Adults.

Racial inequities in blood pressure levels have been extensively documented. Experiences of racial discrimination could explain some of this disparity, although findings from previous studies have been inconsistent. To address limitations of prior literature, including measurement error, we implemented instrumental variable analysis to assess the relationship between racial discrimination in institutional settings and blood pressure. Using data from 3,876 Black and White adults with an average age of 32 years from examination 4 (1992-1993) of the Coronary Artery Risk Development in Young Adults Study, our primary analysis examined the relationship between self-reported experiences of racial discrimination in institutional settings and blood pressure using reflectance meter measurement of skin color as an instrument. Findings suggested that an increase in experiences of racial discrimination was associated with higher systolic and diastolic blood pressure (ß = 2.23 mm Hg (95% confidence interval: 1.85, 2.61) and ß = 1.31 (95% confidence interval: 1.00, 1.62), respectively). Our instrumental variable estimates suggest that experiences of racial discrimination within institutional settings contribute to racial inequities in elevated blood pressure and cardiovascular disease outcomes in a relatively young cohort of adults and may yield clinically relevant differences in cardiovascular health over the life course.

PCI or CABG for left main coronary artery disease: the SWEDEHEART registry.

AIMS: An observational nationwide all-comers prospective register study to analyse outcomes after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in unprotected left main coronary artery (LMCA) disease. METHODS AND RESULTS: All patients undergoing coronary angiography in Sweden are registered in the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Between 01/01/2005 and 12/31/2015, 11 137 patients with LMCA disease underwent CABG (n = 9364) or PCI (n = 1773). Patients with previous CABG, ST-elevation myocardial infarction (MI) or cardiac shock were excluded. Death, MI, stroke, and new revascularization during follow-up until 12/31/2015 were identified using national registries. Cox regression with inverse probability weighting (IPW) and an instrumental variable (IV), administrative region, were used. Patients undergoing PCI were older, had higher prevalence of comorbidity but lower prevalence of three-vessel disease. PCI patients had higher mortality than CABG patients after adjustments for known cofounders with IPW analysis (hazard ratio [HR] 2.0 [95% confidence interval (CI) 1.5-2.7]) and known/unknown confounders with IV analysis (HR 1.5 [95% CI 1.1-2.0]). PCI was associated with higher incidence of major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, or new revascularization) than CABG, with IV analysis (HR 2.8 [95% CI 1.8-4.5]). There was a quantitative interaction for diabetic status regarding mortality (P = 0.014) translating into 3.6 years (95% CI 3.3-4.0) longer median survival time favouring CABG in patients with diabetes. CONCLUSION: In this non-randomized study, CABG in patients with LMCA disease was associated with lower mortality and fewer MACCE compared to PCI after multivariable adjustment for known and unknown confounders.

Evaluation of instrumental variable method using Cox proportional hazard model in epidemiological studies.

The instrumental variable (IV) method with a Cox proportional hazard (PH) model has been used to evaluate treatment effects in epidemiological studies involving survival data. The effectiveness of the IV methods in these circumstances has yet to be fully understood, though. The study aimed to evaluate the performance of IV methods using a Cox model. We evaluated the validity of treatment effects estimated by two-stage IV models using simulated scenarios with varying confounder strengths and baseline hazards. Our simulation demonstrated that when observed confounders were not taken into account in the IV models, and the confounder strength was moderate, the treatment effects based on the two-stage IV models were similar to the true value. However, the effect estimates diverged from the true value when observed confounders were taken into account in the IV models. In the case of a null treatment effect (i.e., hazard ratio=1), the estimates from the unadjusted and adjusted IV models (only two-stage) were close to the true value. The implication of our study findings is that the treatment effects obtained through IV analyses using the Cox PH model remain valid if the estimates are reported from unadjusted IV models with moderate confounding effects or if the treatment does not impact the outcome.•For every simulation, we utilized a sample size of 10,000 and performed 1,000 replications.•The true treatment effects (HR) of 3, 2, and 1 (null effect) were evaluated.•The 95% confidence intervals (CI) were calculated as the range between the 2.5 and 97.5 percentiles of the 1000 estimates.

The estimated effect of season and vitamin D in the first trimester on pubertal timing in girls and boys: a cohort study and an instrumental variable analysis.

BACKGROUND: Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. METHODS: We conducted a follow-up study of 15 819 children born in 2000-03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November-April) relative to high (May-October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. RESULTS: For the combined estimate, girls and boys of mothers who had their first trimester during November-April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May-October: -1.0 months (95% CI: -1.7 to -0.3) and -0.7 months (95% CI: -1.4 to -0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively, -1.3 months (95% CI: -2.1 to -0.4) and -1.0 months (95% CI: -1.8 to -0.2) per SD (22 nmol/L) decrease in 25(OH)D3. CONCLUSIONS: Both first pregnancy trimester during November-April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.

Boys with overweight status lagged behind girls with overweight status in reading: evidence from mendelian randomization.

OBJECTIVES: We investigated the relationship between childhood weight status and academic achievement across sexes and different school subjects in Norway. STUDY DESIGN AND SETTING: We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa), which includes genetic data (N = 13,648, 8-year-old children). We employed within-family mendelian randomization, using a body mass index (BMI) polygenic risk score as an instrument to address unobserved heterogeneity. RESULTS: Contrary to most previous findings, we observed that overweight status (including obesity) has more detrimental effects on reading achievement in boys than in girls; the test scores of boys with overweight were about a standard deviation lower than those of normal weight boys, and the negative effects on reading achievement became stronger in the later grade. CONCLUSION: Previous obesity prevention studies have mainly targeted girls, based on the assumption that the obesity penalty is greater for girls. Our findings highlight that particular attention to boys with overweight may help reduce the existing gender gap in academic achievement.

Application of Instrumental Variable Analysis in Pediatric End-of-Life Research: A Case Study.

Instrumental variable analysis (IVA) has been widely used in many fields, including health care, to determine the comparative effectiveness of a treatment, intervention, or policy. However, its application in pediatric end-of-life care research has been limited. This article provides a brief overview of IVA and its assumptions. It illustrates the use of IVA by investigating the comparative effectiveness of concurrent versus standard hospice care for reducing 1-day hospice enrollments. Concurrent hospice care is a relatively recent type of care enabled by the Affordable Care Act in 2010 for children enrolled in the Medicaid program and allows for receiving life-prolonging medical treatment concurrently with hospice care. The IVA was conducted using observational data from 18,152 pediatric patients enrolled in hospice between 2011 and 2013. The results indicated that enrollment in concurrent hospice care reduced 1-day enrollment by 19.3%.

Mediation and instrumental variable analyses for vaccine-induced antibody titer against influenza B.

OBJECTIVE: Immune correlate analyses for vaccine trials have been applied to investigate associations of vaccine efficacy and surrogate markers such as vaccine-induced antibodies. However, the role of antibody as a surrogate marker in predicting the outcome can vary by time, and surrogate-outcome confounding may have resulted in bias even in randomized trials. We provide a framework for surrogate marker assessment to address the aforementioned issues. STUDY DESIGN AND SETTING: We reanalyzed the vaccine randomized trial for influenza B. We conducted a mediation analysis that enables estimation of vaccine efficacy, mediation effects and proportion of mediation on disease probabilities at various follow-up times. We proposed instrumental variable (IV) analyses with randomized vaccination as an IV accounting for potential unmeasured confounding. RESULTS: The mediation effect of vaccine efficacy by hemagglutination inhibition (HAI) titer was significantly protective at 181 days after vaccination: 63.2% [95% confidence interval, (CI) = (39.9%, 82.0%)], and HAI titer explained 61.1% [95% CI = (36.7%, 96.2%)] of the protective effect of vaccination. CONCLUSIONS: Most of vaccine efficacy is mediated by HAI titer, particularly in children 10 years and older. Our contribution is to provide causal analytics for the role of surrogate marker with weaker assumptions regarding surrogate-disease causation.

Maternal vitamin D levels and male reproductive health: a population-based follow-up study.

Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI - 19 to - 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI - 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.