Marginal Odds Ratio Research Articles

Personal protective effect of wearing surgical face masks in public spaces on self-reported respiratory symptoms in adults: pragmatic randomised superiority trial

ObjectiveTo evaluate the personal protective effects of wearing versus not wearing surgical face masks in public spaces on self-reported respiratory symptoms over a 14 day period.DesignPragmatic randomised superiority trial.SettingNorway.Participants4647 adults...

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection

Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection-like index illness. This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration-approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023. COVID-19 status (positive vs negative) at enrollment. The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms. A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19-positive (range, 2.8%-3.7%) and COVID-19-negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19-positive and COVID-19-negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]). In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection-like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.

No evidence of difference in mortality with amoxicillin versus co-amoxiclav for hospital treatment of community-acquired pneumonia

Current guidelines recommend broad-spectrum antibiotics for high-severity community-acquired pneumonia (CAP), potentially contributing to antimicrobial resistance (AMR). We aim to compare outcomes in CAP patients treated with amoxicillin (narrow-spectrum) versus co-amoxiclav (broad-spectrum), to understand if narrow-spectrum antibiotics could be used more widely. We analysed electronic health records from adults (≥16y) admitted to hospital with a primary diagnosis of pneumonia between 01-January-2016 and 30-September-2023 in Oxfordshire, United Kingdom. Patients receiving baseline ([-12h,+24h] from admission) amoxicillin or co-amoxiclav were included. The association between 30-day all-cause mortality and baseline antibiotic was examined using propensity score (PS) matching and inverse probability treatment weighting (IPTW) to address confounding by baseline characteristics and disease severity. Subgroup analyses by disease severity and sensitivity analyses with missing covariates imputed were also conducted. Among 16,072 admissions with a primary diagnosis of pneumonia, 9685 received either baseline amoxicillin or co-amoxiclav. There was no evidence of a difference in 30-day mortality between patients receiving initial co-amoxiclav vs. amoxicillin (PS matching: marginal odds ratio 0.97 [0.76-1.27], p=0.61; IPTW: 1.02 [0.78-1.33], p=0.87). Results remained similar across stratified analyses of mild, moderate, and severe pneumonia. Results were also similar with missing data imputed. There was also no evidence of an association between 30-day mortality and use of additional macrolides or additional doxycycline. There was no evidence of co-amoxiclav being advantageous over amoxicillin for treatment of CAP in 30-day mortality at a population-level, regardless of disease severity. Wider use of narrow-spectrum empirical treatment of moderate/severe CAP should be considered to curb potential for AMR.

Causal Analyses of Statin to Prevent Liver Disease Progression: A Nationwide Study Using Superlearning Targeted Maximum Likelihood Estimation

Many studies have shown that statins reduce the risk of progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) among at-risk populations. However, causality has not been proved. This study examined whether statins could prevent LC and HCC in patients with progressive and worsening chronic liver disease, using a robust methodology for causality. Between 2002 and 2013, 52,145 patients with chronic liver diseases were identified from the National Health Insurance Service database in South Korea. The inverse probability weighting (IPW) and superlearning targeted maximum likelihood estimation (TMLE) were used to assess the causality of statin use on the risk of LC and HCC, adjusting for sex, age, comorbidities, and co-medications. Multivariable superlearning TMLE revealed that statin use was associated with reduction in the incidence risk of LC (Marginal odds ratio (MOR) 0.59, 95% confidence interval [CI] 0.50-0.65) and HCC (MOR 0.59, 95% CI 0.50-0.67). Such a protective effect was more evident with atorvastatin and lipophilic statin. This population-based observational study indicated the benefit of statin use, particularly atorvastatin and lipophilic statin, for causally reducing the risk of LC and HCC.

Hearing Outcomes in Cisplatin or Cetuximab Combined with Radiation for Patients with HPV-Associated Oropharyngeal Cancer in NRG/RTOG 1016

NRG/RTOG 1016 was a noninferiority phase 3 trial comparing the efficacy of radiation with either cisplatin (RT+Cisp) or cetuximab (RT+Cetux) for patients with HPV+ oropharyngeal cancer (OPC). Perceived hearing handicap was included as a patient-reported outcome (PRO) secondary endpoint. The primary hypothesis was that perceived hearing handicap would be greater for patients receiving RT+Cisp compared to RT+Cetux. Perceived hearing handicap was measured at baseline, end of treatment, 3, 6, and 12-months post-treatment using the Hearing Handicap Inventory for Adults Screening Version (HHIA-S), a 10-item self-assessment questionnaire designed to measure patients' reactions to their hearing loss. Total HHIA-S scores range from 0 to 40; higher total score indicates more severe perceived hearing handicap. Hearing handicap categories (none, mild/moderate, and severe) were also analyzed. Mixed ordinal logistic models were used to analyze the raw HHIA-S scores and handicap categories (2-sided alpha 0.05). Participation in the PRO assessments was optional, with 368 patients participating in the hearing PRO. No significant differences in patient/tumor characteristics were found between PRO participants/non-participants. Pre-treatment (mean [SD]) HHIA-S scores were not different for RT+Cisp (3.23 [6.28]) and RT+Cetux (4.77 [8.14]) groups. Post-treatment HHIA-S scores increased for RT+Cisp, and remained stable at the later follow-up time points. RT+Cetux scores remained stable from baseline. Change score from pre- to post-treatment was higher for RT+Cisp (4.32, 95% CI = [2.57, 6.07]) than RT+Cetux (0.08, 95% CI = [-1.15, 1.31]; p < 0.001). For hearing handicap category, post-treatment RT+Cisp had a significantly higher percentage of mild/moderate and severe cases (32%) compared to RT+Cetux (20%). From pre- to post-treatment, worsening of hearing handicap category from normal to mild/moderate or severe was greater for RT+Cisp (24%) than for RT+Cetux (9%). The conditional odds of being in a higher self-perceived hearing handicap category in the RT+Cisp arm were 3.57 (95% CI [2.04, 6.25]) times that in the RT+Cetux arm. Averaging over patients, the marginal odds ratio was 2.46 (95% CI [1.65, 3.66]). Patients receiving concurrent RT+Cisp for HPV-associated OPC have significantly higher odds of worsening self-perceived hearing handicap after treatment than with RT+Cetux. This was consistent across time through one-year post-treatment. These findings inform hearing-related outcomes for patients with HPV-associated OPC.

Conditional average treatment effect estimation with marginally constrained models

Abstract Treatment effect estimates are often available from randomized controlled trials as a single average treatment effect for a certain patient population. Estimates of the conditional average treatment effect (CATE) are more useful for individualized treatment decision-making, but randomized trials are often too small to estimate the CATE. Examples in medical literature make use of the relative treatment effect (e.g. an odds ratio) reported by randomized trials to estimate the CATE using large observational datasets. One approach to estimating these CATE models is by using the relative treatment effect as an offset, while estimating the covariate-specific untreated risk. We observe that the odds ratios reported in randomized controlled trials are not the odds ratios that are needed in offset models because trials often report the marginal odds ratio. We introduce a constraint or a regularizer to better use marginal odds ratios from randomized controlled trials and find that under the standard observational causal inference assumptions, this approach provides a consistent estimate of the CATE. Next, we show that the offset approach is not valid for CATE estimation in the presence of unobserved confounding. We study if the offset assumption and the marginal constraint lead to better approximations of the CATE relative to the alternative of using the average treatment effect estimate from the randomized trial. We empirically show that when the underlying CATE has sufficient variation, the constraint and offset approaches lead to closer approximations to the CATE.

Causal inference for recurrent events via aggregated marginal odds ratio

SummaryResearchers often work with treatments and outcomes that vary over time. For example, psychologists are interested in the curative effect of cognitive behavior therapies on patients' recurrent depression symptoms. While there are various causal effect measures designed for one‐time treatment, the causal effect measures for time‐varying treatment and recurrent events are relatively under‐developed. In this article, a new causal measure is proposed to quantify the causal effect of time‐varying treatments on recurrent events. We suggest estimators with robust standard errors that are based on various weight models for both conventional causal measures and the proposed measure in different time settings. We outline the approaches and describe how using some stabilized inverse probability weight models are more advantageous than others. We demonstrate that the proposed causal estimand can be consistently estimated for study periods of moderate length, and the estimation results are compared under different treatment settings with various weight models. We also find that the proposed method is suitable for both absorbing and nonabsorbing treatments. The methods are applied to the 1997 National Longitudinal Study of Youth as an illustrative example.

Assessment of electronic health record (EHR) –based machine learning (ML) in predicting risk of brain metastasis among patients with early-stage non–small-cell lung cancer (eNSCLC).

2036 Background: Among patients (pts) with eNSCLC, development ofbrain metastasis (BM) is a poor prognostic sign, but routine surveillance for BM is not recommended post-therapy. EHR-based ML algorithms may identify pts who would benefit from active brain MRI surveillance and/or treatment intensification in the early-stage setting. Methods: ConcertAI Patient360 database, consisting of structured and curated EHR records from pts receiving care in ~900 US oncology clinics, was used to identify pts diagnosed with stage IB-IIIA NSCLC without prior evidence of BM between Jan 2010 – December 2021. Presence of BM was identified from human curation of patient documents. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 3-fold cross-validation were trained and compared to predict risk of BM at two landmarks: 18 and 24 months (mos) from initial diagnosis (index). Pts who did not develop BM and either died or were lost to follow-up prior to landmark times were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived marginal odds ratios (OR). Due to low prevalence of BM, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from GB model were flagged as low-risk vs. high-risk. Results: Among 7473 pts in 18 mos model, median age was 68.4 years (IQR 13.2), 50.5% were female, and 10.9% were black. Demographics were similar for 6863 pts in 24 mos model. 6.4% and 8.3% developed BM at 18 and 24 mos. Ability of GB, RF, and LR models to predict BM was similar with validation AUPRC of 0.109 at 18 mos and 0.137 at 24 mos. In the GB model, BM prevalence in high-risk vs. low-risk group was 10.3% vs. 3.1% at 18 mos and 13.4% vs. 4.4% at 24 mos. In both landmark models, N0 stage and surgery within 90 days after index diagnosis were protective against BM, while presence of EGFR targetable mutations, adenocarcinoma (AD) histology, higher platelets (PLT), and history of pneumonia were risk factors. A glucose-by-histology interaction was found: For pts with normal blood glucose (GLU), risk of BM was independent of histology, for pts with high GLU, AD conferred greater risk of BM. Conclusions: An EHR-based ML model identified risk factors for developing BM among pts with eNSCLC and may identify pts who would benefit from active brain MRI surveillance and treatment intensification. [Table: see text]

Marginal Odds Ratios: What They Are, How to Compute Them, and Why Sociologists Might Want to Use Them

Marginal Odds Ratios: What They Are, How to Compute Them, and Why Sociologists Might Want to Use Them

A transformation perspective on marginal and conditional models.

Clustered observations are ubiquitous in controlled and observational studies and arise naturally in multicenter trials or longitudinal surveys. We present a novel model for the analysis of clustered observations where the marginal distributions are described by a linear transformation model and the correlations by a joint multivariate normal distribution. The joint model provides an analytic formula for the marginal distribution. Owing to the richness of transformation models, the techniques are applicable to any type of response variable, including bounded, skewed, binary, ordinal, or survival responses. We demonstrate how the common normal assumption for reaction times can be relaxed in the sleep deprivation benchmark data set and report marginal odds ratios for the notoriously difficult toe nail data. We furthermore discuss the analysis of two clinical trials aiming at the estimation of marginal treatment effects. In the first trial, pain was repeatedly assessed on a bounded visual analog scale and marginal proportional-odds models are presented. The second trial reported disease-free survival in rectal cancer patients, where the marginal hazard ratio from Weibull and Cox models is of special interest. An empirical evaluation compares the performance of the novel approach to general estimation equations for binary responses and to conditional mixed-effects models for continuous responses. An implementation is available in the tram add-on package to the R system and was benchmarked against established models in the literature.

Logistic regression frequently outperformed propensity score methods, especially for large datasets: a simulation study

ObjectivesIn observational studies, researchers must select a method to control for confounding. Options include propensity score (PS) methods and regression. It remains unclear how dataset characteristics (size, overlap in PSs, and exposure prevalence) influence the relative performance of the methods. Study Design and SettingA simulation study to evaluate the role of dataset characteristics on the performance of PS methods, compared to logistic regression, for estimating a marginal odds ratio was conducted. Dataset size, overlap in PSs, and exposure prevalence were varied. ResultsRegression showed poor coverage for small sample sizes, but with large sample sizes was relatively robust to imbalance in PSs and low exposure prevalence. PS methods displayed suboptimal coverage as overlap in PSs decreased, which was exacerbated at larger sample sizes. Power of matching methods was particularly affected by a lack of overlap, low exposure prevalence, and small sample size. The advantage of regression for large data size was reduced in sensitivity analysis with a complementary log–log outcome generation mechanism and unmeasured confounding, with superior bias and error but inferior coverage to matching methods. ConclusionDataset characteristics influence performance of methods for confounder adjustment. In many scenarios, regression may be the preferable option.

Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.

Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801,+Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080,+Inf; SEAL 3.51‰, controls: 2.21‰). The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program.

Potentially preventable hospitalizations and use of preventive services among people with multiple sclerosis: Large cohort study, USA

BackgroundIndividuals with multiple sclerosis (MS) report barriers to accessing care, including receipt of preventive services. Potentially preventable hospitalization (PPH) is an important marker for access to, and receipt of timely care. However, few national studies have examined PPH risk in people with MS or considered the role of preventive care in reducing PPH risk among this patient population. Our objective was to examine PPH risk among adults with MS compared with their counterparts without MS. MethodsOptum® Clinformatics® Data Mart (2007–2017) was used to identify 6198 individuals with an MS diagnosis and their propensity-score matched counterparts without MS. Diagnostic and procedural codes were used to identify the presence of preventive hospitalizations, which were defined as quality indicators by the Agency for Healthcare Research and Quality (AHRQ) during the 4-year follow-up period since the diagnosis of MS. Information on receipt of preventive services and office visits was also extracted. Adjusted generalized estimating equations were used to examine the association between MS diagnosis and PPHs. To examine the role of preventive services on odds of PPH amongst people with MS, we reported the adjusted marginal odds ratio (OR) and 95% confidence intervals (CI). ResultsThe rate of any PPH among people with MS was double that of those without MS (131.6 vs 62.5 per 10,000). We identified higher odds of specific PPH indicators among people with MS compared to those without. Individuals with MS had 65% higher odds of hospitalization for pneumonia (OR=1.65, 95% CI: 1.01, 2.30), with similar significant findings observed for urinary tract infections (OR=4.90, 95% CI: 2.51, 9.57). In MS patients, receipt of preventive services, namely cholesterol screening (OR=0.76, 95% CI: 0.60, 0.95) and annual wellness visits were associated with lower odds of any PPH (OR=0.57, 95% CI: 0.43, 0.76). ConclusionPeople with MS were at a higher risk for PPHs compared with their counterparts without MS. Use of appropriate preventive services reduced the risk of PPH among the general population and among those with MS. More efforts are needed to encourage and facilitate the use of preventive care among people with MS. Receipt of timely and appropriate preventive care in this population may reduce the risk for PPH.

Survival benefit of extracorporeal membrane oxygenation in severe COVID-19: a multi-centre-matched cohort study.

PurposeExtracorporeal membrane oxygenation (ECMO) has become an established therapy for severe respiratory failure in coronavirus disease 2019 (COVID-19). The added benefit of receiving ECMO in COVID-19 remains uncertain. The aim of this study is to analyse the impact of receiving ECMO at specialist centres on hospital mortality.MethodsA multi-centre retrospective study was conducted in COVID-19 patients from 111 hospitals, referred to two specialist ECMO centres in the United Kingdom (UK) (March 2020 to February 2021). Detailed covariate data were contemporaneously curated from electronic referral systems. We analysed added benefit of ECMO treatment in specialist centres using propensity score matching techniques.Results1363 patients, 243 receiving ECMO, were analysed. The best matching technique generated 209 matches, with a marginal odds ratio (OR) for mortality of 0.44 (95% CI 0.29–0.68, p < 0.001) and absolute mortality reduction of 18.2% (44% vs 25.8%, p < 0.001) for treatment with ECMO in a specialist centre.ConclusionWe found ECMO provided at specialist centres conferred significant survival benefit. Where resources and specialism allow, ECMO should be widely offered.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00134-022-06645-w.

Recombinant hepatitis B vaccine uptake and multiple sclerosis risk: A marginal structural modeling approach

BackgroundThere has been an ongoing debate regarding the association between uptake of recombinant vaccine against hepatitis B virus (HBV) and multiple sclerosis (MS) risk. This case-control study tested the hypothesis whether recombinant HBV vaccination status is causally associated with MS risk using targeted maximum likelihood estimation (TMLE) technique. MethodsConfirmed 110 MS cases and age (± 5 years), sex and nativity matched (1:1) 110 controls were enrolled. Data were collected on sociodemographics, environmental factors, history of vaccinations and past morbidities through face-to-face interview both from cases and controls. To estimate the causal parameters including marginal odds ratio (OR), causal relative risk (RR), causal risk difference (RD) and their 95% confidence intervals (CIs), we implemented case-control-weighted TMLE for a matched design that uses data-adaptive flexible stacked ensemble-based machine learning system namely Super Learner. Additionally, population preventable fraction (PPF) of MS risk was computed. ResultsThis study demonstrated a significant nonspecific protective effect of HBV vaccination against MS risk (marginal OR 0.44; 95% CI: 0.19–0.68; p = 0.006; causal RR 0.64, 95% CI: 0.46–0.89; p = 0.004). The significant causal RD showed that among the vaccinated 19% fewer MS cases occurred owing to their HBV vaccination (causal RD -0.19; 95% CI: -0.32 – -0.06; p = 0.014). In the source population, vaccination against HBV led to 17.4% reduced MS risk (PPF = 17.4%; 95% CI: 3.8%, 36.3%). ConclusionThe results suggest a significant nonspecific protective effect of recombinant HBV vaccine against MS risk. Future studies may contemplate to confirm these results.

Comparison of channel sampling methods and brush heads in surveillance culture of endoscope reprocessing: A propensity score matching and paired study.

Background:Endoscopy-related infections have caused multiple outbreaks. The importance of surveillance culture is gradually recognized, but sampling techniques are not consistent in many guidelines. It is unclear whether the Flush-Brush-Flush sampling method (FBFSM) is more sensitive than the conventional flush sampling method (CFSM) and whether different sampling brushes have different effects.Methods:The propensity score matching method was done with two matching ways, 1:1 nearest neighbor propensity score matching and full matching was used to analyze the surveillance culture data collected by FBFSM and CFSM. We fit a confounder-adjusted multiple generalized linear logistic regression model to estimate the marginal odds ratio (OR). A paired study was applied to compare the sampling effect of polyurethane foam (PU) head brush and polyamide (PA) head brush.Result:From 2016 to 2020, 316 reprocessed endoscope samples were collected from all 59 endoscopy centers in Tianjin. About 279 (88.3%) reprocessed endoscopes met the threshold of Chinese national standards (<20 CFU/Channel). The qualified rate of reprocessed endoscopes sampling by CFSM (91.8%) and FBFSM (81.6%) was statistically different (p < 0.05). The adjusted OR by full matching for FBFSM was 7.98 (95% confidence interval: 3.35-21.78). Forty one pairs of colonoscopes, after reprocessing from 27 centers, were tested by PA and PU brushes, and no difference was found in microbial recovery.Conclusion:FBFSM was confirmed to be a more sensitive sampling technique. PU and PA brushes had no significant difference in sampling effect.

Hospitalization outcomes among brain metastasis patients receiving radiation therapy with or without stereotactic radiosurgery from the 2005–2014 Nationwide Inpatient Sample

The purpose of this study was to comparehospitalization outcomes among US inpatients with brain metastases who received stereotactic radiosurgery (SRS) and/or non-SRS radiation therapies without neurosurgical intervention. A cross-sectional study was conducted whereby existing data on 35,199 hospitalization records (non-SRS alone: 32,981; SRS alone: 1035; SRS + non-SRS: 1183) from 2005 to 2014 Nationwide Inpatient Sample were analyzed. Targeted maximum likelihood estimation and Super Learner algorithms were applied to estimate average treatment effects (ATE), marginal odds ratios (MOR) and causal risk ratio (CRR) for three distinct types of radiation therapy in relation to hospitalization outcomes, including length of stay (‘ ≥ 7 days’ vs. ‘ < 7 days’) and discharge destination (‘non-routine’ vs. ‘routine’), controlling for patient and hospital characteristics. Recipients of SRS alone (ATE = − 0.071, CRR = 0.88, MOR = 0.75) or SRS + non-SRS (ATE = − 0.17, CRR = 0.70, MOR = 0.50) had shorter hospitalizations as compared to recipients of non-SRS alone. Recipients of SRS alone (ATE = − 0.13, CRR = 0.78, MOR = 0.59) or SRS + non-SRS (ATE = − 0.17, CRR = 0.72, MOR = 0.51) had reduced risks of non-routine discharge as compared to recipients of non-SRS alone. Similar analyses suggested recipients of SRS alone had shorter hospitalizations and similar risk of non-routine discharge when compared to recipients of SRS + non-SRS radiation therapies. SRS alone or in combination with non-SRS therapies may reduce the risks of prolonged hospitalization and non-routine discharge among hospitalized US patients with brain metastases who underwent radiation therapy without neurosurgical intervention.

1321Marginal structural model of the causal role of hepatitis B vaccination in multiple sclerosis risk

Abstract Background There are conflicting reports regarding the association between uptake of recombinant vaccine against hepatitis B virus (HBV) and risk of multiple sclerosis (MS). Most cohort or case-control studies found no significant short- or long-term increase in MS risk after immunization. Whereas others reported a significant increase in MS risk within three years of HBV vaccination. The present matched case-control study was conducted to test the hypothesis whether recombinant HBV vaccination status is causally associated with MS risk using targeted maximum likelihood estimation (TMLE) that uses data-adaptive flexible machine learning algorithms to estimate the causal parameters. Methods Confirmed 110 MS incident cases and age (± 5 years), gender and nationality matched (1:1) 110 community controls were enrolled. A pre-tested structured questionnaire was used to collect the data on demographics, environmental factors, comorbidities, history of vaccinations through face-to-face interviews both from cases and controls. We implemented case-control-weighted TMLE – a double robust, multistep procedure to estimate causal relative risk (RR), marginal odds ratio (OR) and population attributable fraction. Results This study demonstrated a non-specific protective effect of HBV vaccine against MS risk as estimated by TMLE (causal RR 0.63, 95% CI: 0.45-0.90; p = 0.004; marginal OR 0.43; 95% CI: 0.18-0.67; p = 0.006). The population attributable fraction was 20% (95% CI: 6%, 34%; p = 0.014)) Conclusions Subject to inherent limitations of the case-control design, this study suggests a non-specific protective effect of recombinant HBV vaccination against MS risk. Future studies may contemplate to confirm these results. Key message Causal analysis showed a non-specific protective causal association between uptake of recombinant HBV vaccine and MS risk in the study population.

Estimating the marginal effect of a continuous exposure on an ordinal outcome using data subject to covariate-driven treatment and visit processes.

In the statistical literature, a number of methods have been proposed to ensure valid inference about marginal effects of variables on a longitudinal outcome in settings with irregular monitoring times. However, the potential biases due to covariate-driven monitoring times and confounding have rarely been considered simultaneously, and never in a setting with an ordinal outcome and a continuous exposure. In this work, we propose and demonstrate a methodology for causal inference in such a setting, relying on a proportional odds model to study the effect of the exposure on the outcome. Irregular observation times are considered via a proportional rate model, and a generalization of inverse probability of treatment weights is used to account for the continuous exposure. We motivate our methodology by the estimation of the marginal (causal) effect of the time spent on video or computer games on suicide attempts in the Add Health study, a longitudinal study in the United States. Although in the Add Health data, observation times are prespecified, our proposed approach is applicable even in more general settings such as when analyzing data from electronic health records where observations are highly irregular. In simulation studies, we let observation times vary across individuals and demonstrate that not accounting for biasing imbalances due to the monitoring and the exposure schemes can bias the estimate for the marginal odds ratio of exposure.

Circadian periodicity affects the type of ventricular arrhythmias and efficacy of implantable defibrillator therapies.

Factors influencing malignant arrhythmia onset are not fully understood. We explored the circadian periodicity of ventricular arrhythmias (VAs) in patients with implantable cardioverter and cardiac resynchronization defibrillators (ICD/CRT-D). Time, morphology (monomorphic/polymorphic), and mode of termination (anti-tachycardia pacing [ATP] or shock) of VAs stored in a database of remote monitoring data were adjudicated. Episodes were grouped in six 4-h timeslots from 00:00 to 24:00. Circadian distributions and adjusted marginal odds ratios (ORs), with 95% confidence interval (CI), were analyzed using mixed-effect models and logit generalized estimating equations, respectively, to account for within-subject correlation of multiple episodes. Among 1303 VA episodes from 446 patients (63% ICD and 37% CRT-D), 120 (9%) self-extinguished, and 842 (65%) were terminated by ATP, 343 (26%) by shock. VAs clustered from 08:00 to 16:00 with 44% of episodes, as compared with 22% from 00:00 to 08:00 (p < .001) and 34% from 16:00 to 24:00 (p = .005). Episodes were more likely to be polymorphic at night with an adjusted marginal OR of 1.66 (CI, 1.15-2.40; p = .007) at 00:00-04:00 versus other timeslots. Episodes were less likely to be terminated by ATP in the 00:00-04:00 (success-to-failure ratio, 0.67; CI, 0.46-0.98; p = .039) and 08:00-12:00 (0.70; CI, 0.51-0.96; p = .02) timeslots, and most likely to be terminated by ATP between 12:00 and 16:00 (success-to-failure ratio 1.42; CI, 1.06-1.91; p = .02). VAs did not distribute uniformly over the 24 h, with a majority of episodes occurring from 08:00 to 16:00. Nocturnal episodes were more likely to be polymorphic. The efficacy of ATP depended on the time of delivery.