Robust causal inference for point exposures with missing confounders.

Large observational databases are often subject to missing data. As such, methods for causal inference must simultaneously handle confounding and missingness; surprisingly little work has been done at this intersection. Motivated by this, we propose an efficient and robust estimator of the causal average treatment effect from cohort studies when confounders are missing at random.

Adjusting for Selection Bias Due to Missing Data in Electronic Health Records-Based Research by Blending Multiple Imputation and Inverse Probability Weighting.

Due to the complex process by which electronic health records (EHR) are generated and collected, missing data is a significant challenge when conducting large observational studies using such data. However, most standard methods that seek to adjust for the potential selection bias induced by restricting to individuals with complete data fail to address the heterogeneous structure of EHR. To address this, a framework was previously proposed that modularizes the data provenance that gives rise to the observed data as a sequence of decisions made by patients, healthcare providers, and the health system.

Frailty Status as a Predictor of Outcomes in Emergency Surgeries for Older Adults: A Systematic Review and Meta-Analysis.

The global aging population has brought increasing attention to frailty as a critical predictor of health outcomes. Defined by the British Geriatric Society as a state of diminished physiological reserve across multiple systems, frailty reflects a heightened vulnerability to adverse events. While the negative impact of frailty is well established in elective surgical settings, its influence on outcomes following emergency abdominal surgery remains less clear.

Pre-disease biomarkers of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) risk in Finland.

Background: Persistent organic pollutants (POPs) are toxic chemicals that bioaccumulate and were used in pesticides and industrial products/processes. POP-exposed occupations and environmental exposure to POPs have been associated with amyotrophic lateral sclerosis (ALS), but no study has evaluated the association with ALS when measuring POPs in samples collected before ALS onset.

Objectives: This study examined the relationship between pre-disease POP exposure and ALS risk.

Estimating weighted quantile treatment effects with missing outcome data by double sampling.

Causal weighted quantile treatment effects (WQTEs) complement standard mean-focused causal contrasts when interest lies at the tails of the counterfactual distribution. However, existing methods for estimating and inferring causal WQTEs assume complete data on all relevant factors, which is often not the case in practice, particularly when the data are not collected for research purposes, such as electronic health records (EHRs) and disease registries. Furthermore, these data may be particularly susceptible to the outcome data being missing-not-at-random (MNAR).

Circulating cyclophilin A levels elevate in animal models and can predict mortality in patients with acute pancreatitis.

Background/objectives: Cyclophilin A (CypA) is released into the blood following cellular injury and correlates with acute pancreatitis (AP) severity, however, investigations into circulating CypA in experimental AP and hypertriglyceridaemia-associated AP (HTG-AP) prevalent cohorts are lacking.

Methods: C57Bl/6 mice received 4, 8, and 12 caerulein injections to induce escalating severity of AP models (CER-AP). Mice were sacrificed 1 h after the last injection of caerulein to assess severity of CER-AP through biochemical and histopathological analyses, and serum CypA levels were also measured.

Multi-omics profiles reveal immune microenvironment alterations associated with PD-L1 checkpoint in acute pancreatitis in the early phase.

Background: Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP.

De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.

The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ~30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent variants in the U4 RNA, transcribed from the gene, and in at least two other genes were discovered to cause neurodevelopmental disorder.

Adjusting for Selection Bias Due to Missing Eligibility Criteria in Emulated Target Trials.

Target trial emulation (TTE) is a popular framework for observational studies based on electronic health records (EHR). A key component of this framework is determining the patient population eligible for inclusion in both a target trial of interest and its observational emulation. Missingness in variables that define eligibility criteria, however, presents a major challenge towards determining the eligible population when emulating a target trial with an observational study.

Right upper quadrant pain after previous blunt abdominal trauma: undiagnosed traumatic diaphragmatic hernia with strangulated right colon.

A woman in her 40s self-presented to an emergency department in a major trauma centre with severe right-sided abdominal pain, a tender right upper quadrant mass and chest pain. Diagnostic imaging showed a previously undiagnosed diaphragmatic hernia containing strangulated right colon. The patient had been the victim of a high-energy road traffic accident 18 months earlier, but at that time had not presented to hospital or undergone any outpatient investigation.

Double Sampling for Informatively Missing Data in Electronic Health Record-Based Comparative Effectiveness Research.

Missing data arise in most applied settings and are ubiquitous in electronic health records (EHR). When data are missing not at random (MNAR) with respect to measured covariates, sensitivity analyses are often considered. These solutions, however, are often unsatisfying in that they are not guaranteed to yield actionable conclusions.

Chaiqin chengqi decoction treatment mitigates hypertriglyceridemia-associated acute pancreatitis by modulating liver-mediated glycerophospholipid metabolism.

Background: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored.

Assumption-lean falsification tests of rate double-robustness of double-machine-learning estimators.

The class of doubly robust (DR) functionals studied by Rotnitzky et al. (2021) is of central importance in economics and biostatistics. It strictly includes both (i) the class of mean-square continuous functionals that can be written as an expectation of an affine functional of a conditional expectation studied by Chernozhukov et al.

Lead exposure across the life course and age at death.

Background: Lead (Pb) exposure has been associated with an increased risk of all-cause mortality, even at low levels. Little is known about how the timing of Pb exposure throughout life may influence these relationships. Quantifying the amount of Pb present in various tissues of the body provides measurements of exposure from different periods of life.

Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci.

Cross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specific cis-regulators of developmental gene expression. Here, we characterize a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging.

On statistical inference with high-dimensional sparse CCA.

We consider asymptotically exact inference on the leading canonical correlation directions and strengths between two high-dimensional vectors under sparsity restrictions. In this regard, our main contribution is developing a novel representation of the Canonical Correlation Analysis problem, based on which one can operationalize a one-step bias correction on reasonable initial estimators. Our analytic results in this regard are adaptive over suitable structural restrictions of the high-dimensional nuisance parameters, which, in this set-up, correspond to the covariance matrices of the variables of interest.

On Support Recovery with Sparse CCA: Information Theoretic and Computational Limits.

In this paper, we consider asymptotically exact support recovery in the context of high dimensional and sparse Canonical Correlation Analysis (CCA). Our main results describe four regimes of interest based on information theoretic and computational considerations. In regimes of "low" sparsity we describe a simple, general, and computationally easy method for support recovery, whereas in a regime of "high" sparsity, it turns out that support recovery is information theoretically impossible.

Wildfire exposure and academic performance in Brazil: A causal inference approach for spatiotemporal data.

As the frequency and intensity of wildfires are projected to globally amplify due to climate change, there is a growing need to quantify the impact of exposure to wildfires in vulnerable populations such as adolescents. In our study, we applied rigorous causal inference methods to estimate the effect of wildfire exposure on the academic performance of high school students in Brazil between 2009 and 2015. Using longitudinal data from 8,183 high schools across 1,571 municipalities in Brazil, we estimated that the average performance in most academic subjects decreases under interventions that increase wildfire exposure, e.

Treatment of age-related macular degeneration with aflibercept using a treat, extend and fixed protocol; A 4-year study of treatment outcomes, durability, safety and quality of life (An extension to the MATE randomised controlled trial).

Purpose: Data are limited pertaining to the long-term benefits of aflibercept treatment for neovascular age-related macular degeneration (nAMD). The aim of this study was to provide outcomes, safety, durability and quality-of-life data with aflibercept using a modified treat, extend and fixed regime over 4 years.

Methods: Prospective, multicentre, single cohort observational study of treatment-naïve nAMD participants treated with aflibercept as 2-year extension of the MATE-trial that compared early and late Treat-and-Extend for 2 years.

Middle Meningeal Artery Embolization in Adjunction to Surgical Evacuation for Treatment of Subdural Hematomas: A Nationwide Comparison of Outcomes With Isolated Surgical Evacuation.

Background And Objectives: Surgical evacuation is the standard treatment for chronic subdural hematomas (CSDHs) but is associated with a high risk of recurrence and readmission. Middle meningeal artery embolization (MMAE) is a novel treatment approach which could be performed upfront or in adjunction to surgical evacuation. MMAE studies are limited by small sample sizes.

Prognostic Serum Biomarkers of Inflammaging in Patients Undergoing Emergency Laparotomy.

Surgeons are increasingly faced with an ageing and frail patient population. There is a significant absence of biomarkers capable of risk stratifying patients undergoing emergency laparotomy. Inflammaging describes a state of chronic inflammation associated with ageing and frailty that may predict worse outcomes after surgery.

The MATE trial: a multicentre, mixed-methodology, pilot, randomised controlled trial in neovascular age-related macular degeneration.

Background/objectives: In healthcare research investigating complex interventions, gaps in understanding of processes can be filled by using qualitative methods alongside a quantitative approach. The aim of this mixed-methods pilot trial was to provide feasibility evidence comparing two treatment regimens for neovascular age-related macular degeneration (nAMD) to inform a future large-scale randomised controlled trial (RCT).

Subjects/methods: Forty-four treatment-naïve nAMD patients were followed over 24 months and randomised to one of two treatment regimens: standard care (SC) or treat and extend (T&E).

Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon-based short-read sequencing strategies.

Background: The widespread adoption of exome sequencing has greatly increased the rate of genetic diagnosis for inherited conditions. However, the detection and validation of large deletions remains challenging. While numerous bioinformatics approaches have been developed to detect deletions from whole - exome sequencing and targeted panels, further work is typically required to define the physical breakpoints or integration sites.