Introducing longitudinal modified treatment policies: a unified framework for studying complex exposures

This tutorial discusses a recently developed methodology for causal inference based on longitudinal modified treatment policies (LMTPs). LMTPs generalize many commonly used parameters for causal inference including average treatment effects, and facilitate the mathematical formalization, identification, and estimation of many novel parameters. LMTPs apply to a wide variety of exposures, including binary, multivariate, and continuous, as well as interventions that result in violations of the positivity assumption. LMTPs can accommodate time-varying treatments and confounders, competing risks, loss-to-follow-up, as well as survival, binary, or continuous outcomes. This tutorial aims to illustrate several practical uses of the LMTP framework, including describing different estimation strategies and their corresponding advantages and disadvantages. We provide numerous examples of types of research questions which can be answered within the proposed framework. We go into more depth with one of these examples -- specifically, estimating the effect of delaying intubation on critically ill COVID-19 patients' mortality. We demonstrate the use of the open source R package lmtp to estimate the effects, and we provide code on https://github.com/kathoffman/lmtp-tutorial

Learning Optimal Dynamic Treatment Regimes from Longitudinal Data

Studies often report estimates of the average treatment effect. While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule. Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments' benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments' benefits vary as relevant circumstances evolve within an individual. The goal of this paper is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. We describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. We then learn a time-varying ODTR for when to increase buprenorphine-naloxone dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Our analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.Comment: Accepted for publication in American Journal of Epidemiolog

Age at First Concussion Influences Number of Subsequent Concussions

Background: Individuals that sustain their first concussion during childhood may be at greater risk for sustaining multiple concussions throughout their lifetime, due to a longer window of vulnerability. Purpose: To estimate the association between age at first concussion with number of subsequent concussions. Methods: A total of 23,582 collegiate athletes from 26 universities and military cadets from three military academies completed a concussion history questionnaire (65% males, age: 19.9±1.4years). Participants self-reported concussions and age at time of each injury. Participants with a history of concussion (n=3,647, 15.5%) were categorized as having sustained their first concussion during childhood (<10 years old - yo) or adolescence (≥10yo & ≤18yo). Poisson regression was used to model age group (childhood, adolescence) predicting number of subsequent concussions (0, 1, 2+). A second Poisson regression was developed to determine whether age at first concussion predicted number of subsequent concussions. Results: Participants self-reporting their first concussion during childhood had an increased risk of sustaining subsequent concussions (RR=2.19, 95% CI: 1.82, 2.64) compared to participants self-reporting their first concussion during adolescence. For every one-year increase in age at first concussion, we observed a 16% reduction in the risk of subsequent concussion (RR=0.84, 95% CI:0.82,0.86). Conclusion(s): Individuals self-reporting a concussion at a young age sustained a higher number of concussions prior to the age of 18. Concussion prevention, recognition, and reporting strategies are of particular need at the youth level

Age at First Concussion Influences Number of Subsequent Concussions

Background: Individuals that sustain their first concussion during childhood may be at greater risk for sustaining multiple concussions throughout their lifetime, due to a longer window of vulnerability. Purpose: To estimate the association between age at first concussion with number of subsequent concussions. Methods: A total of 23,582 collegiate athletes from 26 universities and military cadets from three military academies completed a concussion history questionnaire (65% males, age: 19.9±1.4years). Participants self-reported concussions and age at time of each injury. Participants with a history of concussion (n=3,647, 15.5%) were categorized as having sustained their first concussion during childhood (<10 years old - yo) or adolescence (≥10yo & ≤18yo). Poisson regression was used to model age group (childhood, adolescence) predicting number of subsequent concussions (0, 1, 2+). A second Poisson regression was developed to determine whether age at first concussion predicted number of subsequent concussions. Results: Participants self-reporting their first concussion during childhood had an increased risk of sustaining subsequent concussions (RR=2.19, 95% CI: 1.82, 2.64) compared to participants self-reporting their first concussion during adolescence. For every one-year increase in age at first concussion, we observed a 16% reduction in the risk of subsequent concussion (RR=0.84, 95% CI:0.82,0.86). Conclusion(s): Individuals self-reporting a concussion at a young age sustained a higher number of concussions prior to the age of 18. Concussion prevention, recognition, and reporting strategies are of particular need at the youth level

Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections

Rationale: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. Objectives: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. Methods: We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Measurements and Main Results: Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Conclusions: Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments

A functional definition to distinguish ponds from lakes and wetlands

Ponds are often identified by their small size and shallow depths, but the lack of a universal evidence-based definition hampers science and weakens legal protection. Here, we compile existing pond definitions, compare ecosystem metrics (e.g., metabolism, nutrient concentrations, and gas fluxes) among ponds, wetlands, and lakes, and propose an evidence-based pond definition. Compiled definitions often mentioned surface area and depth, but were largely qualitative and variable. Government legislation rarely defined ponds, despite commonly using the term. Ponds, as defined in published studies, varied in origin and hydroperiod and were often distinct from lakes and wetlands in water chemistry. We also compared how ecosystem metrics related to three variables often seen in waterbody definitions: waterbody size, maximum depth, and emergent vegetation cover. Most ecosystem metrics (e.g., water chemistry, gas fluxes, and metabolism) exhibited nonlinear relationships with these variables, with average threshold changes at 3.7 ± 1.8 ha (median: 1.5 ha) in surface area, 5.8 ± 2.5 m (median: 5.2 m) in depth, and 13.4 ± 6.3% (median: 8.2%) emergent vegetation cover. We use this evidence and prior definitions to define ponds as waterbodies that are small (< 5 ha), shallow (< 5 m), with < 30% emergent vegetation and we highlight areas for further study near these boundaries. This definition will inform the science, policy, and management of globally abundant and ecologically significant pond ecosystems.Fil: Richardson, David C.. State University of New York at New Paltz; Estados UnidosFil: Holgerson, Meredith A.. Cornell University; Estados UnidosFil: Farragher, Matthew J.. University of Maine; Estados UnidosFil: Hoffman, Kathryn K.. No especifíca;Fil: King, Katelyn B. S.. Michigan State University; Estados UnidosFil: Alfonso, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; ArgentinaFil: Andersen, Mikkel R.. No especifíca;Fil: Cheruveil, Kendra Spence. Michigan State University; Estados UnidosFil: Coleman, Kristen A.. University of York; Reino UnidoFil: Farruggia, Mary Jade. University of California at Davis; Estados UnidosFil: Fernandez, Rocio Luz. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hondula, Kelly L.. No especifíca;Fil: López Moreira Mazacotte, Gregorio A.. Leibniz - Institute of Freshwater Ecology and Inland Fisheries; AlemaniaFil: Paul, Katherine. No especifíca;Fil: Peierls, Benjamin L.. No especifíca;Fil: Rabaey, Joseph S.. University of Minnesota; Estados UnidosFil: Sadro, Steven. University of California at Davis; Estados UnidosFil: Sánchez, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Smyth, Robyn L.. No especifíca;Fil: Sweetman, Jon N.. State University of Pennsylvania; Estados Unido

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Ethnic and socioeconomic variation in incidence of congenital heart defects

Introduction: Ethnic differences in the birth prevalence of congenital heart defects (CHDs) have been reported; however, studies of the contemporary UK population are lacking. We investigated ethnic variations in incidence of serious CHDs requiring cardiac intervention before 1 year of age. Methods: All infants who had a cardiac intervention in England and Wales between 1 January 2005 and 31 December 2010 were identified in the national congenital heart disease surgical audit and matched with paediatric intensive care admission records to create linked individual child records. Agreement in reporting of ethnic group by each audit was evaluated. For infants born 1 January 2006 to 31 December 2009, we calculated incidence rate ratios (IRRs) for CHDs by ethnicity and investigated age at intervention, antenatal diagnosis and area deprivation. Results: We identified 5350 infants (2940 (55.0%) boys). Overall CHD incidence was significantly higher in Asian and Black ethnic groups compared with the White reference population (incidence rate ratios (IRR) (95% CIs): Asian 1.5 (1.4 to 1.7); Black 1.4 (1.3 to 1.6)); incidence of specific CHDs varied by ethnicity. No significant differences in age at intervention or antenatal diagnosis rates were identified but affected children from non-White ethnic groups were more likely to be living in deprived areas than White children. Conclusions: Significant ethnic variations exist in the incidence of CHDs, including for specific defects with high infant mortality. It is essential that healthcare provision mitigates ethnic disparity, including through timely identification of CHDs at screening, supporting parental choice and effective interventions. Future research should explore the factors underlying ethnic variation and impact on longer-term outcomes