Pollen and viruses contribute to spatio-temporal variation in asthma-related emergency department visits.

BACKGROUND: Asthma exacerbations are an important cause of emergency department visits but much remains unknown about the role of environmental triggers including viruses and allergenic pollen. A better understanding of spatio-temporal variation in exposure and risk posed by viruses and pollen types could help prioritize public health interventions. OBJECTIVE: Here we quantify the effects of regionally important Cupressaceae pollen, tree pollen, other pollen types, rhinovirus, seasonal coronavirus, respiratory syncytial virus, and influenza on asthma-related emergency department visits for people living near eight pollen monitoring stations in Texas. METHODS: We used age stratified Poisson regression analyses to quantify the effects of allergenic pollen and viruses on asthma-related emergency department visits. RESULTS: Young children (<5 years of age) had high asthma-related emergency department rates (24.1 visits/1,000,000 person-days), which were mainly attributed to viruses (51.2%). School-aged children also had high rates (20.7 visits/1,000,000 person-days), which were attributed to viruses (57.0%), Cupressaceae pollen (0.7%), and tree pollen (2.8%). Adults had lower rates (8.1 visits/1,000,000 person-days) which were attributed to viruses (25.4%), Cupressaceae pollen (0.8%), and tree pollen (2.3%). This risk was spread unevenly across space and time; for example, during peak Cuppressaceae season, this pollen accounted for 8.2% of adult emergency department visits near Austin where these plants are abundant, but 0.4% in cities like Houston where they are not; results for other age groups were similar. CONCLUSIONS: Although viruses are a major contributor to asthma-related emergency department visits, airborne pollen can explain a meaningful portion of visits during peak pollen season and this risk varies over both time and space because of differences in plant composition.

Causal Analysis of Air Pollution Mixtures: Estimands, Positivity, and Extrapolation.

Causal inference for air pollution mixtures is an increasingly important issue with appreciable challenges. When the exposure is a multivariate mixture, there are many exposure contrasts that may be of nominal interest for causal effect estimation, but the complex joint mixture distribution often renders observed data extremely limited in their ability to inform estimates of many commonly-defined causal effects. We use potential outcomes to 1) define causal effects of air pollution mixtures, 2) formalize the key assumption of mixture positivity required for estimation and 3) offer diagnostic metrics for positivity violations in the mixture setting that allow researchers to assess the extent to which data can actually support estimation of mixture effects of interest. For settings where there is limited empirical support, we redefine causal estimands that apportion causal effects according to whether they can be directly informed by observed data versus rely entirely on model extrapolation, isolating key sources of information on the causal effect of an air pollution mixture. The ideas are deployed to assess the ability of a national United States data set on the chemical components of ambient particulate matter air pollution to support estimation of a variety of causal mixture effects.

Chronic household air pollution and exposure patterns among Himalayan nomads.

BACKGROUND: Household air pollution (HAP) is a major risk factor of non-communicable diseases, causing millions of premature deaths each year in developing nations. Populations living at high altitudes are particularly vulnerable to HAP and associated health outcomes. OBJECTIVES: This study aims to explore the relationships between activity patterns, HAP, and an HAP biomarker among 100 Himalayan nomadic households during both cooking and heating-only periods. METHODS: Household CO was monitored in 100 rural homes in Qinghai, China, at 3500 m on the Himalayan Plateau among Himalayan nomads. Carboxyhemoglobin (COHb) was used as a biomarker to assess exposure among 100 male and 100 female heads of household. Linear mixed-effects models were used to explore the relationship between COHb and activity patterns. RESULTS: Cooking periods were associated with 7 times higher household CO concentrations compared with heating periods (94 ± 56 ppm and 13 ± 11 ppm, respectively). Over the three-day biomarker-monitoring period in each house, 99% of subjects had at least one COHb measurement exceeding the WHO safety level of 2%. Cooking was associated with a 32% increase in COHb (p < 0.001). IMPACT STATEMENT: This study on household air pollution (HAP) in high-altitude regions provides important insights into the exposure patterns of nomadic households in Qinghai, China. The study found that cooking is the primary factor influencing acute carbon monoxide (CO) exposure among women, while heating alone is sufficient to elevate CO exposure above WHO guidelines. The results suggest that cooking-only interventions have the potential to reduce HAP exposure among women, but solutions for both cooking and heating may be required to reduce COHb to below WHO guidelines. This study's findings may inform future interventions for fuel and stove selection to reduce HAP and exposure among other populations.

The Role of Neighborhood Air Pollution in Disparate Racial and Ethnic Asthma Acute Care Use.

RATIONALE: The share of Black or Latinx residents in a census tract remains associated with asthma-related Emergency Department visit rates after controlling for socioeconomic factors. The extent to which evident disparities relate to within-city heterogeneity of long-term air pollution exposure remains unclear. OBJECTIVES: To investigate the role of intraurban spatial variability of air pollution in asthma acute care use disparity. METHODS: An administrative database was used to define census tract population-based incidence rates of asthma-related Emergency Department visits. We estimate the association between census tract incidence rates and (a) average fine and coarse particulate matter (PM2.5, PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2); and (b) racial/ethnic composition using generalized linear models controlling for socioeconomic and housing covariates. We additionally examine for attenuation of incidence risk ratios (IRR) associated with race/ethnicity when controlling for air pollution exposure. MEASUREMENTS AND MAIN RESULTS: PM2.5, PM10, and SO2 are each associated with census tract-level incidence rates of asthma-related ED visits and multipollutant models show evidence of independent risk associated with PM10 and SO2. Association between census tract incidence rates and Black resident share (IRR [CI] = 1.51 [1.48-1.54]) is attenuated by 24% when accounting for air pollution (1.39 [1.35-1.42]), and the association with Latinx resident share (1.11 [1.09-1.13]) is attenuated by 32% (1.08 [1.06-1.10]). CONCLUSIONS: Neighborhood-level rates of asthma acute care use are associated with local air pollution. Controlling for air pollution attenuates associations with census tract racial/ethnic composition, suggesting that intracity variability in air pollution could contribute to neighborhood-to-neighborhood asthma morbidity disparities.

Evolution of human H3N2 influenza virus receptor specificity has substantially expanded the receptor-binding domain site.

Hemagglutinins (HAs) from human influenza viruses descend from avian progenitors that bind α2-3-linked sialosides and must adapt to glycans with α2-6-linked sialic acids on human airway cells to transmit within the human population. Since their introduction during the 1968 pandemic, H3N2 viruses have evolved over the past five decades to preferentially recognize human α2-6-sialoside receptors that are elongated through addition of poly-LacNAc. We show that more recent H3N2 viruses now make increasingly complex interactions with elongated receptors while continuously selecting for strains maintaining this phenotype. This change in receptor engagement is accompanied by an extension of the traditional receptor-binding site to include residues in key antigenic sites on the surface of HA trimers. These results help explain the propensity for selection of antigenic variants, leading to vaccine mismatching, when H3N2 viruses are propagated in chicken eggs or cells that do not contain such receptors.

Local exposure misclassification in national models: relationships with urban infrastructure and demographics.

BACKGROUND: National-scale linear regression-based modeling may mischaracterize localized patterns, including hyperlocal peaks and neighborhood- to regional-scale gradients. For studies focused on within-city differences, this mischaracterization poses a risk of exposure misclassification, affecting epidemiological and environmental justice conclusions. OBJECTIVE: Characterize the difference between intraurban pollution patterns predicted by national-scale land use regression modeling and observation-based estimates within a localized domain and examine the relationship between that difference and urban infrastructure and demographics. METHODS: We compare highly resolved (0.01 km2) observations of NO2 mixing ratio and ultrafine particle (UFP) count obtained via mobile monitoring with national model predictions in thirteen neighborhoods in the San Francisco Bay Area. Grid cell-level divergence between modeled and observed concentrations is termed "localized difference." We use a flexible machine learning modeling technique, Bayesian Additive Regression Trees, to investigate potentially nonlinear relationships between discrepancy between localized difference and known local emission sources as well as census block group racial/ethnic composition. RESULTS: We find that observed local pollution extremes are not represented by land use regression predictions and that observed UFP count significantly exceeds regression predictions. Machine learning models show significant nonlinear relationships among localized differences between predictions and observations and the density of several types of pollution-related infrastructure (roadways, commercial and industrial operations). In addition, localized difference was greater in areas with higher population density and a lower share of white non-Hispanic residents, indicating that exposure misclassification by national models differs among subpopulations. IMPACT: Comparing national-scale pollution predictions with hyperlocal observations in the San Francisco Bay Area, we find greater discrepancies near major roadways and food service locations and systematic underestimation of concentrations in neighborhoods with a lower share of non-Hispanic white residents. These findings carry implications for using national-scale models in intraurban epidemiological and environmental justice applications and establish the potential utility of supplementing large-scale estimates with publicly available urban infrastructure and pollution source information.

Revealing the Specificity of Human H1 Influenza A Viruses to Complex N-Glycans.

Influenza virus infection remains a threat to human health since viral hemagglutinins are constantly drifting, escaping infection and vaccine-induced antibody responses. Viral hemagglutinins from different viruses display variability in glycan recognition. In this context, recent H3N2 viruses have specificity for α2,6 sialylated branched N-glycans with at least three N-acetyllactosamine units (tri-LacNAc). In this work, we combined glycan arrays and tissue binding analyses with nuclear magnetic resonance experiments to characterize the glycan specificity of a family of H1 variants, including the one responsible for the 2009 pandemic outbreak. We also analyzed one engineered H6N1 mutant to understand if the preference for tri-LacNAc motifs could be a general trend in human-type receptor-adapted viruses. In addition, we developed a new NMR approach to perform competition experiments between glycans with similar compositions and different lengths. Our results point out that pandemic H1 viruses differ from previous seasonal H1 viruses by a strict preference for a minimum of di-LacNAc structural motifs.

Impacts of wind power on air quality, premature mortality, and exposure disparities in the United States.

Understanding impacts of renewable energy on air quality and associated human exposures is essential for informing future policy. We estimate the impacts of U.S. wind power on air quality and pollution exposure disparities using hourly data from 2011 to 2017 and detailed atmospheric chemistry modeling. Wind power associated with renewable portfolio standards in 2014 resulted in $2.0 billion in health benefits from improved air quality. A total of 29% and 32% of these health benefits accrued to racial/ethnic minority and low-income populations respectively, below a 2021 target by the Biden administration that 40% of the overall benefits of future federal investments flow to disadvantaged communities. Wind power worsened exposure disparities among racial and income groups in some states but improved them in others. Health benefits could be up to $8.4 billion if displacement of fossil fuel generators prioritized those with higher health damages. However, strategies that maximize total health benefits would not mitigate pollution disparities, suggesting that more targeted measures are needed.

A Mechanistic Model of Annual Sulfate Concentrations in the United States.

Understanding how individual pollution sources contribute to ambient sulfate pollution is critical for assessing past and future air quality regulations. Since attribution to specific sources is typically not encoded in spatial air pollution data, we develop a mechanistic model which we use to estimate, with uncertainty, the contribution of ambient sulfate concentrations attributable specifically to sulfur dioxide (SO2) emissions from individual coal-fired power plants in the central United States. We propose a multivariate Ornstein-Uhlenbeck (OU) process approximation to the dynamics of the underlying space-time chemical transport process, and its distributional properties are leveraged to specify novel probability models for spatial data that are viewed as either a snapshot or time-averaged observation of the OU process. Using US EPA SO2 emissions data from 193 power plants and state-of-the-art estimates of ground-level annual mean sulfate concentrations, we estimate that in 2011 - a time of active power plant regulatory action - existing flue-gas desulfurization (FGD) technologies at 66 power plants reduced population-weighted exposure to ambient sulfate by 1.97 µg/m3 (95% CI: 1.80 - 2.15). Furthermore, we anticipate future regulatory benefits by estimating that installing FGD technologies at the five largest SO2-emitting facilities would reduce human exposure to ambient sulfate by an additional 0.45 µg/m3 (95% CI: 0.33 - 0.54).

Cystic adrenal masses: spectrum of multimodality imaging features and pathological correlation.

Adrenal cystic lesions are generally rare and encompass a wide spectrum of benign and malignant entities. Increased utilisation of cross-sectional imaging has led to increased detection of incidentally discovered adrenal lesions. Many of these lesions are cystic or solid with cystic changes, and the majority are benign; however, some may represent malignant lesions and/or even metastases. Therefore, it is vital to characterise these lesions appropriately and follow-up with laboratory tests and imaging if necessary. Key imaging techniques include computed tomography (CT) and magnetic resonance imaging (MRI). Other supplemental imaging tools include metaiodobenzyl-guanidine (MIBG) scintigraphy and 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography (FDG-PET). Accurate diagnosis of adrenal cystic lesions is crucial in guiding appropriate evaluation and management of these patients. This review highlights the clinical presentations, pathological and imaging features, and management of cystic adrenal lesions.

Invited Commentary: The Promise and Pitfalls of Causal Inference With Multivariate Environmental Exposures.

The accompanying article by Keil et al. (Am J Epidemiol. 2021;190(12):2647-2657) deploys Bayesian g-computation to investigate the causal effect of 6 airborne metal exposures linked to power-plant emissions on birth weight. In so doing, it articulates the potential value of framing the analysis of environmental mixtures as an explicit contrast between exposure distributions that might arise in response to a well-defined intervention-here, the decommissioning of coal plants. Framing the mixture analysis as that of an approximate "target trial" is an important approach that deserves incorporation into the already rich literature on the analysis of environmental mixtures. However, its deployment in the power plant example highlights challenges that can arise when the target trial is at odds with the exposure distribution observed in the data, a discordance that seems particularly difficult in studies of environmental mixtures. Bayesian methodology such as model averaging and informative priors can help, but they are ultimately limited for overcoming this salient challenge.

Bipartite Causal Inference with Interference.

Statistical methods to evaluate the effectiveness of interventions are increasingly challenged by the inherent interconnectedness of units. Specifically, a recent flurry of methods research has addressed the problem of interference between observations, which arises when one observational unit's outcome depends not only on its treatment but also the treatment assigned to other units. We introduce the setting of bipartite causal inference with interference, which arises when 1) treatments are defined on observational units that are distinct from those at which outcomes are measured and 2) there is interference between units in the sense that outcomes for some units depend on the treatments assigned to many other units. The focus of this work is to formulate definitions and several possible causal estimands for this setting, highlighting similarities and differences with more commonly considered settings of causal inference with interference. Towards an empirical illustration, an inverse probability of treatment weighted estimator is adapted from existing literature to estimate a subset of simplified, but interesting, estimands. The estimators are deployed to evaluate how interventions to reduce air pollution from 473 power plants in the U.S. causally affect cardiovascular hospitalization among Medicare beneficiaries residing at 18,807 zip code locations.

Nanoparticles Displaying Allergen and Siglec-8 Ligands Suppress IgE-FcεRI-Mediated Anaphylaxis and Desensitize Mast Cells to Subsequent Antigen Challenge.

Siglec-8 is an inhibitory receptor expressed on eosinophils and mast cells. In this study, we took advantage of a novel Siglec-8 transgenic mouse model to assess the impact of modulating IgE-dependent mast cell degranulation and anaphylaxis using a liposomal platform to display an allergen with or without a synthetic glycan ligand for Siglec-8 (Sig8L). The hypothesis is that recruitment of Siglec-8 to the IgE-FcεRI receptor complex will inhibit allergen-induced mast cell degranulation. Codisplay of both allergen and Sig8L on liposomes profoundly suppresses IgE-mediated degranulation of mouse bone marrow-derived mast cells or rat basophilic leukemia cells expressing Siglec-8. In contrast, liposomes displaying only Sig8L have no significant suppression of antigenic liposome-induced degranulation, demonstrating that the inhibitory activity by Siglec-8 occurs only when Ag and Sig8L are on the same particle. In mouse models of anaphylaxis, display of Sig8L on antigenic liposomes completely suppresses IgE-mediated anaphylaxis in transgenic mice with mast cells expressing Siglec-8 but has no protection in mice that do not express Siglec-8. Furthermore, mice protected from anaphylaxis remain desensitized to subsequent allergen challenge because of loss of Ag-specific IgE from the cell surface and accelerated clearance of IgE from the blood. Thus, although expression of human Siglec-8 on murine mast cells does not by itself modulate IgE-FcεRI-mediated cell activation, the enforced recruitment of Siglec-8 to the FcεRI receptor by Sig8L-decorated antigenic liposomes results in inhibition of degranulation and desensitization to subsequent Ag exposure.

Probing the binding specificities of human Siglecs by cell-based glycan arrays.

Siglecs are a family of sialic acid-binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2-3(6-O-sulfo)Galß1-4GlcNAc (6'-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer's disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid-binding proteins.

Four Decades of United States Mobile Source Pollutants: Spatial-Temporal Trends Assessed by Ground-Based Monitors, Air Quality Models, and Satellites.

On-road emissions sources degrade air quality, and these sources have been highly regulated. Epidemiological and environmental justice studies often use road proximity as a proxy for traffic-related air pollution (TRAP) exposure, and other studies employ air quality models or satellite observations. To assess these metrics' abilities to reproduce observed near-road concentration gradients and changes over time, we apply a hierarchical linear regression to ground-based observations, long-term air quality model simulations using Community Multiscale Air Quality (CMAQ), and satellite products. Across 1980-2019, observed TRAP concentrations decreased, and road proximity was positively correlated with TRAP. For all pollutants, concentrations decreased fastest at locations with higher road proximity, resulting in "flatter" concentration fields in recent years. This flattening unfolded at a relatively constant rate for NOx, whereas the flattening of CO concentration fields has slowed. CMAQ largely captures observed spatial-temporal NO2 trends across 2002-2010 but overstates the relationships between CO and elemental carbon fine particulate matter (EC) road proximity. Satellite NOx measures overstate concentration reductions near roads. We show how this perspective provides evidence that California's on-road vehicle regulations led to substantial decreases in NO2, NOx, and EC in California, with other states that adopted California's light-duty automobile standards showing mixed benefits over states that did not adopt these standards.

Comparisons of simple and complex methods for quantifying exposure to individual point source air pollution emissions.

Expanded use of reduced complexity approaches in epidemiology and environmental justice investigations motivates detailed evaluation of these modeling approaches. Chemical transport models (CTMs) remain the most complete representation of atmospheric processes but are limited in applications that require large numbers of runs, such as those that evaluate individual impacts from large numbers of sources. This limitation motivates comparisons between modern CTM-derived techniques and intentionally simpler alternatives. We model population-weighted PM2.5 source impacts from each of greater than 1100 coal power plants operating in the United States in 2006 and 2011 using three approaches: (1) adjoint PM2.5 sensitivities calculated by the GEOS-Chem CTM; (2) a wind field-based Lagrangian model called HyADS; and (3) a simple calculation based on emissions and inverse source-receptor distance. Annual individual power plants' nationwide population-weighted PM2.5 source impacts calculated by HyADS and the inverse distance approach have normalized mean errors between 20 and 28% and root mean square error ranges between 0.0003 and 0.0005 µg m-3 compared with adjoint sensitivities. Reduced complexity approaches are most similar to the GEOS-Chem adjoint sensitivities nearby and downwind of sources, with degrading performance farther from and upwind of sources particularly when wind fields are not accounted for.

Optimizing the development and evaluation of complex interventions: lessons learned from the BetterBirth Program and associated trial.

BACKGROUND: Despite extensive efforts to develop and refine intervention packages, complex interventions often fail to produce the desired health impacts in full-scale evaluations. A recent example of this phenomenon is BetterBirth, a complex intervention designed to implement the World Health Organization's Safe Childbirth Checklist and improve maternal and neonatal health. Using data from the BetterBirth Program and its associated trial as a case study, we identified lessons to assist in the development and evaluation of future complex interventions. METHODS: BetterBirth was refined across three sequential development phases prior to being tested in a matched-pair, cluster randomized trial in Uttar Pradesh, India. We reviewed published and internal materials from all three development phases to identify barriers hindering the identification of an optimal intervention package and identified corresponding lessons learned. For each lesson, we describe its importance and provide an example motivated by the BetterBirth Program's development to illustrate how it could be applied to future studies. RESULTS: We identified three lessons: (1) develop a robust theory of change (TOC); (2) define optimization outcomes, which are used to assess the effectiveness of the intervention across development phases, and corresponding criteria for success, which determine whether the intervention has been sufficiently optimized to warrant full-scale evaluation; and (3) create and capture variation in the implementation intensity of components. When applying these lessons to the BetterBirth intervention, we demonstrate how a TOC could have promoted more complete data collection. We propose an optimization outcome and related criteria for success and illustrate how they could have resulted in additional development phases prior to the full-scale trial. Finally, we show how variation in components' implementation intensities could have been used to identify effective intervention components. CONCLUSION: These lessons learned can be applied during both early and advanced stages of complex intervention development and evaluation. By using examples from a real-world study to demonstrate the relevance of these lessons and illustrating how they can be applied in practice, we hope to encourage future researchers to collect and analyze data in a way that promotes more effective complex intervention development and evaluation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02148952; registered on May 29, 2014.

Statistical considerations for the analysis of massively parallel reporter assays data.

Noncoding DNA contains gene regulatory elements that alter gene expression, and the function of these elements can be modified by genetic variation. Massively parallel reporter assays (MPRA) enable high-throughput identification and characterization of functional genetic variants, but the statistical methods to identify allelic effects in MPRA data have not been fully developed. In this study, we demonstrate how the baseline allelic imbalance in MPRA libraries can produce biased results, and we propose a novel, nonparametric, adaptive testing method that is robust to this bias. We compare the performance of this method with other commonly used methods, and we demonstrate that our novel adaptive method controls Type I error in a wide range of scenarios while maintaining excellent power. We have implemented these tests along with routines for simulating MPRA data in the Analysis Toolset for MPRA (@MPRA), an R package for the design and analyses of MPRA experiments. It is publicly available at http://github.com/redaq/atMPRA.

Uncertainty in the design stage of two-stage Bayesian propensity score analysis.

The two-stage process of propensity score analysis (PSA) includes a design stage where propensity scores (PSs) are estimated and implemented to approximate a randomized experiment and an analysis stage where treatment effects are estimated conditional on the design. This article considers how uncertainty associated with the design stage impacts estimation of causal effects in the analysis stage. Such design uncertainty can derive from the fact that the PS itself is an estimated quantity, but also from other features of the design stage tied to choice of PS implementation. This article offers a procedure for obtaining the posterior distribution of causal effects after marginalizing over a distribution of design-stage outputs, lending a degree of formality to Bayesian methods for PSA that have gained attention in recent literature. Formulation of a probability distribution for the design-stage output depends on how the PS is implemented in the design stage, and propagation of uncertainty into causal estimates depends on how the treatment effect is estimated in the analysis stage. We explore these differences within a sample of commonly used PS implementations (quantile stratification, nearest-neighbor matching, caliper matching, inverse probability of treatment weighting, and doubly robust estimation) and investigate in a simulation study the impact of statistician choice in PS model and implementation on the degree of between- and within-design variability in the estimated treatment effect. The methods are then deployed in an investigation of the association between levels of fine particulate air pollution and elevated exposure to emissions from coal-fired power plants.

Coaching Intensity, Adherence to Essential Birth Practices, and Health Outcomes in the BetterBirth Trial in Uttar Pradesh, India.

BACKGROUND: Coaching can improve the quality of care in primary-level birth facilities and promote birth attendant adherence to essential birth practices (EBPs) that reduce maternal and perinatal mortality. The intensity of coaching needed to promote and sustain behavior change is unknown. We investigated the relationship between coaching intensity, EBP adherence, and maternal and perinatal health outcomes using data from the BetterBirth Trial, which assessed the impact of a complex, coaching-based implementation of the World Health Organization's Safe Childbirth Checklist in Uttar Pradesh, India. METHODS: For each birth, we defined multiple coaching intensity metrics, including coaching frequency (coaching visits per month), cumulative coaching (total coaching visits accrued during the intervention), and scheduling adherence (coaching delivered as scheduled). We considered coaching delivered at both facility and birth attendant levels. We assessed the association between coaching intensity and birth attendant adherence to 18 EBPs and with maternal and perinatal health outcomes using regression models. RESULTS: Coaching frequency was associated with modestly increased EBP adherence. Delivering 6 coaching visits per month to facilities was associated with adherence to 1.3 additional EBPs (95% confidence interval [CI]=0.6, 1.9). High-frequency coaching delivered with high coverage among birth attendants was associated with greater improvements: providing 70% of birth attendants at a facility with at least 1 visit per month was associated with adherence to 2.0 additional EBPs (95% CI=1.0, 2.9). Neither cumulative coaching nor scheduling adherence was associated with EBP adherence. Coaching was generally not associated with health outcomes, possibly due to the small magnitude of association between coaching and EBP adherence. CONCLUSIONS: Frequent coaching may promote behavior change, especially if delivered with high coverage among birth attendants. However, the effects of coaching were modest and did not persist over time, suggesting that future coaching-based interventions should explore providing frequent coaching for longer periods.