MedZIM: Mediation analysis for Zero-Inflated Mediators with applications to microbiome data

The human microbiome can contribute to the pathogenesis of many complex diseases such as cancer and Alzheimer's disease by mediating disease-leading causal pathways. However, standard mediation analysis is not adequate in the context of microbiome data due to the excessive number of zero values in the data. Zero-valued sequencing reads, commonly observed in microbiome studies, arise for technical and/or biological reasons. Mediation analysis approaches for analyzing zero-inflated mediators are still lacking largely because of challenges raised by the zero-inflated data structure: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are actually not zero (i.e., false zeros). We develop a novel mediation analysis method under the potential-outcomes framework to fill this gap. We show that the mediation effect of the microbiome can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. The first component corresponds to the mediation effect attributable to a unit-change over the positive relative abundance and the second component corresponds to the mediation effect attributable to discrete binary change of the mediator from zero to a non-zero state. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the applications in two real microbiome studies demonstrate that our approach outperforms existing mediation analysis approaches.Comment: Corresponding: Zhigang L

Evolving patterns of sterodynamic sea-level rise under mitigation scenarios and insights from linear system theory

Long-term behaviour of sea-level rise is an important factor in assessing the impact of climate change on multi-century timescales. Under the stabilisation scenario RCP4.5, Sterodynamic Sea-Level (SdynSL) and ocean density change in the CMIP5 models exhibit distinct patterns over the periods before and after Radiative Forcing (RF) stabilisation (2000–2070 vs. 2100–2300). The stabilisation pattern is more geographically uniform and involves deeper penetration of density change than the transient pattern. In RCP2.6, 4.5 and 8.5, the spatiotemporal evolution of SdynSL change can be approximated as a linear combination of the transient and stabilisation patterns. Specifically, SdynSL change is dominated by the transient pattern when RF increases rapidly, but it is increasingly affected by the stabilisation pattern once RF starts to stabilise. The growth of the stabilisation pattern could persist for centuries after RF ceases increasing. The evolving patterns of SdynSL change can also be approximated as a linear system's responses (characterised by its Green’s function) to time-dependent boundary conditions. By examining SdynSL change simulated in linear system models with different estimates of Green's functions, we find that both the climatological ocean circulation and the ocean's dynamical response to RF play a role in shaping the patterns of SdynSL change. The linear system model is more accurate than the univariate pattern scaling in emulating the CMIP5 SdynSL change beyond 2100. The emergence of the stabilisation pattern leads to a 1–10% decrease in the ocean's expansion efficiency of heat over 2000–2300 in RCP2.6 and 4.5

Ocean‐Only FAFMIP: Understanding Regional Patterns of Ocean Heat Content and Dynamic Sea Level Change

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Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Estimating ocean heat uptake using boundary Green's functions: A perfect-model test of the method

Ocean heat uptake is caused by "excess heat" being added to the ocean surface by air-sea fluxes and then carried to depths by ocean transports. One way to estimate excess heat in the ocean is to propagate observed Sea Surface Temperature (SST) anomalies downward using a Green's Function (GF) representation of ocean transports. Taking a "perfect-model" approach, we test this GF method using a historical simulation, in which the true excess heat is diagnosed. We derive GFs from two approaches: 1) simulating GFs using idealised tracers, and 2) inferring GFs from simulated CFCs and climatological tracers. In the model world, we find that combining simulated GFs with SST anomalies reconstructs the Indo-Pacific excess heat with a root-mean-square error of 26% for depth-integrated changes; the corresponding number is 34% for inferred GFs. Simulated GFs are inaccurate because they are coarse grained in space and time to reduce computational cost. Inferred GFs are inaccurate because observations are insufficient constraints. Both kinds of GFs neglect the slowdown of the North Atlantic heat uptake as the ocean warms up. SST boundary conditions contain redistributive cooling in the Southern Ocean, which causes an underestimate of heat uptake there. All these errors are of comparable magnitude, and tend to compensate each other partially. Inferred excess heat is not sensitive to: 1) small changes in the shape of prior GFs, or 2) additional constraints from SF6 and bomb 14C

Absorption of ocean heat along and across Isopycnals in HadCM3

Anthropogenic warming added to the climate system accumulates mostly in the ocean interior and discrepancies in how this is modelled contribute to uncertainties in predicting sea level rise. Temperature changes are partitioned between excess, due to perturbed surface heat fluxes, and redistribution, that arises from the changing circulation and perturbations to mixing. In a model (HadCM3) with realistic historical forcing (anthropogenic and natural) from 1960 to 2011, we firstly compare this excess-redistribution partitioning with the spice and heave decomposition, in which ocean interior temperature anomalies occur along or across isopycnals, respectively. This comparison reveals that in subtropical gyres (except in the North Atlantic) heave mostly captures excess warming in the top 2000 m, as expected from Ekman pumping, whereas spice captures redistributive cooling. At high-latitudes and in the subtropical Atlantic, however, spice predicts excess warming at the winter mixed layer whereas below this layer, spice represents redistributive warming in southern high latitudes. Secondly, we use Eulerian heat budgets of the ocean interior to identify the process responsible for excess and redistributive warming. In southern high latitudes, spice warming results from reduced convective cooling and increased warming by isopycnal diffusion, which account for the deep redistributive and shallow excess warming, respectively. In the North Atlantic, excess warming due to advection contains both cross-isopycnal warming (heave found in subtropical gyres) and along-isopycnal warming (spice). Finally, projections of heat budgets —coupled with salinity budgets— into thermohaline and spiciness-density coordinates inform us about how water mass formation occurs with varying T-S slopes. Such formation happens preferentially along isopycnal surfaces at high-latitudes and along isospiciness surfaces at mid-latitudes, and along both coordinates in the subtropical Atlantic. Because spice and heave depend only on temperature and salinity, our study suggests a method to detect excess warming in observations

MarZIC: A Marginal Mediation Model for Zero-Inflated Compositional Mediators with Applications to Microbiome Data

Background: The human microbiome can contribute to pathogeneses of many complex diseases by mediating disease-leading causal pathways. However, standard mediation analysis methods are not adequate to analyze the microbiome as a mediator due to the excessive number of zero-valued sequencing reads in the data and that the relative abundances have to sum to one. The two main challenges raised by the zero-inflated data structure are: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are not zero (i.e., false zeros). Methods: We develop a novel marginal mediation analysis method under the potential-outcomes framework to address the issues. We also show that the marginal model can account for the compositional structure of microbiome data. Results: The mediation effect can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the application in a real microbiome study showcase our approach in comparison with existing approaches. Conclusions: When analyzing the zero-inflated microbiome composition as the mediators, MarZIC approach has better performance than standard causal mediation analysis approaches and existing competing approach