Predicting post-liver transplant outcomes in patients with acute-on-chronic liver failure using Expert-Augmented Machine Learning.

Liver transplantation (LT) is a treatment for acute-on-chronic liver failure (ACLF), but high post-LT mortality has been reported. Existing post-LT models in ACLF have been limited. We developed an Expert-Augmented Machine Learning (EAML) model to predict post-LT outcomes. We identified ACLF patients who underwent LT in the University of California Health Data Warehouse. We applied the RuleFit machine learning (ML) algorithm to extract rules from decision trees and create intermediate models. We asked human experts to rate the rules generated by RuleFit and incorporated these ratings to generate final EAML models. We identified 1384 ACLF patients. For death at 1 year, areas under the receiver-operating characteristic curve were 0.707 (confidence interval [CI] 0.625-0.793) for EAML and 0.719 (CI 0.640-0.800) for RuleFit. For death at 90 days, areas under the receiver-operating characteristic curve were 0.678 (CI 0.581-0.776) for EAML and 0.707 (CI 0.615-0.800) for RuleFit. In pairwise comparisons, both EAML and RuleFit models outperformed cross-sectional models. Significant discrepancies between experts and ML occurred in rankings of biomarkers used in clinical practice. EAML may serve as a method for ML-guided hypothesis generation in further ACLF research.

Differential Use of Outpatient Palliative Care by Demographic and Clinical Characteristics.

CONTEXT: Little is known about equity in utilization of outpatient palliative care (PC). OBJECTIVES: To explore whether patient-level factors are associated with completing initial and follow-up visits among patients referred to outpatient PC. METHODS: Using electronic health record data, we generated a cohort of all adults referred to outpatient PC at University of California, San Francisco October 2017-October 2021. We assessed whether demographic and clinical characteristics were associated with completion of 1) an initial PC visit and 2) at least one follow-up visit. RESULTS: Of patients referred to outpatient PC (N = 6,871), 60% completed an initial visit; 66% of those who established care returned for follow-up. In multivariable models, patients who were less likely to complete an initial visit were older (OR per decade 0.94; 95% confidence interval [CI] 0.89-0.98), Black (OR 0.71; 95% CI 0.56-0.90), Latinx (OR 0.69; 95% CI 0.57-0.83), unpartnered (OR 0.80; 95% CI 0.71-0.90), and had Medicaid (OR 0.82; 95% CI 0.69-0.97). Among patients who completed an initial visit, those less likely to complete a follow-up visit were older (OR 0.88; 95% CI 0.82-0.94), male (OR 0.83; 95% CI 0.71-0.96), preferred a language other than English (0.71; 95% CI 0.54-0.95), and had a serious illness other than cancer (OR 0.74; 95% CI 0.61-0.90). CONCLUSION: We found that Black and Latinx patients were less likely to complete an initial visit and those with a preferred language other than English were less likely to complete a follow-up visit. To promote equity in PC, these differences and their impact on outcomes must be explored.

Breakthrough SARS-CoV-2 infection outcomes in vaccinated patients with chronic liver disease and cirrhosis: A National COVID Cohort Collaborative study.

BACKGROUND AND AIMS: Outcomes of breakthrough SARS-CoV-2 infections have not been well characterized in non-veteran vaccinated patients with chronic liver diseases (CLD). We used the National COVID Cohort Collaborative (N3C) to describe these outcomes. APPROACH AND RESULTS: We identified all CLD patients with or without cirrhosis who had SARS-CoV-2 testing in the N3C Data Enclave as of January 15, 2022. We used Poisson regression to estimate incidence rates of breakthrough infections and Cox survival analyses to associate vaccination status with all-cause mortality at 30 days among infected CLD patients. We isolated 278,457 total CLD patients: 43,079 (15%) vaccinated and 235,378 (85%) unvaccinated. Of 43,079 vaccinated patients, 32,838 (76%) were without cirrhosis and 10,441 (24%) with cirrhosis. Breakthrough infection incidences were 5.4 and 4.9 per 1000 person-months for fully vaccinated CLD patients without cirrhosis and with cirrhosis, respectively. Of the 68,048 unvaccinated and 10,441 vaccinated CLD patients with cirrhosis, 15% and 3.7%, respectively, developed SARS-CoV-2 infection. The 30-day outcome of mechanical ventilation or death after SARS-CoV-2 infection for unvaccinated and vaccinated CLD patients with cirrhosis were 15.2% and 7.7%, respectively. Compared to unvaccinated patients with cirrhosis, full vaccination was associated with a 0.34-times adjusted hazard of death at 30 days. CONCLUSIONS: In this N3C study, breakthrough infection rates were similar among CLD patients with and without cirrhosis. Full vaccination was associated with a 66% reduction in risk of all-cause mortality for breakthrough infection among CLD patients with cirrhosis. These results provide an additional impetus for increasing vaccination uptake in CLD populations.

Breakthrough SARS-CoV-2 Infection Outcomes in Vaccinated Patients with Chronic Liver Disease and Cirrhosis: A National COVID Cohort Collaborative Study.

Background and Aims: The incidence and outcomes of breakthrough SARS-CoV-2 infections in vaccinated chronic liver disease (CLD) patients have not been well-characterized in non-veteran populations. We used the National COVID Cohort Collaborative (N3C), a dataset of 10.7 million patients, of whom 0.9 million have vaccination data, to describe outcomes in vaccinated CLD patients. Methods: We identified all CLD patients with or without cirrhosis regardless of vaccination status who had SARS-CoV-2 testing in the N3C Data Enclave as of 1/15/2022. We used Poisson regression to estimate incidence rates of breakthrough infections and Cox survival analyses to associate vaccination status with all-cause mortality at 30 days among infected CLD patients. Results: We isolated 278,457 total CLD patients: 43,079 (15%) vaccinated and 235,378 (85%) unvaccinated. Of the 43,079 vaccinated CLD patients, 32,838 (76%) were without cirrhosis and 10,441 (24%) were with cirrhosis. Estimated incidence rates for breakthrough infections were 5.6 and 5.1 per 1,000 person-months for 27,235 fully vaccinated CLD patients without cirrhosis and for 8,218 fully vaccinated CLD patients with cirrhosis, respectively.Of the 68,048 unvaccinated and 10,441 vaccinated CLD patients with cirrhosis in our cohort, 15% and 3.7%, respectively, developed SARS-CoV-2 infection. The combined 30-day all-cause rate of mechanical ventilation (without death) or death after SARS-CoV-2 infection for unvaccinated and vaccinated CLD patients with cirrhosis were 15.2% and 7.7%, respectively. Compared to unvaccinated patients with cirrhosis, full vaccination was associated with a 0.34-times adjusted hazard of death at 30 days. Conclusions: In this N3C Data Enclave study, breakthrough infection rates were similar amongst CLD patients with and without cirrhosis. Full vaccination was associated with a 66% reduction in risk of all-cause mortality among CLD patients with cirrhosis after infection. These results provide an additional impetus for increasing vaccination uptake among patients with severe liver disease.

Genetic variation that determines TAPBP expression levels associates with the course of malaria in an HLA allotype-dependent manner.

HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP), an integral component of the peptide-loading complex, to present peptides on the cell surface. We identified two single-nucleotide polymorphisms that regulate TAPBP messenger RNA (mRNA) expression in Africans, rs111686073 (G/C) and rs59097151 (A/G), located in an AP-2α transcription factor binding site and a microRNA (miR)-4486 binding site, respectively. rs111686073G and rs59097151A induced significantly higher TAPBP mRNA expression relative to the alternative alleles due to higher affinity for AP-2α and abrogation of miR-4486 binding, respectively. These variants associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA-I allotypes, presumably by augmenting peptide loading, whereas tapasin-independent allotypes associated with relative protection, regardless of imputed TAPBP mRNA expression levels. Thus, an attenuated course of malaria may occur through enhanced breadth and/or magnitude of antigen presentation, an important consideration when evaluating vaccine efficacy.

The Effect of Readmission for Phototherapy on Early Breast Milk Feeding.

OBJECTIVES: To estimate the effect of readmission for inpatient phototherapy on parent-reported exclusive and any breast milk feeding at 2-month well-child visits. METHODS: We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥35 weeks' gestation with outpatient total serum bilirubin levels ranging from 1 mg/dL below to 2.9 mg/dL above the American Academy of Pediatrics phototherapy threshold at <15 days of age. We compared breast milk feeding at 2-month well-child visits among those readmitted and not readmitted to the hospital for phototherapy, adjusting for bilirubin and other confounding variables. RESULTS: Approximately one-quarter (26.5%) of the cohort (n = 7729) were readmitted for phototherapy. Almost half (48.5%) of the infants who were not readmitted for phototherapy received exclusively breast milk at the 2-month visit compared with slightly fewer infants who were readmitted (42.9%). In both groups of infants, most (82.2% not readmitted and 81.2% readmitted) received any breast milk. Readmission for phototherapy was associated with a lower adjusted risk of exclusive breast milk feeding (adjusted risk ratio 0.90; 95% confidence interval [CI], 0.84 to 0.96), corresponding to a marginal absolute reduction in exclusive breast milk feeding of 5.0% (95% CI, -7.9% to -2.1%). It was not associated with a reduction in any breast milk feeding (adjusted risk ratio, 1.00; 95% CI, 0.97 to 1.02). CONCLUSIONS: Infants readmitted for phototherapy were more likely to receive any formula, but no less likely to receive any breast milk at 2-month well-child visits.

Tutorial on directed acyclic graphs.

Directed acyclic graphs (DAGs) are an intuitive yet rigorous tool to communicate about causal questions in clinical and epidemiologic research and inform study design and statistical analysis. DAGs are constructed to depict prior knowledge about biological and behavioral systems related to specific causal research questions. DAG components portray who receives treatment or experiences exposures; mechanisms by which treatments and exposures operate; and other factors that influence the outcome of interest or which persons are included in an analysis. Once assembled, DAGs - via a few simple rules - guide the researcher in identifying whether the causal effect of interest can be identified without bias and, if so, what must be done either in study design or data analysis to achieve this. Specifically, DAGs can identify variables that, if controlled for in the design or analysis phase, are sufficient to eliminate confounding and some forms of selection bias. DAGs also help recognize variables that, if controlled for, bias the analysis (e.g., mediators or factors influenced by both exposure and outcome). Finally, DAGs help researchers recognize insidious sources of bias introduced by selection of individuals into studies or failure to completely observe all individuals until study outcomes are reached. DAGs, however, are not infallible, largely owing to limitations in prior knowledge about the system in question. In such instances, several alternative DAGs are plausible, and researchers should assess whether results differ meaningfully across analyses guided by different DAGs and be forthright about uncertainty. DAGs are powerful tools to guide the conduct of clinical research.

Update on Phototherapy and Childhood Cancer in a Northern California Cohort.

OBJECTIVES: We aimed to reassess the relationship between phototherapy and cancer in an extended version of a previous cohort and to replicate a report from Quebec of increased cancer risk after phototherapy beginning at age 4 years. METHODS: This cohort study included 139 100 children born at ≥35 weeks' gestation from 1995 to 2017, followed through March 16, 2019, in Kaiser Permanente Northern California hospitals who had a qualifying bilirubin level from -3 mg/dL to +4.9 mg/dL from the American Academy of Pediatrics phototherapy threshold; an additional 40 780 children and 5 years of follow-up from our previous report. The exposure was inpatient phototherapy (yes or no), and the outcomes were various types of childhood cancer. We used Cox proportional hazard models, controlling for propensity-score quintiles, and allowed for time-dependent exposure effects to assess for the risk of cancer after a latent period. RESULTS: Over a mean (SD) follow-up of 8.2 (5.7) years, the crude incidence of cancer per 100 000 person-years was 25.1 among those exposed to phototherapy and 19.2 among those not exposed (233 cases of cancer). After propensity adjustment, phototherapy was not associated with any cancer (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.83-1.54), hematopoietic cancer (HR: 1.17, 95% CI: 0.74-1.83), or solid tumors (HR: 1.01, 95% CI: 0.65-1.58). We also found no association with cancer diagnoses at age ≥4 years. CONCLUSIONS: We did not confirm previous, concerning associations between phototherapy and adjusted risk of any cancer, nonlymphocytic leukemia, or brain and/or central nervous systems tumors in later childhood.

Study Designs to Assess Real-World Interventions to Prevent COVID-19.

Background: In the face of the novel virus SARS-CoV-2, scientists and the public are eager for evidence about what measures are effective at slowing its spread and preventing morbidity and mortality. Other than mathematical modeling, studies thus far evaluating public health and behavioral interventions at scale have largely been observational and ecologic, focusing on aggregate summaries. Conclusions from these studies are susceptible to bias from threats to validity such as unmeasured confounding, concurrent policy changes, and trends over time. We offer recommendations on how to strengthen frequently applied study designs which have been used to understand the impact of interventions to reduce the spread of COVID-19, and suggest implementation-focused, pragmatic designs that, moving forward, could be used to build a robust evidence base for public health practice. Methods: We conducted a literature search of studies that evaluated the effectiveness of non-pharmaceutical interventions and policies to reduce spread, morbidity, and mortality of COVID-19. Our targeted review of the literature aimed to explore strengths and weaknesses of implemented studies, provide recommendations for improvement, and explore alternative real-world study design methods to enhance evidence-based decision-making. Results:Study designs such as pre/post, interrupted time series, and difference-in-differences have been used to evaluate policy effects at the state or country level of a range of interventions, such as shelter-in-place, face mask mandates, and school closures. Key challenges with these designs include the difficulty of disentangling the effects of contemporaneous changes in policy and correctly modeling infectious disease dynamics. Pragmatic study designs such as the SMART (Sequential, Multiple-Assignment Randomized Trial), stepped wedge, and preference designs could be used to evaluate community re-openings such as schools, and other policy changes. Conclusions: As the epidemic progresses, we need to move from post-hoc analyses of available data (appropriate for the beginning of the pandemic) to proactive evaluation to ensure the most rigorous approaches possible to evaluate the impact of COVID-19 prevention interventions. Pragmatic study designs, while requiring initial planning and community buy-in, could offer more robust evidence on what is effective and for whom to combat the global pandemic we face and future policy decisions.

The effect of hospital phototherapy on early breastmilk feeding.

BACKGROUND: The effect of phototherapy on breastmilk feeding is unclear. OBJECTIVE: To estimate the effect of inpatient phototherapy on breastmilk feeding at 2-month well-child visits. METHODS: We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥ 35 weeks' gestation with total serum bilirubin levels close to the American Academy of Pediatrics 2004 phototherapy threshold during their birth hospitalisation. We compared self-reported breastmilk feeding at 2-month well-child visits among those who had and had not received birth hospitalisation phototherapy, adjusting for bilirubin levels and other confounding variables. We used multiple imputation (K = 200) to address missing data. RESULTS: Approximately a quarter of infants in the cohort (24.5%) received phototherapy during their birth hospitalisation. At the 2-month visit, exclusive breastmilk feeding was less common (RR 0.91, 95% interval [CI] 0.88, 0.95) among those who received phototherapy (41.3%) than those who did not (45.2%). However, no association remained after adjusting for potential confounders (RR 0.99, 95% CI 0.95, 1.04; average treatment effect on the treated [ATET] -0.2%, 95% CI -2.0%, 1.5%). In contrast, any breastmilk feeding was similar between infants who did (76.8%) and did not get phototherapy (77.9%). After adjusting for confounders, phototherapy had a slightly positive association with any breastmilk feeding at 2 months (RR 1.02, 95% CI 1.00, 1.04). Among infants who received phototherapy, the proportion being fed any breastmilk at the 2-month visit was an estimated 1.6 percentage points higher than it would have been if they had not received phototherapy (ATET 1.6%, 95% CI 0.1%, 3.1%). Multiple imputation results were similar. CONCLUSIONS: Birth hospitalisation phototherapy can be delivered in a way that does not adversely affect breastmilk feeding at 2 months.

HLA Alleles B*53:01 and C*06:02 Are Associated With Higher Risk of P. falciparum Parasitemia in a Cohort in Uganda.

Variation within the HLA locus been shown to play an important role in the susceptibility to and outcomes of numerous infections, but its influence on immunity to P. falciparum malaria is unclear. Increasing evidence indicates that acquired immunity to P. falciparum is mediated in part by the cellular immune response, including NK cells, CD4 and CD8 T cells, and semi-invariant γδ T cells. HLA molecules expressed by these lymphocytes influence the epitopes recognized by P. falciparum-specific T cells, and class I HLA molecules also serve as ligands for inhibitory receptors including KIR. Here we assessed the relationship of HLA class I and II alleles to the risk of P. falciparum infection and symptomatic malaria in a cohort of 892 Ugandan children and adults followed prospectively via both active and passive surveillance. We identified two HLA class I alleles, HLA-B*53:01 and HLA-C*06:02, that were associated with a higher prevalence of P. falciparum infection. Notably, no class I or II HLA alleles were found to be associated with protection from P. falciparum parasitemia or symptomatic malaria. These findings suggest that class I HLA plays a role in the ability to restrict parasitemia, supporting an essential role for the cellular immune response in P. falciparum immunity. Our findings underscore the need for better tools to enable mechanistic studies of the T cell response to P. falciparum at the epitope level and suggest that further study of the role of HLA in regulating pre-erythrocytic stages of the P. falciparum life cycle is warranted.

Association of Inhibitory Killer Cell Immunoglobulin-like Receptor Ligands With Higher Plasmodium falciparum Parasite Prevalence.

Killer cell immunoglobulin-like receptors (KIRs) and their HLA ligands influence the outcome of many infectious diseases. We analyzed the relationship of compound KIR-HLA genotypes with risk of Plasmodium falciparum infection in a longitudinal cohort of 890 Ugandan individuals. We found that presence of HLA-C2 and HLA-Bw4, ligands for inhibitory KIR2DL1 and KIR3DL1, respectively, increased the likelihood of P. falciparum parasitemia in an additive manner. Individuals homozygous for HLA-C2, which mediates strong inhibition via KIR2DL1, had the highest odds of parasitemia, HLA-C1/C2 heterozygotes had intermediate odds, and individuals homozygous for HLA-C1, which mediates weaker inhibition through KIR2DL2/3, had the lowest odds of parasitemia. In addition, higher surface expression of HLA-C, the ligand for inhibitory KIR2DL1/2/3, was associated with a higher likelihood of parasitemia. Together these data indicate that stronger KIR-mediated inhibition confers a higher risk of P. falciparum parasitemia and suggest that KIR-expressing effector cells play a role in mediating antiparasite immunity.