A Weighted Survival Regression Framework for Incorporating External Prediction Information.

In this article, we develop a weighted approach to estimation for right-censored time to event data in the presence of external predictions available from a prediction model. There are several advantages to the proposed approach. First, the method allows for arbitrary forms for the external prediction model.

Dietary Intake Mendelian Randomization: Assessment and Development of Methods for Instrument Selection and Robust Inference.

Background: Mendelian randomization (MR) uses genetic instruments (GI) to infer causality between exposures, like dietary intake, and health outcomes. Almost all MR of dietary intake use the full set of genome-wide significant (GWS) variants in the GI, and therefore, causal estimates are likely biased by variants that act indirectly on diet.

Objective: First, we performed an assessment of the diet MR literature to evaluate the applications and approaches common in the field.

cytoKernel: robust kernel embeddings for assessing differential expression of single-cell data.

Motivation: High-throughput sequencing of single-cell data can be used to rigorously evaluate cell specification and enable intricate variations between groups or conditions to be identified. Many popular existing methods for differential expression target differences in aggregate measurement (mean, median, sum) and limit their approaches to detect only global differential changes.

Results: We present a robust method for differential expression of single-cell data using a kernel-based score test, cytoKernel.

Mediation analysis with the mediator and outcome missing not at random.

Mediation analysis is widely used for investigating direct and indirect causal pathways through which an effect arises. However, many mediation analysis studies are challenged by missingness in the mediator and outcome. In general, when the mediator and outcome are missing not at random, the direct and indirect effects are not identifiable without further assumptions.

A hypomorphic Il2rb mutant mouse model recapitulates and reveals mechanisms of human T cell immune dysregulation in IL-2Rβ deficiency.

Here, we describe the use of a homologous knockin mouse model to further decipher the mechanism(s) of a novel human homozygous IL2RB hypomorphic mutation. Our model recapitulates the human immune dysregulation phenotype, showing decreased mutant interleukin-2Rβ (IL-2Rβ) cell-surface expression, impaired IL-2/15-dependent STAT5 signaling, elevated serum IL-2/15 levels, expanded effector memory CD8 T cells, and severely reduced regulatory T cells (Tregs). Using mixed bone marrow chimeras (BMCs) and wild-type (WT) Treg transfers, we distinguish receptor-intrinsic from receptor-extrinsic immunopathogenesis.

A surrogate endpoint-based provisional approval causal roadmap, illustrated by vaccine development.

For many rare diseases with no approved preventive interventions, promising interventions exist. However, it has proven difficult to conduct a pivotal phase 3 trial that could provide direct evidence demonstrating a beneficial effect of the intervention on the target disease outcome. When a promising putative surrogate endpoint(s) for the target outcome is available, surrogate-based provisional approval of an intervention may be pursued.

Real-world cardiovascular effects of liraglutide: transportability analysis of the LEADER trial.

Objective: To evaluate generalizability of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized clinical trial (RCT) - a cardiovascular outcomes study of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide - to US Veterans Affairs Healthcare System (VA) patients with diabetes, a population at high cardiovascular disease risk lacking direct RCT evidence of GLP-1RA efficacy.

Design: Transportability analysis that integrates real-world and RCT data to estimate the average treatment effect of liraglutide versus placebo had LEADER enrolled VA diabetes patients.

Setting: Multi-national RCT and US VA.

Impact of Vgsc-1014 mutations on the feeding pattern of Phlebotomus argentipes.

Knockdown resistance alleles (kdr alleles) within the para voltage-gated sodium channel gene (Vgsc) are a common mechanism of DDT and pyrethroid resistance in insect vectors. In the primary Asian visceral leishmaniasis vector, Phlebotomus argentipes, two kdr alleles in codon 1014 of the Vgsc are associated with insecticide resistance, potentially presenting challenges to vector control efforts in the Indian subcontinent. Here, we screened Vgsc-1014 alleles and blood meal origin in P.

Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood-Onset Lupus Nephritis Due to Activated Phosphoinositide 3-Kinase δ Syndrome.

Objective: The objective of this study was to investigate the mechanistic underpinnings and treatment response of lupus nephritis (LN) in activated phosphoinositide 3-kinase δ syndrome type 1 (APDS1) using pathway-specific therapy and advanced spatial proteomics.

Methods: We conducted mechanistic investigation of refractory class V LN in an 18-year-old female patient with genetically confirmed APDS1 (PIK3CD c.3061G>A, p.

The Science of Statistical Practice.

Emerging technologies, such as artificial intelligence, emphasize the importance of quantitative methods and their applications when conducting increasingly data-intensive research. The scientific discipline of statistical practice is critical for achieving rigor in research addressing important domain-level questions. The misconception that statistical practice is not a science but rather a service threatens scientific rigor and compromises the quality of its contribution to clinical and translational research.

The Lifecycle of Phlebotomus argentipes (Diptera: Psychodidae) Sand Fly in a Newly Developed Colony in Bangladesh.

Laboratory-established sand fly colonies provide important material for leishmaniasis research; however, the establishment and maintenance of such colonies can be complicated. In this study, a colony of Phlebotomus argentipes (P. argentipes) was established using wild-caught sand flies in Bangladesh by following standard procedures described in the published literature.

Exposures from Oil and Gas Development and Childhood Leukemia Risk in Colorado: A Population-Based Case-Control Study.

Background: Children living in upstream oil and natural gas (O&G) areas may be exposed to leukemogens and at increased risk for acute lymphoblastic leukemia (ALL).

Methods: We conducted a case-control study of children born in Colorado between 1992 and 2019. We matched 451 children diagnosed with ALL at ages 2 to 9 years starting in 2002 to 2,706 controls based on birth month/year and Hispanic ethnicity.

DisCo P-ad: Distance-Correlation-Based -Value Adjustment Enhances Multiple Testing Corrections for Metabolomics.

Background: Due to scientific advancements in high-throughput data production technologies, omics studies, such as genomics and metabolomics, often give rise to numerous measurements per sample/subject containing several noisy variables that potentially cloud the true signals relevant to the desired study outcome(s). Therefore, correcting for multiple testing is critical while performing any statistical test of significance to minimize the chances of false or missed discoveries. Such correction practice is commonplace in genome-wide association studies (GWAS) but is also becoming increasingly relevant to metabolome-wide association studies (MWAS).

Evaluating a rapid molecular assay in a mobile laboratory for improved diagnosis of dengue in Bangladesh.

Objectives: Dengue emerged as a significant health threat in endemic regions in recent years. However, inconsistent diagnostic accuracy in sequential dengue infections necessitate improved testing methods to ensure effective management of dengue cases. Here, we evaluated a portable, rapid, and sensitive molecular assay-reverse transcriptase recombinase polymerase amplification assay (RT-RAA)-utilizing a mobile suitcase laboratory to detect infections in suspected dengue cases in Bangladesh.

Kernel machine tests of association using extrinsic and intrinsic cluster evaluation metrics.

Modeling the network topology of the human brain within the mesoscale has become an increasing focus within the neuroscientific community due to its variation across diverse cognitive processes, in the presence of neuropsychiatric disease or injury, and over the lifespan. Much research has been done on the creation of algorithms to detect these mesoscopic structures, called communities or modules, but less has been done to conduct inference on these structures. The literature on analysis of these community detection algorithms has focused on comparing them within the same subject.

cytoKernel: Robust kernel embeddings for assessing differential expression of single cell data.

High-throughput sequencing of single-cell data can be used to rigorously evlauate cell specification and enable intricate variations between groups or conditions. Many popular existing methods for differential expression target differences in aggregate measurements (mean, median, sum) and limit their approaches to detect only global differential changes. We present a robust method for differential expression of single-cell data using a kernel-based score test, cytoKernel.

Post kala-azar dermal leishmaniasis burden at the village level in selected high visceral leishmaniasis endemic upazilas in Bangladesh.

Objectives: As post kala-azar Dermal Leishmaniasis (PKDL) threatens the success of the Visceral Leishmaniasis (VL) elimination initiative, we aimed to investigate the PKDL burden, including an active search for PKDL in leprosy-negative skin lesion cases. We also investigated their health-seeking behavior and perceived level of stigma.

Methods: This was a cross-sectional survey among inhabitants in the VL-endemic villages of the five most VL-endemic upazilas.

Trained Immunity Generated by the Recombinant Zoster Vaccine.

Trained immunity may play a role in vaccine-induced protection against infections. We showed that the highly efficacious recombinant VZV-gE zoster vaccine (RZV) generated trained immunity in monocytes, natural killer (NK) cells, and dendritic cells (DCs) and that the less efficacious live zoster vaccine did not. RZV stimulated ex vivo gE-specific monocyte, DC and NK cell responses that did not correlate with CD4 + T-cell responses.

Does behavior mediate the effect of weather on SARS-CoV-2 transmission? evidence from cell-phone data.

There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting.

Did COVID-19 ICU patient mortality risk increase as Colorado hospitals filled? A retrospective cohort study.

Objectives: To assess whether increasing levels of hospital stress-measured by intensive care unit (ICU) bed occupancy (primary), ventilators in use and emergency department (ED) overflow-were associated with decreasing COVID-19 ICU patient survival in Colorado ICUs during the pre-Delta, Delta and Omicron variant eras.

Design: A retrospective cohort study using discrete-time survival models, fit with generalised estimating equations.

Setting: 34 hospital systems in Colorado, USA, with the highest patient volume ICUs during the COVID-19 pandemic.

Electrochemical and photochemical reaction of isatins: a decade update.

This review presents the latest progress in photochemical and electrochemical reactions involving isatins. Isatin and its functionalized scaffolds , oxindoles, spirooxindoles, and quinolines are privileged heterocycles as they are largely present in several agrochemical, natural products, and pharmaceuticals. Thus, the functionalization of isatins using sustainable approaches, , electro- and photochemical methods is of recent research interest worldwide.

Does behavior mediate the effect of weather on SARS-CoV-2 transmission? Evidence from cell-phone data.

Background: There is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting.

Improving Generalizability of PET DL Algorithms: List-Mode Reconstructions Improve DOTATATE PET Hepatic Lesion Detection Performance.

Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data.

Feasibility and limitations of using commercial databases to evaluate residential mobility in registry-based research on childhood cancer.

Background: Researchers have used commercial databases containing residential addresses to reduce exposure misclassification in case-control studies. Our objective is to evaluate the potential systematic bias regarding case status when reconstructing residential locations from commercial databases.

Methods: Our study population of 3640 Colorado-born children includes 520 children diagnosed with acute lymphocytic leukemia between 2002 and 2019.