An inverse probability weighting method for estimating the net benefit in survival analyses in observational studies

Background: Recently, in the context of randomized trials, a measure on the difference scale called the net benefit was developed for survival analysis. As this measure does not require the assumption of proportional hazards, it is an attractive new measure of the treatment effect to apply instead of the hazard ratio calculated under this assumption. However, no method for estimating it has been presented in observational studies. Therefore, we describe a simple method to estimate the net benefit adjusted for confounding.  Methods: We reviewed a method for estimating the net benefit in a randomized trial and extended it to a method that adjusts for confounding using inverse probability of treatment weights.  Results: We performed Monte Carlo simulations to test the performance of our method. The results show that our method estimated adjusted net benefits in an unbiased manner regardless of whether the assumption of proportional hazards held. In addition, we illustrated our method using data from an observational study evaluating disease-free survival of Ewing’s sarcoma patients. Our method yielded an adjusted net benefit of –0.032, whereas an existing method, used to analyze data from randomized trials, yielded an unadjusted net benefit of 0.284.  Conclusions: In observational studies with a time-to-event outcome, the net benefit adjusted for confounding can readily be estimated using inverse probability of treatment weights

Sensitivity analysis for direct and indirect effects in the presence of exposure-induced mediator-outcome confounders

Questions of mediation are often of interest in reasoning about mechanisms, and methods have been developed to address these questions. However, these methods make strong assumptions about the absence of confounding. Even if exposure is randomized, there may be mediator-outcome confounding variables. Inference about direct and indirect effects is particularly challenging if these mediator-outcome confounders are affected by the exposure because in this case these effects are not identified irrespective of whether data is available on these exposure-induced mediator-outcome confounders. In this paper, we provide a sensitivity analysis technique for natural direct and indirect effects that is applicable even if there are mediator-outcome confounders affected by the exposure. We give techniques for both the difference and risk ratio scales and compare the technique to other possible approache

Sample Size Calculation of Exact Tests for the Weak Causal Null Hypothesis in Randomized Trials with a Binary Outcome

Abstract The main purpose in many randomized trials is to make an inference about the average causal effect of a treatment. Therefore, on a binary outcome, the null hypothesis for the hypothesis test should be that the causal risks are equal in the two groups. This null hypothesis is referred to as the weak causal null hypothesis. Nevertheless, at present, hypothesis tests applied in actual randomized trials are not for this null hypothesis; Fisher's exact test is a test for the sharp causal null hypothesis that the causal effect of treatment is the same for all subjects. In general, the rejection of the sharp causal null hypothesis does not mean that the weak causal null hypothesis is rejected. Recently, Chiba developed new exact tests for the weak causal null hypothesis: a conditional exact test, which requires that a marginal total is fixed, and an unconditional exact test, which does not require that a marginal total is fixed and depends rather on the ratio of random assignment. To apply these exact tests in actual randomized trials, it is inevitable that the sample size calculation must be performed during the study design. In this paper, we present a sample size calculation procedure for these exact tests. Given the sample size, the procedure can derive the exact test power, because it examines all the patterns that can be obtained as observed data under the alternative hypothesis without large sample theories and any assumptions

シロイヌナズナNRT1/PTR FAMILY (NPF) の植物ホルモン輸送体としての機能解析

NPF (NRT1/PTR FAMILY) proteins were originally identified as nitrate or di/tri-peptide transporters. However, recent studies revealed that the members of this transporter family also transport plant hormones, including auxin (indole-3-acetic acid; IAA), abscisic acid (ABA) and gibberellin (GA), as well as secondary metabolite, such as glucosinolates. In the present study, I developed the modified yeast two-hybrid (Y2H) systems with the receptor complexes for GA and Jasmonates (JA-Ile) to detect the hormone transport activities of proteins expressed in the yeast cells. By using the Y2H receptor complex systems for ABA, GA and JA-Ile, I determined the activities of Arabidopsis NPFs for ABA, GA and JA-Ile transport. Several NPFs induced the formation of receptor complexes under relatively low hormone concentrations. Hormone transport activities were confirmed for some NPFs by direct analysis of hormone uptake of yeast cells using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These results suggested that at least some NPF proteins function as hormone transporters in vivo.首都大学東京, 2015-03-25, 博士（理学）, 甲第533号首都大学東

Bispectral index-guided propofol sedation during endoscopic ultrasonography

Background/Aims Bispectral index (BIS) monitors process and display electroencephalographic data are used to assess the depth of anesthesia. This study retrospectively evaluated the usefulness of BIS monitoring during endoscopic ultrasonography (EUS). Methods This study included 725 consecutive patients who underwent EUS under sedation with propofol. BIS monitoring was used in 364 patients and was not used in 361. The following parameters were evaluated: (1) median dose of propofol; (2) respiratory and circulatory depression; (3) occurrence of body movements; (4) awakening score >8 at the time; and (5) awakening score 2 hours after leaving the endoscopy room. Results The BIS group received a significantly lower median dose of propofol than the non-BIS group (159.2 mg vs. 167.5 mg; p=0.015) in all age groups. For patients aged ≥75 years, the reduction in heart rate was significantly lower in the BIS group than in the non-BIS group (1.2% vs. 9.1%; p=0.023). Moreover, the occurrence of body movements was markedly lower in the BIS group than in the non-BIS group (8.5% vs. 39.4%; p<0.001). Conclusions During EUS examination, BIS monitoring is useful for maintaining a constant depth of anesthesia, especially in patients 75 years of age or older

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target