Postoperative chemoradiotherapy with capecitabine and oxaliplatin vs.capecitabine for pathological stage N2 rectal cancer

Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.

Medical Resource Utilizations and Economic Burden in Chinese Cancer Patients with Chemotherapy-induced Anemia:A Populational Database Study

Objective： Most of published studies emphasized the medical cost of treating chemotherapy-induced anemia （CIA） by using specific agents, for example, epoetin α, epoetin β, darbepoetin α or combined with red blood cell transfusions, however, the investigation of the overall medical resources utilizations and economic burden of CIA is still limited. Besides, such studies which emphasized Chinese population still lack. The aim of this study is to investigate the medical resource utilization and the economic burden of Chinese cancer patients with CIA by using a populational representative claim database. Methods： The data for this study are from the 2000-2003 Population Health Insurance Research Database （PHIRD） in Taiwan. On the basis of issuing catastrophic illness cards in the enrollment data files, a total of 26,053 beneficiaries were identified from the PHIRD, who were newly diagnosed with these four cancers in 2001 and 2002 （2001： n=12,954; 2002： n=13099）. A generalized linear model （GLM） was employed for analyzing the differences of medical resource utilization and economic burden between the anemic and non-anemic groups. Results： Analyses showed that the anemic patients were significantly more likely to have longer length of hospital stay than non-anemic patients （P〈0.05） across all these four cancers and in two study periods （except women breast cancer in 2002/03）. As regards the health care expenditures, the average one-year total medical cost was USD$8,982 （2001/02） and USD$8,990 （2002/03） for anemic patients among these four cancers, and USD$7,769 （2001/02） and USD$7713 （2002/03） for non-anemic patients （P〈0.0001）. As for ambulatory costs, anemic patients＇ was significantly higher than non-anemic patients＇ for lung cancer （in 2001/02）, women breast cancer （in 2001/02 and 2002103） and the summarized data （in 2001/02）. As for inpatient costs, anemic patients＇ was significantly higher than non-anemic patients＇ for gastric cancer （in 2002/03）, colon and rectal cancer （in 2001/02 and 2002/03）, lung cancer （in 2001/02 and 2002/03）, women breast cancer （in 2001/02） and the summarized data （in 2001/02 and 2002/03）. Conclusion： This study is the first study to demonstrate that cancer patients who receive chemotherapy and with anemia utilize more medical resources and have heavier economic burden among Chinese cancer patients. Although the Population Health Insurance Program in Taiwan was established to provide more low-burdened medical care for all cancer patients, further effort is still needed to reduce the economic burden for cancer patients who have specific complications.

Sample sizes based on three popular indices of risks

Sample size justification is a very crucial part in the design of clinical trials. In this paper, the authors derive a new formula to calculate the sample size for a binary outcome given one of the three popular indices of risk difference.The sample size based on the absolute difference is the fundamental one, which can be easily used to derive sample size given the risk ratio or OR.

Inconsistency between overall and subgroup analyses

Suppose we have a sample of subjects in two treatment groups.To study the difference of the treatment effects,we can analyse the data using all subjects(overall analysis).We may also divide the subjects into several subgroups based on some covariates of interest(eg,gender),and study the treatment effects within each subgroup.The results of these two analyses may be different or even in opposite directions.In this paper,we give a general sufficient condition of consistency between the overall and subgroup analyses.

Partial least squares regression and principal component analysis:similarity and differences between two popular variable reduction approaches

SUMMARY In many statistical applications,composite variables are constructed to reduce the number of variables and improve the performances of statistical analyses of these variables,especially when some of the variables are highly correlated.Principal component analysis(PCA)and factor analysis(FA)are generally used for such purposes.If the variables are used as explanatory or independent variables in linear regression analysis,partial least squares(PLS)regression is a better alternative.Unlike PCA and FA,PLS creates composite variables by also taking into account the response,or dependent variable,so that they have higher correlations with the response than composites from their PCA and FA counterparts.In this report,we provide an introduction to this useful approach and illustrate it with data from a real study.

Delay in Early Infant Diagnosis and High Loss to Follow-Up among Infant Born to HIV-Infected Women in Ethiopia

Background: Many HIV-infected infants and children die from HIV related causes without their HIV status being known or receiving HIV care. All HIV exposed infants should be tested by Dried Blood Spots (DBS)-PCR before or at 6 weeks of age. Testing is a crucial step to facilitate early access to antiretroviral treatment (ART). However, studies that assess the level of use and implementation of HIV DNA testing in Ethiopia are lacking. Objective: To investigate the rate of early infant diagnosis (EID), defined as having blood drawn for HIV DNA-PCR testing, and predictive factors of EID among infants born to HIV infected women. Method: A multicentre retrospective cohort study was conducted from April to June 2012 in three public hospitals and three health centers, in Northwest Ethiopia. Mother-infant pairs were followed from delivery until the time of the HIV diagnostic test. Data were captured using standardized forms. The time-to-diagnostic test was estimated using Kaplan-Meier estimators. Factors associated with EID were evaluated using logistic regression. Result: Of the 266 HIV-exposed infants identified from the health facilities, only 109 (41.0%) infants had early HIV DNA-PCR tests. The median age at the time of HIV diagnostic testing was 60 days (95% CI: 47 - 73 days), and the median turnaround time between blood draw for DNA-PCR testing to delivery of a test result to the respective health facility was 36 days (95% CI: 33 - 40 days). A total of 35 (13.2%) infants were diagnosed with HIV infection. The predictors of EID were the mother having prenatal care, maternal receipt of ART during pregnancy and place of birth. Conclusion: Three out of five HIV-infected women did not bring their infant for HIV testing during the recommended 6 week interval after birth. Special attention is required for infants born to HIV-infected women who did not receive ART or delivered at home or a private health facility to ensure early infant diagnosis, reduce loss to follow-up and prevent late initiation of ART for HIV-infected infants.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for diffuse large B-cell lymphoma:A systematic review and meta-analysis

Objective:To evaluate whether improved progression-free survival(PFS)from radiotherapy(RT)translates into an overall survival(OS)benefit for diffuse large B-cell lymphoma(DLBCL).Methods:A systematic literature search identified randomized controlled trials(RCTs)and retrospective studies that compared combined-modality therapy(CMT)with chemotherapy(CT)alone.Weighted regression analyses were used to estimate the correlation between OS and PFS benefits.Cohen’s kappa statistic assessed the consis-tency between DLBCL risk-models and PFS patterns.Furthermore,the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio(HR)according to the PFS patterns.Results:For both 7 RCTs and 52 retrospective studies,correlations were found between PFS HR(HRPFS)and OS HR(HROS)at trial level(r=0.639-0.876),and between PFS and OS rates at treatment-arm level,regardless of CT regimens(r=0.882-0.964).Incorporating RT into CT increased about 18%of PFS,and revealed a different OS benefit profile.Patients were stratified into four CT-generated PFS patterns(>80%,>60-80%,>40-60%,and≤40%),which was consistent with risk-stratified subgroups(kappa>0.6).Absolute gain in OS from RT ranged from≤5%at PFS>80%to about 21%at PFS≤40%,with pooled HROS from 0.70(95%CI,0.51-0.97)to 0.48(95%CI,0.36-0.63)after rituximab-based CT.The OS benefit of RT was predominant in intermediate-and high-risk patients with PFS≤80%.Conclusion:We demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

On testing proportional odds assumptions for proportional odds models

Proportional odds models are commonly used to model ordinal responses,but the proportional odds assumption may not hold in practice,leading to biased inference.Tests such as score,Wald and likelihood ratio(LR)have been proposed to evaluate the proportional odds assumption based on models without the assumption.Brant has proposed an independent binary model-based Wald-type test,and Wolfe and Gould have extended the idea to propose an LR-type test.This paper provides a brief review of the Brant and Wolfe-Gould tests for evaluating the proportional odds assumption and evaluates their performance through simulation studies and a real data example.Sample programs are provided in SAS,SPSS and Stata to facilitate the implementation of these tests using standard statistical software packages.This study highlights the importance of evaluating the proportional odds assumption when using proportional odds models for ordinal responses.The sample programs provided in this paper make it easy for researchers to apply these tests in their own analyses using standard statistical software packages.

On modelling relative risks for longitudinal binomial responses:implications from two dueling paradigms

Although logistic regression is the most popular for modelling regression relationships with binary responses,many find relative risk(RR),or risk ratio,easier to interpret and prefer to use this measure of risk in regression analysis.Indeed,since Zou published his modified Poisson regression approach for modelling RR for cross-sectional data,his paper has been cited over 7000 times,demonstrating the popularity of this alternative measure of risk in regression analysis involving binary responses.As longitudinal studies have become increasingly popular in clinical trials and observational studies,it is imperative to extend Zou’s approach for longitudinal data.The two most popular approaches for longitudinal data analysis are the generalised linear mixed-effects model(GLMM)and generalised estimating equations(GEE).However,the parametric GLMM cannot be used for the extension within the current context,because Zou’s approach treats the binary response as a Poisson variable,which is at odds with the Bernoulli distribution for the binary response.On the other hand,as it imposes no mathematical model on data distributions,the semiparametric GEE is coherent with Zou’s modified Poisson regression.In this paper,we develop a GEE-based longitudinal model for binary responses to provide inference about RR.

Deciphering the‘gut-brain axis’through microbiome diversity

Incentivised by breakthroughs and data generated by the high-throughput sequencing technology,this paper proposes a distance-based framework to fulfil the emerging needs in elucidating insights from the high-dimensional microbiome data in psychiatric studies.By shifting focus from traditional methods that focus on the observations from each subject to the between-subject attributes that aggregate two or more subjects’entire feature vectors,the described approach revolutionises the conventional prescription for high-dimensional observations via microbiome diversity.To this end,we enrich the classical generalised linear models to articulate the multivariable regression relationship between distance-based variables.We also discuss a robust and computationally feasible semiparametric inference technique.Benefitting from the latest advances in the semiparametric efficiency theory for such attributes,the proposed estimators enjoy robustness and good asymptotic properties that guarantee sensitivity in detecting signals between clinical outcomes and microbiome diversity.It offers a readily implementable and easily interpretable solution for deciphering the gut–brain axis in mental health research.

Outcomes of critically ill children with pre-existing mental health conditions

Importance:Critically ill children with pre-existing mental health conditions may have an increased risk of poor health outcomes.Objective:We aimed to evaluate if pre-existing mental health conditions in critically ill pediatric patients would be associated with worse clinical outcomes,compared to children with no documented mental health conditions.Methods:This retrospective observational cohort study utilized the TriNetX electronic health record database of critically ill subjects aged 12-18 years.Data were analyzed for demographics,pre-existing conditions,diagnostic,medication,procedural codes,and mortality.Results:From a dataset of 102027 critically ill children,we analyzed 1999 subjects(284[14.2%]with a pre-existing mental health condition and 1715[85.8%]with no pre-existing mental health condition).Multivariable analysis demonstrated that death within one year was associated with the presence of pre-existing mental health conditions(odds ratio 8.97[3.48-23.15],P<0.001),even after controlling for the presence of a complex chronic condition.Interpretation:The present study demonstrates that the presence of pre-existing mental health conditions was associated with higher odds of death within 1 year after receiving critical care.However,the confidence interval was wide and hence,the findings are inconclusive.Future studies with a larger sample size may be necessary to evaluate the true long-term impact of children with pre-existing mental health conditions who require critical care services.

Real-world treatment patterns and clinical outcomes in EGFR-mutant locally advanced lung adenocarcinoma:A multi-center cohort study

Objective:To investigate the optimal management of patients with epidermal growth factor receptor gene(EGFR)mutant locally advanced non-small cell lung cancer(LA-NSCLC).Methods:Patients with unresectable stage III lung adenocarcinoma(LAC)harboring EGFR mutations from 2012 to 2018 were analyzed retrospectively,and were categorized into three groups according to the primary treat-ment:chemoradiotherpy(CRT)(group 1),combined radiation therapy(RT)and EGFR-tyrosine kinase inhibitors(TKI)with/without chemotherapy(group 2),and EGFR-TKI alone until tumor progression(group 3).Inverse probability of multiple treatment weighting(IPTW)of propensity score was used to compare overall survival(OS)and progression free survival(PFS)between treatments and account for confounding.Results:A total of 104,105,and 231 patients were categorized into groups 1,2,and 3,respectively.After IPTW adjustment,the median PFS for each group was 12.4,26.2,and 16.2 months(log-rank P<0.001),and the median OS was 51.0,67.4 and 49.3 months(log-rank P=0.084),respectively.Compared with those in group 1,patients in group 2 had significantly improved PFS[adjusted hazard ratio HR(aHR),0.40;95% confidence interval(CI):0.29,0.54;P<0.001]and OS(aHR,0.61;95%CI:0.38,0.98;P=0.039).Patients in group 3 had prolonged PFS(aHR,0.66;95%CI:0.50,0.87;P=0.003),but not OS(aHR,0.90;95%CI:0.62,1.32;P=0.595).Doubly robust IPTW analysis and multivariable Cox regression analysis yielded similar findings.Conclusions:EGFR-TKIs after chemoradiation or combined with radiation alone correlated with the longest PFS and OS(versus CRT or TKIs alone)in patients with EGFR-mutant unresectable LA-NSCLC.Well-designed prospec-tive trials were warranted.

针灸研究中组间症状积分的定量比较与组内分级定性法利弊的探讨

近年来,在中医针灸随机对照临床试验(randomized controlled trial,RCT)中恰当地应用统计学方法日益受到重视。基于假设检验的统计推断是临床试验与循证医学的基础,根据临床试验设计的基本统计原则,本文探讨了中西方文献中针灸RCT设计与分析方法学的差异。国内针刺临床试验多采用3级或4级定性法进行临床统计分析,而国外的临床试验则多采用组间症状积分的定量比较。本文以针刺治疗疼痛的临床试验为例,讨论了两种分析方法的利弊。我们认为两种方法可以兼用,但应以定量分析方法为主,分级定性法为辅,以取各自方法的所长。本文的目的是希望通过提出问题来抛砖引玉,以期引起更多的学术讨论,从而提高中医针灸临床研究的科学性和严谨性。

辛普森悖论的范例（英文）

概述:辛普森悖论普遍存在于很多领域。它具有数据的条件性和边缘性解释之间的不一致特征。在本文中,我们通过一些例子来阐述辛普森悖论是如何在连续性、分类和时间-事件数据中产生的。

Post-hoc power analysis:a conceptually valid approach for power based on observed study data

Power analysis is a key component of planning prospective studies such as clinical trials.However,some journals in biomedical and psychosocial sciences request power analysis for data already collected and analysed before acceptingmanuscripts for publication.Many have raised concerns about the conceptual basis for such post-hoc power analyses.More recently,Zhang et al showed by using simulation studies that such power analyses do not indicate true power for detecting statistical significance since post-hoc power estimates vary in the range of practical interests and can be very different from the true power.On the other hand,journals'request for information about the reliability of statistical findings in a manuscript due to small sample sizes is justified since the sample size plays an important role in the reproducibility of statistical findings.The problem is the wording of the journals'request,as the current power analysis paradigm is not designed to address journals'concerns about the reliability of the statistical findings.In this paper,we propose an alternate formulation of power analysis to provide a conceptually valid approach to the journals'wrongly worded but practically significant concern.

Early-life EV-A71 infection augments allergen-induced airway inflammation in asthma through trained macrophage immunity

Virus-induced asthma is prevalent among children,but its underlying mechanisms are unclear.Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma.Nonetheless,the relationship between systemic virus infections,such as enterovirus infection,and the ensuing effects on allergic asthma development is unknown.Early-life enterovirus infection was correlated with higher risks of allergic diseases in children.Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period.Bone marrow-derived macrophages(BMDMs)from recovered EV-A71-infected mice showed sustained innate immune memory(trained immunity)that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites.Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice,which was inhibited by 2-deoxy-D-glucose(2-DG)pretreatment,suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.