Proportional Hazards Assumption Research Articles

Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial

Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected clinical data. Eligible patients were aged 60 years or older who were receiving aspirin at a daily dose of 325 mg or less (with four or more 28-day prescriptions in the past year) and had a positive C13 urea breath test for H pylori at screening. Patients receiving ulcerogenic or gastroprotective medication were excluded. Participants were randomly assigned (1:1) to receive either a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (active eradication), or oral placebo (control), twice daily for 1 week. Participants, their general practitioners and health-care providers, and the research nurses, trial team, adjudication committee, and analysis team were all masked to group allocation throughout the trial. Follow-up was by scrutiny of electronic data in primary and secondary care. The primary outcome was time to hospitalisation or death due to definite or probable peptic ulcer bleeding, and was analysed by Cox proportional hazards methods in the intention-to-treat population. This trial is registered with EudraCT, 2011-003425-96. Between Sept 14, 2012, and Nov 22, 2017, 30 166 patients had breath testing for H pylori, 5367 had a positive result, and 5352 were randomly assigned to receive active eradication (n=2677) or placebo (n=2675) and were followed up for a median of 5·0 years (IQR 3·9-6·4). Analysis of the primary outcome showed a significant departure from proportional hazards assumptions (p=0·0068), requiring analysis over separate time periods. There was a significant reduction in incidence of the primary outcome in the active eradication group in the first 2·5 years of follow-up compared with the control group (six episodes adjudicated as definite or probable peptic ulcer bleeds, rate 0·92 [95% CI 0·41-2·04] per 1000 person-years vs 17 episodes, rate 2·61 [1·62-4·19] per 1000 person-years; hazard ratio [HR] 0·35 [95% CI 0·14-0·89]; p=0·028). This advantage remained significant after adjusting for the competing risk of death (p=0·028) but was lost with longer follow-up (HR 1·31 [95% CI 0·55-3·11] in the period after the first 2·5 years; p=0·54). Reports of adverse events were actively solicited; taste disturbance was the most common event (787 patients). H pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term. National Institute for Health and Care Research Health Technology Assessment.

125P A parametric network meta-analysis of PD-1 inhibitors in second-line treatment for advanced esophageal squamous cell carcinoma

The Network meta-analysis (NMA) of survival data is often based on the reported hazard ratios and relies on the proportional hazard (PH) assumption. To address the violation of the PH assumption, a non-proportional hazard (NPH) NMA was conducted using pseudo-patient-level data to assess the comparative efficacy of PD-1 inhibitors and chemotherapy in second-line treatment for advanced esophageal squamous cell carcinoma.

Blended Survival Curves: A New Approach to Extrapolation for Time-to-Event Outcomes from Clinical Trials in Health Technology Assessment.

Survival extrapolation is essential in cost-effectiveness analysis to quantify the lifetime survival benefit associated with a new intervention, due to the restricted duration of randomized controlled trials (RCTs). Current approaches of extrapolation often assume that the treatment effect observed in the trial can continue indefinitely, which is unrealistic and may have a huge impact on decisions for resource allocation. We introduce a novel methodology as a possible solution to alleviate the problem of survival extrapolation with heavily censored data from clinical trials. The main idea is to mix a flexible model (e.g., Cox semiparametric) to fit as well as possible the observed data and a parametric model encoding assumptions on the expected behavior of underlying long-term survival. The two are "blended" into a single survival curve that is identical with the Cox model over the range of observed times and gradually approaching the parametric model over the extrapolation period based on a weight function. The weight function regulates the way two survival curves are blended, determining how the internal and external sources contribute to the estimated survival over time. A 4-y follow-up RCT of rituximab in combination with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide alone for the first-line treatment of chronic lymphocytic leukemia is used to illustrate the method. Long-term extrapolation from immature trial data may lead to significantly different estimates with various modelling assumptions. The blending approach provides sufficient flexibility, allowing a wide range of plausible scenarios to be considered as well as the inclusion of external information, based, for example, on hard data or expert opinion. Both internal and external validity can be carefully examined. Interim analyses of trials with limited follow-up are often subject to high degrees of administrative censoring, which may result in implausible long-term extrapolations using standard approaches.In this article, we present an innovative methodology based on "blending" survival curves to relax the traditional proportional hazard assumption and simultaneously incorporate external information to guide the extrapolation.The blended method provides a simple and powerful framework to allow a careful consideration of a wide range of plausible scenarios, accounting for model fit to the short-term data as well as the plausibility of long-term extrapolations.

Development and validation of a population-based prognostic nomogram for primary colorectal lymphoma patients.

Primary colorectal lymphoma (PCL) is a relatively rare cancer type, constituting 15%-20% of primary gastrointestinal lymphoma and <1% of all colorectal malignancies. Given its low incidence, standard guidelines for case management are not available. This large population-based study aims to construct a nomogram to predict survival outcomes and to help tailor individualised treatment decisions in patients with PCL. A retrospective cohort study of patients with PCL was developed using data registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1990 and 2015. The prognostic nomogram was constructed using R software after univariate and multivariate Cox regression analyses. Cox regression models were assessed using the proportional hazards (PH) assumption. Kaplan-Meier survival analysis was used to analyze survival outcomes. The 1-, 3-, 5-, and 10-year area under the curve (AUC) values of ROC (receiver operating characteristic) curves, the concordance index (C-index), and calibration curves were calculated to verify the predictive performance of the nomogram. The final nomogram included age, Ann Arbor stage, histology, location, marital status, and treatment, all of which had an important effect on overall survival (OS). The discrimination of the nomogram revealed good prognostic accuracy and clinical applicability as indicated by C-index values of 0.713 and 0.711 in the training and validation cohorts, respectively. Kaplan-Meier survival curves were significantly different for distinct conditions. This study developed and validated a six-factor nomogram for predicting PCL patient prognosis. This nomogram might be useful for risk stratification and making better individualised decisions for PCL patients.

Temporalis muscle thickness predicts early relapse and short survival in primary CNS lymphoma.

Most patients with primary CNS lymphoma (PCNSL) achieve durable remission whereas a minority die in the first year. Sarcopenia is a powerful predictor of mortality in the brain and systemic cancers. Temporalis muscle thickness (TMT) is a validated radiographic measure of sarcopenia. We hypothesized that patients with thin TMT at diagnosis would have early progression and short survival. Two blinded operators retrospectively measured TMT in 99 consecutive brain MRIs from untreated patients with PCNSL. We generated a receiver operator characteristic curve and chose a single threshold defining thin TMT in all patients as <5.65 mm, at which specificity and sensitivity for 1-year progression were 98.4% and 29.7% and for 1-year mortality were 97.4% and 43.5% respectively. Those with thin TMT were both more likely to progress (P < .001) and had higher rates of mortality (P < .001). These effects were independent of the effect of age, sex, and Eastern Cooperative Oncology Group performance status in a cox regression. Memorial Sloan Kettering Cancer Center score did not predict progression-free survival or overall survival as well as TMT. Patients with thin TMT received fewer cycles of high-dose methotrexate and were less likely to receive consolidation but neither variable could be included in the Cox regression due to violation of the proportional hazards assumption. We conclude that PCNSL patients with thin TMT are at high risk for early relapse and short survival. Future trials should stratify patients by TMT to avoid confounding.

Prevalence and mortality of infective endocarditis among community acquired and healthcare acquired staphylococcus aureus bacteremia: a nationwide study

Abstract Background Staphylococcus aureus bacteremia (SAB) may be community acquired or healthcare acquired, and prior small studies have suggested that the place of acquisition impacts the subsequent prevalence of infective endocarditis (IE) and also patient outcomes. However, data on this relationship is sparse and this may influence optimal work-up and treatment of these patients. Purpose To examine the prevalence of IE among patients with community acquired and healthcare acquired SAB. Further, to investigate one-year mortality among patients with SAB-IE stratified by place of acquisition. Methods Patients with first-time SAB from 2010–2018 were identified using Danish nationwide registries and categorized into either community acquired (no health care contact within 30 days) or healthcare acquired (either a. hospital admission or emergency room visit within 30 days, b. SAB &amp;gt;48 hours after hospital admission, or c. out-patient dialysis). SAB was then related to IE and compared between the two study groups using multivariable adjusted logistic regression analysis. The one-year mortality was compared using multivariable adjusted Cox proportional hazard analysis for patients with SAB-IE stratified by place of bacteremia acquisition. The proportional hazard assumption was violated, and a landmark analysis was conducted comparing mortality between groups with a) 0–40 days of follow-up, and b) 40–365 days of follow-up. Results We identified 13,040 patients with SAB; 5,512 (62.3% male, median age 71.0 years) were community acquired and 7,528 (63.1% male, median age 69.0 years) were healthcare acquired. The prevalence of IE was 12.0% among patients with community acquired SAB and 6.6% among patients with healthcare acquired SAB, Figure. After accounting for patient characteristics, community acquired SAB was associated with a higher odds of IE as compared with healthcare acquired SAB, adjusted OR=2.12 (95% CI: 1.86–2.41). Sex- and age groups did not modify this association. The one-year mortality was 37.3% for community acquired SAB-IE and 47.3% for healthcare acquired SAB-IE, Figure. With up to 40 days after IE admission, no difference in associated mortality was seen between groups in adjusted analysis, HR=1.07 (95% CI: 0.83–1.37) with healthcare acquired SAB-IE as reference group. Beyond 40 days of follow-up patients with community acquired SAB-IE was associated with a lower mortality as compared with healthcare acquired SAB-IE, HR=0.71 (95% CI: 0.53–0.95). Conclusion Community acquired SAB was associated with twice the odds of IE as compared with healthcare acquired SAB. SAB-IE was associated with high mortality rates, with no difference between groups at short-term follow-up, however long-term follow-up revealed an associated lower mortality in patients with community acquired SAB-IE. These findings indicate a need for an intensified work-up strategy for IE in patients with community acquired SAB. Funding Acknowledgement Type of funding sources: None.

Ablation therapies for paroxysmal atrial fibrillation: a systematic review and patient-level network meta-analysis

Abstract Background Despite numerous promising trials, catheter ablation is still regarded as a second-line alternative to antiarrhythmic drugs (AAD) in the treatment of paroxysmal atrial fibrillation (PAF). There remains a role for a broad comparison of the effectiveness of various ablation therapies against each other, and versus AAD. Purpose To conduct a systematic review and network meta-analysis of ablation therapies and AAD in the treatment of PAF. Ablation therapies were hypothesized to be superior to AAD in preventing atrial fibrillation (AF) recurrence. Methods An electronic literature search was conducted to retrieve randomized controlled trials or propensity score-matched studies comparing freedom from AF recurrence among any combination of ablation modalities or AAD. Kaplan-Meier curves and risk tables for this outcome were graphically reconstructed to extract individual patient data (IPD). A Frequentist network meta-analysis (NMA) was performed using the derived hazard ratios (HRs) of each study to compare various ablation therapies and AAD. Two separate NMAs were also conducted with restricted mean survival time (RMST) analysis, using RMST absolute differences and ratios, in light of violation of the proportional-hazards assumption. Treatment strategies were ranked using P-scores. Pairwise comparisons were also performed between treatment pairs with three or more studies reporting direct comparisons. Results Across 24 studies comparing six ablation therapies, comprising 5274 patients, Frequentist NMA-derived HRs of AF recurrence compared to AAD were 0.35 (95% CI: 0.26–0.48) for cryoballoon ablation (CBA), 0.33 (95% CI: 0.25–0.45) for radiofrequency ablation (RFA), 0.21 (95% CI: 0.09–0.49) for combined CBA and RFA, 0.20 (95% CI: 0.11–0.39) for hot-balloon ablation (HBA), 0.44 (95% CI: 0.16–1.22) for laser-balloon ablation, and 0.33 (95% CI: 0.19–0.56) for pulmonary vein ablation catheter. RMST-based NMAs similarly showed a significant benefit of all ablation therapies over AAD in preventing AF recurrence. Although none of the HRs between pairs of ablation modalities were significant, P-scores for HBA and combined CBA and RFA were consistently higher than those of other treatments. Independent pairwise comparisons of RFA and CBA versus AAD were greatly in favor of ablation (shared-frailty HR=0.24, 95% CI: 0.19–0.31, p&amp;lt;0.001; shared-frailty HR=0.44, 95% CI: 0.35–0.56, p&amp;lt;0.001, respectively). Conclusions To our knowledge, this is the first network meta-analysis comparing a wide range of ablation therapies to AAD, synthesizing IPD from high-quality studies in three separate NMA models. The advantage of ablation therapies over AAD in preventing AF recurrence was consistently found across all three models. This strongly suggests that ablation should replace AAD as the first-line treatment for PAF in patients who are fit for the procedure. Moreover, the promising results of HBA underscore the need for more high-quality trials to be conducted. Funding Acknowledgement Type of funding sources: None.

A family of slope tests for comparing survival curves under nonproportional hazards

Censored data are nearly ubiquitous in survival analysis. If the proportional hazard assumption is invalid, traditional test methods, such as the log-rank tests, rapidly lose power. In this article, a new slope strategy is presented to improve the power of the test. The aim of this study is to establish effective tests that are familiar in biomedical research and medical practice for censored data. Four tests based on slope are proposed in this article, and Monte Carlo simulations with different survival curves, sample sizes, and censoring rate scenarios are performed to evaluate the test power. Four common tests, the log-rank test, Gehan–Wilcoxon test, and Fleming–Harrington with different parameters, are compared with four new slope tests. The slope tests are more effective when the censoring rate is greater than or equal to 30%, especially for scenarios involving early hazard function differences. Two clinical cases also indicate that the proposed slope methods can detect differences for real data. Slope tests may supplement computing methods of survival curve tests, and they will be more useful when considering higher censoring rates.

A flexible-hazards cure model with application to patients with soft tissue sarcoma.

In medical research, it is often of great interest to have an accurate estimation of cure rates by different treatment options and for different patient groups. If the follow-up time is sufficiently long and the sample size is large, the proportion of cured patients will make the Kaplan-Meier estimator of survival function have a flat plateau at its tail, whose value indicates the overall cure rate. However, it may be difficult to estimate and compare the cure rates for all the subsets of interest in this way, due to the limit of sample sizes and curse of dimensionality. In the current literature, most regression models for estimating cure rates assume proportional hazards (PH) between different subgroups. It turns out that the estimation of cure rates for subgroups is highly sensitive to this assumption,so more flexible models are needed, especially when this PH assumption is clearly violated. We propose a new cure model to simultaneously incorporate both PH and non-PH scenarios for different covariates. We develop a stable and easily implementable iterative procedure for parameter estimation through maximization of the nonparametric likelihood function. The covariance matrix is estimated by adding perturbation weights to the estimation procedure. In simulation studies, the proposed method provides unbiased estimation for the regression coefficients, survival curves, and cure rates given covariates,while existing models are biased. Our model is applied to a study of stage III soft tissue sarcoma and provides trustworthy estimation of cure rates for different treatment and demographic groups.

Relationship between corticosteroid use and incidence of ventilator-associated pneumonia in COVID-19 patients: a retrospective multicenter study

BackgroundVentilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP.MethodsPlanned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox’s proportional hazard models with adjustment on pre-specified confounders.ResultsAmong the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21.ConclusionsNo significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.

Generalized pairwise comparisons for censored data: An overview.

The method of generalized pairwise comparisons (GPC) is an extension of the well-known nonparametric Wilcoxon-Mann-Whitney test for comparing two groups of observations. Multiple generalizations of Wilcoxon-Mann-Whitney test and other GPC methods have been proposed over the years to handle censored data. These methods apply different approaches to handling loss of information due to censoring: ignoring noninformative pairwise comparisons due to censoring (Gehan, Harrell, and Buyse); imputation using estimates of the survival distribution (Efron, Péron, and Latta); or inverse probability of censoring weighting (IPCW, Datta and Dong). Based on the GPC statistic, a measure of treatment effect, the "net benefit," can be defined. It quantifies the difference between the probabilities that a randomly selected individual from one group is doing better than an individual from the other group. This paper aims at evaluating GPC methods for censored data, both in the context of hypothesis testing and estimation, and providing recommendations related to their choice in various situations. The methods that ignore uninformative pairs have comparable power to more complex and computationally demanding methods in situations of low censoring, and are slightly superior for high proportions (>40%) of censoring. If one is interested in estimation of the net benefit, Harrell's c index is an unbiased estimator if the proportional hazards assumption holds. Otherwise, the imputation (Efron or Peron) or IPCW (Datta, Dong) methods provide unbiased estimators in case of proportions of drop-out censoring up to 60%.

Recurrent events analysis with piece-wise exponential additive mixed models

Recurrent events analysis plays an important role in many applications, including the study of chronic diseases or recurrence of infections. Historically, many models for recurrent events have been variants of the Cox model. In this article we introduce and describe the application of the piece-wise exponential Additive Mixed Model (PAMM) for recurrent events analysis and illustrate how PAMMs can be used to flexibly model the dependencies in recurrent events data. Simulations confirm that PAMMs provide unbiased estimates as well as equivalence to the Cox model when proportional hazards are assumed. Applications to recurrence of staphylococcus aureus and malaria in children illustrate the estimation of seasonality, bivariate non-linear effects, multiple timescales and relaxation of the proportional hazards assumption via time-varying effects. The R package pammtools is extended to facilitate estimation and visualization of PAMMs for recurrent events data.

Immunotherapy in advanced kidney cancer: an alternative meta-analytic method using reconstructed survival data in case of proportional hazard assumption violation

BackgroundWith the advent of immuno-oncology compounds in randomized trials, we observe more and more survival curves crossing. From a statistical standpoint this corresponds to violation of the proportional hazard assumption. When this occurs, the hazard ratio from the Cox regression is not reliable as an estimate. Herein, we aimed to identify the most appropriate IO-based therapy for metastatic renal cell carcinoma applying an alternative method to overcome the issue of hazard assumption violation for meta-analyses.MethodsPubmed, EMBASE, Web of Science and Scopus databases were searched. Only phase III randomized clinical trials on IO-IO (nivo-ipi) or IO-TKI combinations were included. An algorithm to obtain survival data from published Kaplan-Meier curves was used to reconstruct data on overall survival (OS), progression-free survival (PFS) and duration of response (DoR). Differences in restricted mean survival time (RMST) were used for comparisons.Resultsindividual survival data from 4,206 patients from five trials were reconciled. Patients who received nivo-ipi or IO-TKI had better OS, PFS and DoR relative to sunitinib (all p<0.001). Patients who received IO-TKI had similar OS and PFS relative to nivo-ipi, with a 36-month ΔRMST of -0.55 (95% CI: -1.71-0.60; p=0.3) and -1.5 (95% CI: -2.9-0.0; p=0.051) months, respectively. Regarding DoR, patients who received nivo-ipi had longer duration of response relative to IO-TKI, with a 24-month ΔRMST of 1.5 (95% CI: 0.2-2.8; p=0.02) months.ConclusionDespite overall similar OS and PFS for patients receiving nivo-ipi and IO-TKI combinations, DoR was more favorable in patients who received nivo-ipi compared to IO-TKI. A meta-analysis based on differences in RMST is a useful alternative whenever the proportional hazard assumption is violated. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021241421.

Clinical Prediction Nomograms to Assess Overall Survival and Disease-Specific Survival of Patients with Salivary Gland Adenoid Cystic Carcinoma.

Aim Salivary gland adenoid cystic carcinoma (SACC) is the second highest incidence of malignant salivary gland tumor. The purpose of this study was to establish nomograms combined with SACC patients based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods Patients with SACC were included in the SEER∗Stat Database from 2004 to 2016. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to filter potential prognostic clinical variables. Multivariate analysis from the Cox proportional hazards model was performed to determine the independent prognostic factors on overall survival (OS) and disease-specific survival (DSS), applied to develop nomograms. The Schönfeld residual test verified the proportional hazard assumption. The discrimination and consistency of nomograms was assessed and validated according to concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration curves using an internal 1,000 times bootstrap resampling. The nomogram's net clinical benefit was assessed through decision curve analysis (DCA). Results A total of 658 patients with SACC were included. Age, T stage, N stage, M stage, histologic grade, and surgery were independent prognostic factors for OS and DSS. Based on these independent prognostic factors, nomograms were developed to predict 3-, 5-, and 10-year OS and DSS. In the validation of 1,000 times bootstrap resampling, the C-index and ROC curves had good discriminatory ability. The calibration curves indicated excellent consistency between the predicted and actual survival results in the nomograms. The DCA curves demonstrated that the nomograms had good clinical benefit and were superior to the TNM stage and other variables. Conclusions Two nomograms developed in this study precisely predicted the 3-, 5-, and 10-year OS and DSS rates of patients with SACC in accordance with independent prognostic factors, and their clinical value is better than TNM staging, providing a prognostic reference for other SACC patients.

Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations.

Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

Time to recovery from severe acute malnutrition and its predictors among children aged 6-59 months at Asosa general hospital, Northwest Ethiopia. A retrospective follow up study.

BackgroundSevere Acute Malnutrition (SAM) has become a major public health challenge in developing countries including Ethiopia, especially among the underprivileged population. Ethiopia is among the developing countries with the highest burden of acute malnutrition among under-five children. Though, plenty of studies were done on the magnitude of acute malnutrition among under-five children in Ethiopia, there is a limited evidence on time to recovery from SAM and its predictors among children aged 6–59 months in Ethiopia, particularly in the study area.ObjectivesThe study was aimed to assess the time to recovery from SAM and its predictors among children aged 6–59 months at Asosa general hospital (AGH), Benishangul Gumuz, Ethiopia.MethodsA Five years retrospective follow-up study design was employed among 454 children admitted with SAM in AGH from January 2015 to December 2019. The data were extracted from the patient medical records using checklist. The data were coded and entered into Epi-Data 3.1; then exported to STATA/SE-14 for analysis. Proportional Cox regression was performed to identify predictors of recovery time. A proportional hazard assumption was checked. Variables with AHR at 95% CI and P-value less than 0.05 in the multivariable Cox proportional regression was considered as significant predictors of recovery time.FindingsAmong the 454 included records of children with SAM, 65.4% (95%CI: 50.1, 69.2) of them were recovered at the end of the follow-up with a median recovery time of 15 IQR(11–18)days. The incidence rate of recovery was 5.28 per 100 child days’ observations. Being HIV Negative (AHR = 2.19: 95% CI 1.28, 3.73), Marasmic (AHR = 1.69: 95% CI 1.18, 2.42), and marasmic-kwashiorkor child (AHR = 1.60: 95% CI (1.09, 2.37) independently predicted recovery time.ConclusionsThough the time to recovery from severe acute malnutrition was in the acceptable range, the proportion of recovery was found to be low in the study area compared to sphere standard. The prognosis of children with severe acute malnutrition was determined by the HIV status of the child and the type of malnutrition experienced. Further strengthening of malnutrition therapeutic centers and routine checkup of the nutritional status of HIV positive children should be emphasized to reduce child mortality and morbidity from under-nutrition.

Investigations of methods for multiple time-to-event endpoints:A chronic myeloid leukemia data analysis.

In randomized controlled trials, multiple time-to-event endpoints are commonly used to determine treatment effects. However, choosing an appropriate method to address multiple endpoints, according to different purposes of clinical practice, is a challenge for researchers. We applied single endpoint, composite endpoint and win ratio analysis to chronic myeloid leukemia (CML) data to illustrate the distinctions with different multiple endpoints, including relapse, recoveryand death after transplantation. Regarding relapse and death, the hazard ratio in single endpoint analysis(HRs ) were 1.281 (95% CI: 1.061-1.546) and hazard ratio in composite endpoint analysis(HRc ) were 1.286 (95% CI: 1.112-1.486) and 1/WR (win ratio) was 1.292 (95% CI: 1.115-1.497) indicated a similar negative effect for non-prophylaxis patients. However, when considering recovery and death, the corresponding HRs = 1.280 (95% CI: 1.056-1.552) may not be enough to describe the effect on death with nonproportional hazards (p < 0.05), and for the composite endpoint analysis, the HRc = 0.828 (95% CI: 0.740-0.926) cannot quantify and interpret the clinical effect on the composite endpoint with the combination of recovery and death, while the 1/WR = 1.351 (95% CI: 1.207-1.513) showed an unfavourable effect for non-prophylaxis patients CONCLUSIONS: When dealing with multiple endpoints, single endpoints, researchers may choose single endpoints, composite endpoints and WR analysis due to different clinical applications and purposes. However, both single and composite endpoint analyses are hazard-based measures, and thus, the proportional hazards assumption should be considered. Moreover, composite endpoint analysis should be applied for endpoints with similar clinical meanings but not opposing implications. Win ratio analysis can be considered for different clinical importance of multiple endpoints, but the meaning of 'winner'needs to be specified for desired or undesired endpoints.

High plasma lipoprotein lipase is associated with a lower risk for future major adverse cardiovascular events in patients following carotid endarterectomy

Background and Aims : Since carotid plaque intraplaque hemorrhage is associated with plaque progression leading to cardiovascular events, we hypothesized that blood proteins associated with carotid plaque IPH are also likely to be associated with MACE after CEA.Methods: In 688 patients undergoing CEA of the Athero-Express biobank, we measured 276 proteins using three OLINK® proteomics immunoassays in preoperative blood samples. We analyzed the association of proteins with IPH using logistic regression analyses. In addition, we analyzed the association of candidate proteins with the three-year postoperative risk of MACE (including stroke, myocardial infarction, and cardiovascular death).Results: A total of 130 patients (18,9%) developed MACE during the three-year follow-up. We found six proteins to be significantly associated with IPH, from which Lipoprotein Lipase was associated with the postoperative risk of MACE undergoing CEA. We analyzed the association of LPL with MACE within two different time periods, since the proportional hazard assumption for LPL was violated. High LPL was associated with an increased risk for 30-day MACE (adjusted HR per SD:1.60(1.10-2.30), p=0.014), while high LPL was associated with a lower risk for MACE within 30-days up and till 3-year (adjusted HR per SD:0.80(0.65-0.99), p=0.036).Conclusions: Of the six proteins that were associated with IPH, only LPL was associated with the risk for MACE. High LPL was independently associated with an increased risk of MACE within the first 30-days after CEA, while high LPL was associated with a lower risk of MACE in the period 30 days up and till 3-years. Background and Aims : Since carotid plaque intraplaque hemorrhage is associated with plaque progression leading to cardiovascular events, we hypothesized that blood proteins associated with carotid plaque IPH are also likely to be associated with MACE after CEA. Methods: In 688 patients undergoing CEA of the Athero-Express biobank, we measured 276 proteins using three OLINK® proteomics immunoassays in preoperative blood samples. We analyzed the association of proteins with IPH using logistic regression analyses. In addition, we analyzed the association of candidate proteins with the three-year postoperative risk of MACE (including stroke, myocardial infarction, and cardiovascular death). Results: A total of 130 patients (18,9%) developed MACE during the three-year follow-up. We found six proteins to be significantly associated with IPH, from which Lipoprotein Lipase was associated with the postoperative risk of MACE undergoing CEA. We analyzed the association of LPL with MACE within two different time periods, since the proportional hazard assumption for LPL was violated. High LPL was associated with an increased risk for 30-day MACE (adjusted HR per SD:1.60(1.10-2.30), p=0.014), while high LPL was associated with a lower risk for MACE within 30-days up and till 3-year (adjusted HR per SD:0.80(0.65-0.99), p=0.036). Conclusions: Of the six proteins that were associated with IPH, only LPL was associated with the risk for MACE. High LPL was independently associated with an increased risk of MACE within the first 30-days after CEA, while high LPL was associated with a lower risk of MACE in the period 30 days up and till 3-years.

The influence of the dietary intake of vitamin C and vitamin E on the risk of gastric intestinal metaplasia in a cohort of Koreans.

Studies have suggested that the dietary intake of antioxidant vitamins, such as vitamin C and vitamin E, has a potential role in inhibiting gastric carcinogenesis. The present study investigated the effect of antioxidant vitamins on the incidence of gastric intestinal metaplasia (GIM). This study included 67,657 Koreans free of GIM who periodically underwent health check-ups. Dietary intake was assessed by a semiquantitative food frequency questionnaire based on the Korean National Health and Nutrition Examination Survey. Participants were categorized into 4 groups by quartiles of dietary vitamin C and vitamin E intake. The Cox proportional hazard assumption was used to determine the multivariable hazard ratio (HR) and 95% confidence interval (95% CI) for GIM. The third and fourth quartiles of vitamin C intake had a lower risk of GIM than the first quartile (multivariable-adjusted HR, 0.95; 95% CI, 0.88 to 1.03 in the second quartile, HR, 0.88; 95% CI, 0.81 to 0.97 in the third quartile, and HR, 0.85; 95% CI, 0.76 to 0.95 in the fourth quartile). Vitamin E intake greater than the second quartile level was significantly associated with a lower risk of GIM than the first quartile (multivariable-adjusted HR, 0.90; 95% CI, 0.82 to 0.97 in the second quartile, HR, 0.90; 95% CI, 0.82 to 0.99 in the third quartile, and HR, 0.83; 95% CI, 0.74 to 0.94 in the fourth quartile). This association was observed only in the subgroup analysis for men. Higher dietary intake of vitamin C and vitamin E was associated with a lower risk of GIM.

Bayesian analysis for partly linear Cox model with measurement error and time-varying covariate effect.

The Cox proportional hazards model is commonly used to estimate the association between time-to-event and covariates. Under the proportional hazards assumption, covariate effects are assumed to be constant in the follow-up period of study. When measurement error presents, common estimation methods that adjust for an error-contaminated covariate in the Cox proportional hazards model assume that the true function on the covariate is parametric and specified. We consider a semiparametric partly linear Cox model that allows the hazard to depend on an unspecified function of an error-contaminated covariate and an error-free covariate with time-varying effect, which simultaneously relaxes the assumption on the functional form of the error-contaminated covariate and allows for nonconstant effect of the error-free covariate. We take a Bayesian approach and approximate the unspecified function by a B-spline. Simulation studies are conducted to assess the finite sample performance of the proposed approach. The results demonstrate that our proposed method has favorable statistical performance. The proposed method is also illustrated by an application to data from the AIDS Clinical Trials Group Protocol 175.