Indirect Treatment Comparison/Network Meta-Analysis Study Questionnaire to Assess Relevance and Credibility to Inform Health Care Decision Making: An ISPOR-AMCP-NPC Good Practice Task Force Report

Despite the great realized or potential value of network meta-analysis of randomized controlled trial evidence to inform health care decision making, many decision makers might not be familiar with these techniques. The Task Force developed a consensus-based 26-item questionnaire to help decision makers assess the relevance and credibility of indirect treatment comparisons and network meta-analysis to help inform health care decision making. The relevance domain of the questionnaire (4 questions) calls for assessments about the applicability of network meta-analysis results to the setting of interest to the decision maker. The remaining 22 questions belong to an overall credibility domain and pertain to assessments about whether the network meta-analysis results provide a valid answer to the question they are designed to answer by examining 1) the used evidence base, 2) analysis methods, 3) reporting quality and transparency, 4) interpretation of findings, and 5) conflicts of interest. The questionnaire aims to help readers of network meta-analysis opine about their confidence in the credibility and applicability of the results of a network meta-analysis, and help make decision makers aware of the subtleties involved in the analysis of networks of randomized trial evidence. It is anticipated that user feedback will permit periodic evaluation and modification of the questionnaire.     

A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma

ObjectivesNetwork meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results.MethodsThe following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA.ResultsFor progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time.ConclusionsWhen the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.     

Network Meta-Analysis: Development of a Three-Level Hierarchical Modeling Approach Incorporating Dose-Related Constraints

BackgroundNetwork meta-analysis (NMA) is commonly used in evidence synthesis; however, in situations in which there are a large number of treatment options, which may be subdivided into classes, and relatively few trials, NMAs produce considerable uncertainty in the estimated treatment effects, and consequently, identification of the most beneficial intervention remains inconclusive.ObjectiveTo develop and demonstrate the use of evidence synthesis methods to evaluate extensive treatment networks with a limited number of trials, making use of classes.MethodsUsing Bayesian Markov chain Monte Carlo methods, we build on the existing work of a random effects NMA to develop a three-level hierarchical NMA model that accounts for the exchangeability between treatments within the same class as well as for the residual between-study heterogeneity. We demonstrate the application of these methods to a continuous and binary outcome, using a motivating example of overactive bladder. We illustrate methods for incorporating ordering constraints in increasing doses, model selection, and assessing inconsistency between the direct and indirect evidence.ResultsThe methods were applied to a data set obtained from a systematic literature review of trials for overactive bladder, evaluating the mean reduction in incontinence episodes from baseline and the number of patients reporting one or more adverse events. The data set involved 72 trials comparing 34 interventions that were categorized into nine classes of interventions, including placebo.ConclusionsBayesian three-level hierarchical NMAs have the potential to increase the precision in the effect estimates while maintaining the interpretability of the individual interventions for decision making.     

Searching for Indirect Evidence and Extending the Network of Studies for Network Meta-Analysis: Case Study in Venous Thromboembolic Events Prevention Following Elective Total Knee Replacement Surgery

ObjectiveTo evaluate the effect of study identification methods and network size on the relative effectiveness and cost-effectiveness of recommended pharmacological venous thromboembolic events (VTEs) prophylaxis for adult patients undergoing elective total knee replacement surgery in the United Kingdom.MethodsA stepwise literature search specifically designed to identify indirect evidence was conducted to extend the original clinical review from the latest National Institute for Health and Care Excellence (NICE) VTE technology appraisal. Different network sizes or network orders, based on the successive searches, informed three network meta-analyses (NMAs), which were compared with a replicated base case. The resulting comparative estimates were inputted in an economic model to investigate the effect of network size on cost-effectiveness probabilities.ResultsSearches increased the number of indirect comparisons between VTE interventions, progressively widening the relevant network of studies for NMA. Precision around mean relative treatment effects was increased as the network was extended from the base case to first-order NMA, but further extensions had limited effect. Cost-effectiveness analysis results were largely insensitive to variation in clinical inputs from the different NMA orders.ConclusionsNo standard methodology is currently recommended by NICE to identify the most relevant network of studies for NMA. Our study showed that optimizing the identification of studies for NMA can extend the evidence base for analysis and reduce the uncertainty in relative effectiveness estimates. Although in our example network extensions did not affect the acceptability of available treatments in VTE prevention based on cost-effectiveness results, it may in other applications.     

The Potential Clinical and Economic Outcomes of Pharmacogenomic Approaches to EGFR-Tyrosine Kinase Inhibitor Therapy in Non–Small-Cell Lung Cancer

Objectives:  Pharmacogenomic applications in oncology offer significant promise, but the clinical and economic implications remain unclear. The objective of this study was to evaluate the potential cost-utility of implementing epidermal growth factor receptor (EGFR) testing before initiating second-line therapy for advanced refractory non–small-cell lung cancer (NSCLC).
Methods:  We developed a decision analytic model to evaluate the cost-utility of EGFR protein expression or gene copy number testing compared to standard care with erlotinib in refractory advanced NSCLC patients. Costs and utilities were obtained from publicly available sources. We performed sensitivity analyses to evaluate uncertainty in the results.
Results:  The quality-adjusted life expectancies for erlotinib, EGFR protein expression testing, and gene copy number testing were: 0.44, 0.48, and 0.50 quality-adjusted life years (QALYs); and the costs were: $57,238, $63,512, and $66,447, respectively. The most cost-effective testing option, EGFR gene copy number testing, produced an incremental cost-effectiveness ratio of $162,018/QALY compared to no testing (erlotinib). The results were most sensitive to the survival estimates, health state utilities, and cost of disease progression. In the probabilistic sensitivity analyses, erlotinib without testing was the optimal treatment strategy until the $150,000/QALY willingness-to-pay threshold, after which gene copy testing was optimal. The discounted expected value of perfect information at a $100,000/QALY threshold in the USA over 5 years was $31.4 million.
Conclusions:  The study results suggest that EGFR pharmacogenomic testing has the potential to improve quality-adjusted life expectancy in the treatment of refractory NSCLC by a clinically meaningful margin at a value commensurate with the approved therapies in this setting. Additional research in this area is warranted.     

Bazedoxifene versus Oral Bisphosphonates for the Prevention of Nonvertebral Fractures in Postmenopausal Women with Osteoporosis at Higher Risk of Fracture: A Network Meta-Analysis

ObjectiveTo compare the efficacy of bazedoxifene and oral bisphosphonates for the prevention of nonvertebral fractures (NVFs) in women with higher risk of postmenopausal osteoporosis (i.e., the Fracture Risk Assessment Tool [FRAX] score ≥ 20%), based on currently available evidence from randomized controlled trials.MethodsRandomized controlled trials evaluating the NVF relative risk reduction (RRR) with oral bisphosphonates or bazedoxifene were identified by a systematic literature review and combined by means of a network meta-analysis. A subgroup of patients with a FRAX score of 20% or more in the bazedoxifene phase III osteoporosis study was selected as the population of interest on the basis of the bazedoxifene label. In one analysis (analysis 1), the placebo response of the subgroup with a FRAX score of 20% or more was the benchmark to select comparable bisphosphonate trials. Additional analyses incorporated the aggregate data from the bisphosphonate trials with all the FRAX subgroups (analysis 2) or with the individual patient data from the bazedoxifene trial (analysis 3).ResultsNine identified bisphosphonate trials (alendronate, ibandronate, risedronate; N = 23,440 patients) with a similar placebo response as observed for the subgroup of high risk patients in the bazedoxifene trial were included in analysis 1. The results of the network meta-analysis of this study set suggest that bazedoxifene is expected to have an RRR of 0.43 (95% credible interval [CrI] ?0.19 to 0.72) versus alendronate, 0.58 (95% CrI 0.05–0.81) versus ibandronate, and 0.39 (95% CrI ?0.29 to 0.70) versus risedronate. Analyses in which treatment effects with bisphosphonates were projected to a population with a FRAX score of 20% or more with meta-regression approaches (analysis 2 and analysis 3) provide similar findings.ConclusionBased on an indirect comparison of randomized trials, bazedoxifene is expected to have at least a comparable RRR of NVF as alendronate, ibandronate, and risedronate in women with higher risk of postmenopausal osteoporosis.     

Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression

Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06–1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08–1.35) and non-medics (RR = 1.18, 95% CI = 1.07–1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.     

Costs of First-Line Doublet Chemotherapy and Lifetime Medical Care in Advanced Non–small-Cell Lung Cancer in the United States

ObjectivesThe purpose of this study was to identify total lifetime medical-care costs and costs associated with first-line chemotherapy treatment among older patients with stage IIIB/IV non–small-cell lung cancer treated with commonly used two-drug chemotherapy (“doublet”) regimens in the United States.MethodsStudy patients included individuals aged 65 years and older who received a diagnosis of stage IIIB/IV non–small-cell lung cancer in a Surveillance, Epidemiology and End Results cancer registry between 1997 and 2002 and who received first-line treatment with commonly used doublet regimens. Patients were followed retrospectively in the Surveillance, Epidemiology and End Results—Medicare database to evaluate lifetime medical-care costs and costs while on first-line chemotherapy treatment. Pairwise comparisons of treatment costs were estimated by using nonparametric bootstrap methods.ResultsLifetime medical-care costs totaled approximately $70,000 and on-treatment costs for first-line chemotherapy totaled approximately $30,000 among study patients and were dominated by hospitalization and physician costs. Lifetime costs were significantly higher among patients treated with first-line cisplatin/carboplatin (platinum) plus a taxane compared with those who received platinum plus gemcitabine [difference: $4781 ($1558–$8039)] or other doublet therapy [difference: $5961 ($2333–$9614)]. Total on-treatment costs for first-line chemotherapy were significantly higher among patients treated with platinum plus a taxane compared with those who received platinum plus gemcitabine [difference: $5825 ($3872–$7770)], platinum plus another agent [difference: $5968 ($3995–$7975)], or another doublet therapy [difference: $3663 ($1620–$5740)].ConclusionsThere is a cost differential between first-line doublet regimens in terms of lifetime and on-treatment costs. Although doublet therapy with platinum and a taxane was the most frequently utilized regimen, it was associated with the highest lifetime and on-treatment costs.     

Evaluating Matching‐Adjusted Indirect Comparisons in Practice: A Case Study of Patients with Attention‐Deficit/Hyperactivity Disorder

Differences in patient characteristics across trials may bias efficacy estimates from indirect treatment comparisons. To address this issue, matching‐adjusted indirect comparison (MAIC) measures treatment efficacy after weighting individual patient data to match patient characteristics across trials. To date, however, there is no consensus on how best to implement MAIC. To address this issue, we applied MAIC to measure how two attention‐deficit/hyperactivity disorder (ADHD) treatments (guanfacine extended release and atomoxetine hydrochloride) affect patients' ADHD symptoms, as measured by the ADHD Rating Scale IV score. We tested MAIC sensitivity to: matched patient characteristics, matched statistical moments, weighting matrix, and placebo‐arm matching (i.e., matching on outcomes in the placebo arm). After applying MAIC, guanfacine and atomoxetine had similar reductions in ADHD symptoms (Δ: 0.4, p < 0.737). The results were similar for three of four sensitivity analyses. When we applied MAIC with placebo‐arm matching, however, guanfacine reduced symptoms more than atomoxetine (Δ: ?3.9, p < 0.004). We discuss the implication of this finding and advise MAIC practitioners to carefully consider the use of placebo‐arm matching, depending on the presence of residual confounding across trials. Copyright © 2016 John Wiley & Sons, Ltd.     

Physical Activity and Risk of Breast Cancer: A Meta-Analysis of 38 Cohort Studies in 45 Study Reports

Objectives

To evaluate and quantify the association between physical activity (PA) and risk of breast cancer.

上海市宝山区肺癌危险因素的病例对照研究

[目的]探讨室内装修及其他生活危险因素与肺癌的关系。[方法]采用1：1配对的病例对照研究方法,以2007年确诊的163例肺癌患者为病例组,选择在年龄、性别、住址方面相匹配的非肿瘤患者为对照组,进行条件Logistic回归分析。[结果]多因素分析结果存在统计学意义的因素包括肿瘤家族史（OR=4.090,P=0.001）、被动吸烟（OR=2.528,P=0.009）、住房10年内有过装修（OR=2.074,P=0.039）、室内经常通风（OR=0.160,P=0.028）、室内种植绿色植物（OR=0.483,P=0.027）和使用实木地板（OR=0.487,P=0.045）。[结论]有肿瘤家族史、被动吸烟和曾室内装修是肺癌的危险因素,室内经常通风、种植绿色植物、使用实木地板是肺癌的保护性因素。     

Effectiveness of Different Topical Treatments in the Healing of Pressure Injuries: A Network Meta-analysis

Objectives

Pressure injuries (PIs) are one of the most common types of complex wounds and impose a huge economic burden on the healthcare system and the patients. A plethora of topical treatments is widely available for PI treatment, yet there is a paucity of evidence with regard to the most effective treatment. The objective of this study was to compare the effect of various topical treatments and identify the best treatment choice(s) for PI healing.

病因分值在病例对照研究中的应用──肺癌危险因素的交互效应

对广东省２００例原发性女性肺癌的现患病人作１：１配对病例对照研究，在Ｍａｎｔｅｌ－Ｈａｅｎｓｚｅｌ分层分析和条件ｌｏｇｉｓｔｉｃ回归分析的基础上，探讨女性肺癌危险因素的病因分值以及被动吸烟与其他各种危险因素间的交互效应。多因素条件ｌｏｇｉｓｔｉｃ回归分析结果显示：被动吸烟，厨房通风，喜吃咸食，慢性支气管炎、家庭肿瘤史，肺结核，。服和避孕药是女性肺癌独立的危险因素。     

病因分值在病例对照研究中的应用──肺癌危险因素的交互效应

对广东省200例原发性女性肺癌的现患病人作1：1配对病例对照研究，在Mantel-Haenszel分层分析和条件logistic回归分析的基础上，探讨女性肺癌危险因素的病因分值以及被动吸烟与其他各种危险因素间的交互效应。多因素条件logistic回归分析结果显示：被动吸烟（丈夫）、厨房通风、喜吃咸食、慢性支气管炎史、家族肿瘤史、肺结核、服用避孕药是女性肺癌独立的危险因素（OR=2.16～40．55，P＜0．05）。它们的病因分值分别是0.535.0．432、0.252、0．124、0.115、0．072.0．069。分析被动吸烟（丈夫）与口服避孕药、家族肿瘤史、厨房通风、肺结核史、经常吃咸色或腌菜间交互作用，其病因分值分别为0．848、0．499、0．479、0.416、0．346.交互作用指数是0．906、0．543、0．578、0．427、0．441。研究提示被动吸烟是女性肺癌的重要危险因素，特别是丈夫吸烟，尤其是在与服用避孕药这一因素并存的情况下，增加女性肺癌的危险性。     

Long-term Changes in the Premature Death Rate in Lung Cancer in a Developed Region of China: Population-based Study

BackgroundLung cancer is a leading cause of death worldwide, and its incidence shows an upward trend. A study of the long-term changes in the premature death rate in lung cancer in a developed region of China has great exploratory significance to further clarify the effectiveness of intervention measures.ObjectiveThis study examined long-term changes in premature lung cancer death rates in order to understand the changes in mortality and to design future prevention plans in Pudong New Area (PNA), Shanghai, China.MethodsCancer death data were collected from the Mortality Registration System of PNA. We analyzed the crude mortality rate (CMR), age-standardized mortality rate by Segi’s world standard population (ASMRW), and years of life lost (YLL) of patients with lung cancer from 1973 to 2019. Temporal trends in the CMR, ASMRW, and YLL rate were calculated by joinpoint regression expressed as an average annual percentage change (AAPC) with the corresponding 95% CI.ResultsAll registered permanent residents in PNA (80,543,137 person-years) from 1973 to 2019 were enrolled in this study. There were 42,229 deaths from lung cancer. The CMR and ASMRW were 52.43/10⁵ and 27.79/10⁵ person-years, respectively. The YLL due to premature death from lung cancer was 481779.14 years, and the YLL rate was 598.16/10⁵ person-years. The CMR and YLL rate showed significantly increasing trends in men, women, and the total population (P<.001). The CMR of the total population increased by 2.86% (95% CI 2.66-3.07, P<.001) per year during the study period. The YLL rate increased with an AAPC of 2.21% (95% CI 1.92-2.51, P<.001) per year. The contribution rates of increased CMR values caused by demographic factors were more evident than those caused by nondemographic factors.ConclusionsLung cancer deaths showed an increasing trend in PNA from 1973 to 2019. Demographic factors, such as the aging population, contributed more to an increased CMR. Our research can help us understand the changes in lung cancer mortality and can be used for similar cities in designing future prevention plans.     

The Associations of Dietary Iron Intake and the Transferrin Receptor (TFRC) rs9846149 Polymorphism with the Risk of Gastric Cancer: A Case–Control Study Conducted in Korea

Background: A positive association between a high iron intake and colorectal cancer has been identified; however, the effect of dietary iron on gastric cancer (GC) remains unclear. Here, we investigate whether dietary iron is related to GC risk and whether the transferrin receptor (TFRC) rs9846149 polymorphism modifies this association. Methods: A case–control study was designed to assess this association among 374 GC patients and 754 healthy controls. A self-administered questionnaire was used to collect information on demographics, medical history and lifestyle. Dietary iron intake was assessed using a semi-quantitative food frequency questionnaire. TFRC rs9846149 was genetically analyzed using the Affymetrix Axiom Exom 319 Array platform. Results: A higher total dietary iron was significantly associated with decreased GC risk [OR = 0.65 (0.45–0.94), p for trend = 0.018]. A similar association was observed with nonheme iron [OR = 0.64 (0.44–0.92), p for trend = 0.018]. Individuals with a major allele of TFRC rs9846149 (CC/GC) and higher intake of total iron had a significantly lower GC risk than those with a lower intake [OR = 0.60 (0.41–0.88), p interaction = 0.035]. Conclusion: Our findings show the protective effects of total dietary iron, especially nonheme iron, against GC risk, and this association can be modified by TFRC rs9846149.