Individual Participant Data Network Meta-analysis Research Articles

Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis.

Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {β: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [β: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [β: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled β: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous β: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.

Are web-based stress management interventions effective as an indirect treatment for depression? An individual participant data meta-analysis of six randomised trials

QuestionDepression is highly prevalent and associated with numerous adverse consequences for both individuals and society. Due to low uptake of direct treatment, interventions that target related, but less stigmatising problems,...

Optimizing cord management for each preterm baby – Challenges of collating individual participant data and recommendations for future collaborative research

The optimal cord management strategy at birth for each preterm baby is still unknown, despite more than 100 randomized controlled trials (RCTs) undertaken on this question. To address this, we brought together all RCTs examining cord management strategies at preterm birth in the iCOMP (individual participant data on COrd Management at Preterm birth) Collaboration, to perform an individual participant data network meta-analysis. In this paper, we describe the trials and tribulations around obtaining individual participant data to resolve controversies around cord clamping, and we derive key recommendations for future collaborative research in perinatology. To reliably answer outstanding questions, future cord management research needs to be collaborative and coordinated, by aligning core protocol elements, ensuring quality and reporting standards are met, and carefully considering and reporting on vulnerable sub-populations. The iCOMP Collaboration is an example of the power of collaboration to address priority research questions, and ultimately improve neonatal outcomes worldwide.

Complex speech-language therapy interventions for stroke-related aphasia: the RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Complex speech-language therapy interventions for stroke-related aphasia: the RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Using individual participant data to improve network meta-analysis projects

A network meta-analysis combines the evidence from existing randomised trials about the comparative efficacy of multiple treatments. It allows direct and indirect evidence about each comparison to be included in...

NETwork Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (NETMOTION): A Protocol for Systematic Review and Individual Participant Data Network Meta-Analysis of Preterm Infants

Background: Internationally recognized guidelines recommend the judicious use of low oxygen (21–30%), titrated to peripheral oxygen saturation targets, for the initiation of resuscitation of very and extremely preterm infants (<32 weeks’ gestation). However, despite more than 10 randomized controlled trials on this question, the ideal initial oxygen concentration for this group of vulnerable infants remains uncertain. Aims: This study aims to assess the effect of various initial oxygen concentrations on (1) all-cause mortality, chronic lung disease, intraventricular hemorrhage, and retinopathy of prematurity; and (2) reaching the prescribed oxygen saturation targets by 5 min after birth, in preterm infants requiring resuscitation. Methods: We will conduct a systematic review and network meta-analysis using individual participant data. Studies of preterm infants <32 weeks’ gestation, randomized to initial oxygen concentration, will be included. We will systematically search medical databases and trial registries for eligible studies (published or unpublished). Records will be screened by two independent reviewers, with conflicts resolved by the inclusion of a third reviewer. Identified initial oxygen concentrations will be grouped into the following nodes: low (≤30%), intermediate (60%), and high (≥90%) oxygen. A two-step random-effects contrast-based network meta-regression will be calculated to compare and rank different oxygen concentrations. Analyses will be intention-to-treat, with the primary outcome of all-cause mortality. Discussion: This is the first individual participant data network meta-analysis of initial oxygen concentrations for the resuscitation of preterm infants. This novel approach may address long-standing uncertainty regarding optimal oxygen supplementation practice for the resuscitation of preterm infants <32 weeks’ gestation.

Dosage, Intensity, and Frequency of Language Therapy for Aphasia: A Systematic Review-Based, Individual Participant Data Network Meta-Analysis.

Optimizing speech and language therapy (SLT) regimens for maximal aphasia recovery is a clinical research priority. We examined associations between SLT intensity (hours/week), dosage (total hours), frequency (days/week), duration (weeks), delivery (face to face, computer supported, individual tailoring, and home practice), content, and language outcomes for people with aphasia. Databases including MEDLINE and Embase were searched (inception to September 2015). Published, unpublished, and emerging trials including SLT and ≥10 individual participant data on aphasia, language outcomes, and time post-onset were selected. Patient-level data on stroke, language, SLT, and trial risk of bias were independently extracted. Outcome measurement scores were standardized. A statistical inferencing, one-stage, random effects, network meta-analysis approach filtered individual participant data into an optimal model examining SLT regimen for overall language, auditory comprehension, naming, and functional communication pre-post intervention gains, adjusting for a priori-defined covariates (age, sex, time poststroke, and baseline aphasia severity), reporting estimates of mean change scores (95% CI). Data from 959 individual participant data (25 trials) were included. Greatest gains in overall language and comprehension were associated with >20 to 50 hours SLT dosage (18.37 [10.58-26.16] Western Aphasia Battery-Aphasia Quotient; 5.23 [1.51-8.95] Aachen Aphasia Test-Token Test). Greatest clinical overall language, functional communication, and comprehension gains were associated with 2 to 4 and 9+ SLT hours/week. Greatest clinical gains were associated with frequent SLT for overall language, functional communication (3-5+ days/week), and comprehension (4-5 days/week). Evidence of comprehension gains was absent for SLT ≤20 hours, <3 hours/week, and ≤3 days/week. Mixed receptive-expressive therapy, functionally tailored, with prescribed home practice was associated with the greatest overall gains. Relative variance was <30%. Risk of trial bias was low to moderate; low for meta-biases. Greatest language recovery was associated with frequent, functionally tailored, receptive-expressive SLT, with prescribed home practice at a greater intensity and duration than reports of usual clinical services internationally. These exploratory findings suggest critical therapeutic ranges, informing hypothesis-testing trials and tailoring of clinical services. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018110947.

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

SummaryBackgroundBlood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials.MethodsWe performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists’ Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons.Findings145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84–0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76–0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76–0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of β blockers (RR 1·48 [1·27–1·72]) and thiazide diuretics (RR 1·20 [1·07–1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92–1·13]).InterpretationBlood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes.FundingBritish Heart Foundation, National Institute for Health Research, and Oxford Martin School.

PRIME-IPD SERIES Part 3. The PRIME-IPD tool fills a gap in guidance for preparing IPD for analysis

We thank Levis et al. for their interest in our study and for sharing their perspective on preparing IPD for analysis. We wish to emphasize that our paper's purpose was to provide guidance on the different steps that should be undertaken when preparing IPD for analysis, but not to be prescriptive about how each step should be performed. The examples provided in the manuscript are examples of how we applied PRIME (Preparation, Replication, Imputation, Merging, Evaluation) to our Network Meta-Analysis and are in no way comprehensive [ [1] Welch VA Hossain A Ghogomu E Riddle A Cousens S Gaffey M et al. Deworming children for soil-transmitted helminths in low and middle-income countries: systematic review and individual participant data network meta-analysis. J Dev Effect. 2019; 11: 288-306 Crossref PubMed Scopus (4) Google Scholar , [2] Welch VA Ghogomu E Hossain A Riddle A Gaffey M Arora P et al. Mass deworming for improving health and cognition of children in endemic helminth areas: a systematic review and individual participant data network meta-analysis. Campbell Syst Rev. 2019; 15: e1058 Crossref Scopus (7) Google Scholar . The suggestions provided by Levis et al. in their commentary emphasize the importance of having a structured process for managing IPD. We agree that the finer details of that structured process may vary since they should be determined by the nature of the datasets and share Levis et al.’s desire to see our framework refined in order to develop a robust scientific process to answer the research questions with validity.

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol

IntroductionTiming of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials...

Mass deworming for improving health and cognition of children in endemic helminth areas: A systematic review and individual participant data network meta-analysis.

Soil transmitted (or intestinal) helminths and schistosomes affect millions of children worldwide. To use individual participant data network meta-analysis (NMA) to explore the effects of different types and frequency of deworming drugs on anaemia, cognition and growth across potential effect modifiers. We developed a search strategy with an information scientist to search MEDLINE, CINAHL, LILACS, Embase, the Cochrane Library, Econlit, Internet Documents in Economics Access Service (IDEAS), Public Affairs Information Service (PAIS), Social Services Abstracts, Global Health CABI and CAB Abstracts up to March 27, 2018. We also searched grey literature, websites, contacted authors and screened references of relevant systematic reviews. We included randomised and quasirandomised deworming trials in children for deworming compared to placebo or other interventions with data on baseline infection. We conducted NMA with individual participant data (IPD), using a frequentist approach for random-effects NMA. The covariates were: age, sex, weight, height, haemoglobin and infection intensity. The effect estimate chosen was the mean difference for the continuous outcome of interest. We received data from 19 randomized controlled trials with 31,945 participants. Overall risk of bias was low. There were no statistically significant subgroup effects across any of the potential effect modifiers. However, analyses showed that there may be greater effects on weight for moderate to heavily infected children (very low certainty evidence). This analysis reinforces the case against mass deworming at a population-level, finding little effect on nutritional status or cognition. However, children with heavier intensity infections may benefit more. We urge the global community to adopt calls to make data available in open repositories to facilitate IPD analyses such as this, which aim to assess effects for the most vulnerable individuals.

Deworming children for soil-transmitted helminths in low and middle-income countries: systematic review and individual participant data network meta-analysis

ABSTRACTIntestinal parasites affect millions of children globally. We aimed to assess effects of deworming children on nutritional and cognitive outcomes across potential effect modifiers using individual participant data (IPD). We searched multiple databases to 27 March 2018, grey literature, and other sources. We included randomised and quasi randomised trials of deworming compared to placebo or other nutritional interventions with data on baseline infection. We used a random-effects network meta-analysis with IPD and assessed overall quality, following a pre-specified protocol. We received IPD from 19 trials of STH deworming. Overall risk of bias was low. There were no statistically significant subgroup effects across age, sex, nutritional status or infection intensity for each type of STH. These analyses showed that children with moderate or heavy intensity infections, deworming for STH may increase weight gain (very low certainty). The added value of this review is an exploration of effects on growth and cognition in children with moderate to heavy infections as well as replicating prior systematic review results of small effects at the population level. Policy implications are that complementary public health strategies need to be assessed and considered to achieve growth and cognition benefits for children in helminth endemic areas.

Guided or self-guided internet-based cognitive–behavioural therapy (iCBT) for depression? Study protocol of an individual participant data network meta-analysis

IntroductionAlthough guided forms of internet-based cognitive–behavioural therapy (iCBT) result in a substantial reduction in depression, it seems that the most scalable way to deliver iCBT is without guidance. However, direct...

A framework for identifying treatment-covariate interactions in individual participant data network meta-analysis.

Background: Stratified medicine seeks to identify patients most likely to respond to treatment. Individual participant data (IPD) network meta‐analysis (NMA) models have greater power than individual trials to identify treatment‐covariate interactions (TCIs). Treatment‐covariate interactions contain “within” and “across” trial interactions, where the across‐trial interaction is more susceptible to confounding and ecological bias. Methods: We considered a network of IPD from 37 trials (5922 patients) for cervical cancer (2394 events), where previous research identified disease stage as a potential interaction covariate. We compare 2 models for NMA with TCIs: (1) 2 effects separating within‐ and across‐trial interactions and (2) a single effect combining within‐ and across‐trial interactions. We argue for a visual assessment of consistency of within‐ and across‐trial interactions and consider more detailed aspects of interaction modelling, eg, common vs trial‐specific effects of the covariate. This leads us to propose a practical framework for IPD NMA with TCIs. Results: Following our framework, we found no evidence in the cervical cancer network for a treatment‐stage interaction on the basis of the within‐trial interaction. The NMA provided additional power for an across‐trial interaction over and above the pairwise evidence. Following our proposed framework, we found that the within‐ and across‐trial interactions should not be combined. Conclusion: Across‐trial interactions are susceptible to confounding and ecological bias. It is important to separate the sources of evidence to check their consistency and identify which sources of evidence are driving the conclusion. Our framework provides practical guidance for researchers, reducing the risk of unduly optimistic interpretation of TCIs.

Deworming Children for Soil-Transmitted Helminths in Low and Middle Income Countries: Systematic Review and Individual Participant Data Network Meta-Analysis

Background: Mass deworming affects millions of children afflicted by intestinal parasites.We aimed to assess differences in effects of deworming on nutritional and cognitive outcomes across potential effect modifiers. Methods: For this systematic review and network meta-analysis of individual participant data (IPD), we searched MEDLINE, CINAHL, LILACS, EMBASE, the Cochrane Library, Econlit, Internet Documents in Economics Access Service, Public Affairs Information Service, Social Services Abstracts, Global Health CABI and CAB Abstracts to March 27, 2018. We searched grey literature, contacted authors and screened reviews. We included randomized and quasi randomized trials of deworming children compared to placebo or other nutritional or deworming interventions with data on baseline infection. We used a frequentist approach for random-effects network meta-analysis with IPD using General Linear Mixed Models, assessed Cochrane Risk of Bias and GRADE for overall quality, following a pre-specified protocol. The main outcomes were weight, height, haemoglobin and cognition. Findings: We received IPD from 19 RCTs of STH deworming with 31,945 participants. For deworming for schistosomiasis alone, we received too few studies. Overall risk of bias was low. STH deworming vs. placebo effect on weight was 0.01 kg (95%CI: -0.08 to 0.11), height 0.09 cm (95%CI: -0.08, to 0.27) (moderate certainty), and haemoglobin 0.32 g/L (95%CI: -0.63 to 1.26) (low certainty). No study showed important effects on cognition (low certainty). There were no statistically significant subgroup effects across age, sex, nutritional status or infection intensity. Confidence limits included important effects on weight and haemoglobin for children with higher intensity infections. Interpretation: Deworming for STH alone is insufficient to improve child nutrition and cognition at population level in areas with light intensity infections. Funding Statement: Bill and Melinda Gates Foundation Declaration of Interests: Dr. Friis reports grants from ARLA Food for Health Center, grants from Danish Dairy Research Foundation, grants from Nutriset, outside the submitted work. Dr. Elliott reports grants from Wellcome Trust, during the conduct of the study. Dr. King reports grants from World Health Organization for work included in the study. Dr. LIU reports grants from International Initiative for Impact Evaluation, grants from National Natural Science Foundation of China, during the conduct of the study. All other authors state they have nothing to disclose. Ethics Approval Statement: This study was approved by the Bruyere Research Institute and SickKids research ethics boards.

PROTOCOL: Mass deworming for improving health and cognition of children in endemic helminth areas: a systematic review and individual participant data network meta-analysis.

PROTOCOL: Mass deworming for improving health and cognition of children in endemic helminth areas: a systematic review and individual participant data network meta-analysis.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis

IntroductionDespite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of...