Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

What Are Effective Program Characteristics of Self-Management Interventions in Patients With Heart Failure? : An Individual Patient Data Meta-analysis

Background To identify those characteristics of self-management interventions in patients with heart failure (HF) that are effective in influencing health-related quality of life, mortality, and hospitalizations. Methods and Results Randomized trials on self-management interventions conducted between January 1985 and June 2013 were identified and individual patient data were requested for meta-analysis. Generalized mixed effects models and Cox proportional hazard models including frailty terms were used to assess the relation between characteristics of interventions and health-related outcomes. Twenty randomized trials (5624 patients) were included. Longer intervention duration reduced mortality risk (hazard ratio 0.99, 95% confidence interval [CI] 0.97–0.999 per month increase in duration), risk of HF-related hospitalization (hazard ratio 0.98, 95% CI 0.96–0.99), and HF-related hospitalization at 6 months (risk ratio 0.96, 95% CI 0.92–0.995). Although results were not consistent across outcomes, interventions comprising standardized training of interventionists, peer contact, log keeping, or goal-setting skills appeared less effective than interventions without these characteristics. Conclusion No specific program characteristics were consistently associated with better effects of self-management interventions, but longer duration seemed to improve the effect of self-management interventions on several outcomes. Future research using factorial trial designs and process evaluations is needed to understand the working mechanism of specific program characteristics of self-management interventions in HF patients.

Effectiveness of vertebroplasty using individual patient data from two randomised placebo controlled trials : meta-analysis

Objective To determine whether vertebroplasty is more effective than placebo for patients with pain of recent onset (≤6 weeks) or severe pain (score ≥8 on 0-10 numerical rating scale).

Design Meta-analysis of combined individual patient level data.

Setting Two multicentred randomised controlled trials of vertebroplasty; one based in Australia, the other in the United States.

Participants 209 participants (Australian trial n=78, US trial n=131) with at least one radiographically confirmed vertebral compression fracture. 57 (27%) participants had pain of recent onset (vertebroplasty n=25, placebo n=32) and 99 (47%) had severe pain at baseline (vertebroplasty n=50, placebo n=49).

Intervention Percutaneous vertebroplasty versus a placebo procedure.

Main outcome measure Scores for pain (0-10 scale) and function (modified, 23 item Roland-Morris disability questionnaire) at one month.

Results For participants with pain of recent onset, between group differences in mean change scores at one month for pain and disability were 0.1 (95% confidence interval −1.4 to 1.6) and 0.2 (−3.0 to 3.4), respectively. For participants with severe pain at baseline, between group differences for pain and disability scores at one month were 0.3 (−0.8 to 1.5) and 1.4 (−1.2 to 3.9), respectively. At one month those in the vertebroplasty group were more likely to be using opioids.

Conclusions Individual patient data meta-analysis from two blinded trials of vertebroplasty, powered for subgroup analyses, failed to show an advantage of vertebroplasty over placebo for participants with recent onset fracture or severe pain. These results do not support the hypothesis that selected subgroups would benefit from vertebroplasty.

Additional weekend therapy may reduce length of rehabilitation stay after stroke: a meta-analysis of individual patient data

QUESTIONS: Among people receiving inpatient rehabilitation after stroke, does additional weekend physiotherapy and/or occupational therapy reduce the length of rehabilitation hospital stay compared to those who receive a weekday-only service, and does this change after controlling for individual factors? Does additional weekend therapy improve the ability to walk and perform activities of daily living, measured at discharge? Does additional weekend therapy improve health-related quality of life, measured 6 months after discharge from rehabilitation? Which individual, clinical and hospital characteristics are associated with shorter length of rehabilitation hospital stay? DESIGN: This study pooled individual data from two randomised, controlled trials (n=350) using an individual patient data meta-analysis and multivariate regression. PARTICIPANTS: People with stroke admitted to inpatient rehabilitation facilities. INTERVENTION: Additional weekend therapy (physiotherapy and/or occupational therapy) compared to usual care (5 days/week therapy). OUTCOME MEASURES: Length of rehabilitation hospital stay, independence in activities of daily living measured with the Functional Independence Measure, walking speed and health-related quality of life. RESULTS: Participants who received weekend therapy had a shorter length of rehabilitation hospital stay. In the un-adjusted analysis, this was not statistically significant (MD -5.7 days, 95% CI -13.0 to 1.5). Controlling for hospital site, age, walking speed and Functional Independence Measure score on admission, receiving weekend therapy was significantly associated with a shorter length of rehabilitation hospital stay (β=7.5, 95% CI 1.7 to 13.4, p=0.001). There were no significant between-group differences in Functional Independence Measure scores (MD 1.9 points, 95% CI -2.8 to 6.6), walking speed (MD 0.06 m/second, 95% CI -0.15 to 0.04) or health-related quality of life (SMD -0.04, 95% CI -0.26 to 0.19) at discharge. DISCUSSION: Modest evidence indicates that additional weekend therapy might reduce rehabilitation hospital length of stay.

Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis.

AIMS The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). METHODS AND RESULTS Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. CONCLUSION We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients.

Job Strain and Tobacco Smoking:An Individual-Participant Data Meta-Analysis of 166 130 Adults in 15 European Studies

BACKGROUND: Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults. METHODOLOGY AND PRINCIPAL FINDINGS: We analysed cross-sectional data from 15 European studies comprising 166 130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166 130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking. CONCLUSIONS: Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.

Intravaginal practices, bacterial vaginosis, and HIV infection in women: individual participant data meta-analysis

Background Identifying modifiable factors that increase women's vulnerability to HIV is a critical step in developing effective female-initiated prevention interventions. The primary objective of this study was to pool individual participant data from prospective longitudinal studies to investigate the association between intravaginal practices and acquisition of HIV infection among women in sub-Saharan Africa. Secondary objectives were to investigate associations between intravaginal practices and disrupted vaginal flora; and between disrupted vaginal flora and HIV acquisition. Methods and Findings We conducted a meta-analysis of individual participant data from 13 prospective cohort studies involving 14,874 women, of whom 791 acquired HIV infection during 21,218 woman years of follow-up. Data were pooled using random-effects meta-analysis. The level of between-study heterogeneity was low in all analyses (I2 values 0.0%–16.1%). Intravaginal use of cloth or paper (pooled adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.18–1.83), insertion of products to dry or tighten the vagina (aHR 1.31, 95% CI 1.00–1.71), and intravaginal cleaning with soap (aHR 1.24, 95% CI 1.01–1.53) remained associated with HIV acquisition after controlling for age, marital status, and number of sex partners in the past 3 months. Intravaginal cleaning with soap was also associated with the development of intermediate vaginal flora and bacterial vaginosis in women with normal vaginal flora at baseline (pooled adjusted odds ratio [OR] 1.24, 95% CI 1.04–1.47). Use of cloth or paper was not associated with the development of disrupted vaginal flora. Intermediate vaginal flora and bacterial vaginosis were each associated with HIV acquisition in multivariable models when measured at baseline (aHR 1.54 and 1.69, p<0.001) or at the visit before the estimated date of HIV infection (aHR 1.41 and 1.53, p<0.001), respectively. Conclusions This study provides evidence to suggest that some intravaginal practices increase the risk of HIV acquisition but a direct causal pathway linking intravaginal cleaning with soap, disruption of vaginal flora, and HIV acquisition has not yet been demonstrated. More consistency in the definition and measurement of specific intravaginal practices is warranted so that the effects of specific intravaginal practices and products can be further elucidated.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Text2PreventCVD: Protocol for a systematic review and individual participant data meta-analysis of text-message based interventions for the prevention of cardiovascular diseases.

Introduction Text message interventions have been shown to be effective in prevention and management of several non-communicable disease risk factors. However, the extent to which their effects might vary in different participants and settings is uncertain. We aim to conduct a systematic review and individual participant data (IPD) meta-analysis of randomised clinical trials examining text message interventions aimed to prevent cardiovascular diseases (CVD) through modification of cardiovascular risk factors (CVRFs). Methods and analysis Systematic review and IPD meta-analysis will be conducted according to Preferred Reporting Items for Systematic review and Meta-Analysis of IPD (PRISMA-IPD) guidelines. Electronic database of published studies (MEDLINE, EMBASE, PsycINFO and Cochrane Library) and international trial registries will be searched to identify relevant randomised clinical trials. Authors of studies meeting the inclusion criteria will be invited to join the IPD meta-analysis group and contribute study data to the common database. The primary outcome will be the difference between intervention and control groups in blood pressure at 6-month follow-up. Key secondary outcomes include effects on lipid parameters, body mass index, smoking levels and self-reported quality of life. If sufficient data is available, we will also analyse blood pressure and other secondary outcomes at 12 months. IPD meta-analysis will be performed using a one-step approach and modelling data simultaneously while accounting for the clustering of the participants within studies. This study will use the existing data to assess the effectiveness of text message-based interventions on CVRFs, the consistency of any effects by participant subgroups and across different healthcare settings. Ethics and dissemination Ethical approval was obtained for the individual studies by the trial investigators from relevant local ethics committees. This study will include anonymised data for secondary analysis and investigators will be asked to check that this is consistent with their existing approvals. Results will be disseminated via scientific forums including peer-reviewed publications and presentations at international conferences.

The Early Prevention of Obesity in CHildren (EPOCH) collaboration : an individual patient data prospective meta-analysis

Background: Efforts to prevent the development of overweight and obesity have increasingly focused early in the life course as we recognise that both metabolic and behavioural patterns are often established within the first few years of life. Randomised controlled trials (RCTs) of interventions are even more powerful when, with forethought, they are synthesised into an individual patient data (IPD) prospective meta-analysis (PMA). An IPD PMA is a unique research design where several trials are identified for inclusion in an analysis before any of the individual trial results become known and the data are provided for each randomised patient. This methodology minimises the publication and selection bias often associated with a retrospective meta-analysis by allowing hypotheses, analysis methods and selection criteria to be specified a priori. Methods/Design: The Early Prevention of Obesity in CHildren (EPOCH) Collaboration was formed in 2009. The main objective of the EPOCH Collaboration is to determine if early intervention for childhood obesity impacts on body mass index (BMI) z scores at age 18-24 months. Additional research questions will focus on whether early intervention has an impact on children’s dietary quality, TV viewing time, duration of breastfeeding and parenting styles. This protocol includes the hypotheses, inclusion criteria and outcome measures to be used in the IPD PMA. The sample size of the combined dataset at final outcome assessment (approximately 1800 infants) will allow greater precision when exploring differences in the effect of early intervention with respect to pre-specified participant- and intervention-level characteristics. Discussion: Finalisation of the data collection procedures and analysis plans will be complete by the end of 2010. Data collection and analysis will occur during 2011-2012 and results should be available by 2013. Trial registration number: ACTRN12610000789066

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

Aims/hypothesis: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. Methods: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. Results: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. Conclusions/interpretation: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes. © 2010 Springer-Verlag.


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Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials

Background: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.
Methods: We undertook a meta-analysis of individual patient data for 10?801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.
Findings: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (=20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
Interpretation: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
Funding: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.