Effect of immunosuppressive treatment on biomarkers in adult atopic dermatitis patients.

BACKGROUND: Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD). OBJECTIVE: Primary aim: To identify biomarkers reflecting therapeutic response in patients with AD treated systemically. Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non-FLG mutations carriers. METHODS: Thirty-eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation-inducing ligand, B-cell activating factor of the TNF family, thymus and activation-regulated chemokine (chemokine (C-C motif) ligand 17) (TARC (CCl-17)), interleukin-1 receptor antagonist (IL-1RA), interleukin-1 bèta, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-18, IL-31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C-X-C motif) ligand 9), interferon gamma-induced protein 10 (C-X-C motif chemokine Ligand 10), monocyte chemoattractant protein-1 (chemokine (C-C Motif) ligand 2), macrophage inflammatory protein-1 beta (chemokine (C-C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C-C motif) ligand 5), Cutaneous T-cell-attracting chemokine (chemokine (C-C motif) ligand 27) (CTACK (CCL-27)), thymic stromal lymphopoietin, IL-5, interleukin-1 alpha and granulocyte-colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status. RESULTS: Thymus and activation-regulated chemokine, CTACK, IL-13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non-responders, and FLG and non-FLG mutants showed similar biomarker profiles. CONCLUSION: Thymus and activation-regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL-13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non-responders, or FLG genotype status.

Diagnostic accuracy of tests for leprosy: a systematic review and meta-analysis.

OBJECTIVES: Owing to difficulties in the clinical diagnosis of leprosy, several complementary tests have been developed and used. The aim was to systematically summarize the accuracy of diagnostic tests for leprosy. METHODS: We searched for relevant articles in Embase, Medline, and Global Health databases, until June 2017. Studies evaluating the accuracy of any diagnostic techniques for differentiating between people with and without leprosy were included. Studies solely focusing on differentiating between the separate forms of leprosy were excluded. Our protocol was registered on PROSPERO (CRD42017071803). We assessed study quality using the QUADAS-2 checklist. A bivariate random effects regression model was used for the meta-analyses. RESULTS: We included 78 studies, most of those evaluating the detection of IgM antibodies against phenolic glycolipid I using ELISA. Sensitivity of the 39 studies evaluating ELISA was 63.8% (95% CI 55.0-71.8); specificity 91.0% (95% CI 86.9-93.9). The lateral flow test (nine studies) and the agglutination test (five studies) had a slightly higher sensitivity and a slightly lower specificity. Sensitivity of qPCR was (five studies) 78.5% (95% CI 61.9-89.2) and specificity 89.3% (95% CI 61.4-97.8). Sensitivity of conventional PCR was (17 studies) 75.3% (95% CI 67.9-81.5) and specificity 94.5% (95% CI 91.4-96.5). CONCLUSIONS: Although the test accuracy looks reasonable, the studies suffered from heterogeneity and low methodological quality.

How to: evaluate a diagnostic test.

BACKGROUND: The development of an in vitro diagnostic test from a good idea to a clinically relevant tool takes several steps, with more stringent requirements at every step. OBJECTIVES: This article aims to summarize the necessary questions to be asked about a test and to illustrate study designs answering these questions. We also aim to relate Regulation (EU) 2017/746 to the needs of evidence-based diagnostic testing, where applicable. SOURCES: We used literature on evidence-based diagnostics, a text book on clinical trials in the development and marketing of medical devices and the English version of Regulation 2017/746 of the European Parliament and of the Council on in vitro diagnostic medical devices. CONTENT: The combination of different test uses and different stages of development determine the required test characteristics and suitability of study designs. In an earlier stage of test development it may be crucial to know whether a test can differentiate diseased persons from healthy controls, although this tells us little about how a test will perform in practice. Later stages focus on the diagnostic accuracy of a test in a clinically relevant situation. However, a test that perfectly distinguishes between patients with and without a certain condition may still have little effect on patient outcomes. Therefore, randomized controlled trials of testing may be needed, as well as post-marketing monitoring. IMPLICATIONS: Both researchers and users of tests need to be aware of the limitations of diagnostic test accuracy and realize that accuracy is only indirectly linked to people's health status.

[Dilemma: to test or not to test for Lyme borreliosis in general practice]. / Dilemma: wel of niet testen op lymeziekte in de huisartsenpraktijk?

There is no such thing as a perfect diagnostic test and the value of a test depends on the situation in which the test is being used. Here, we discuss two options for dealing with the diagnostic process for Lyme borreliosis in general practice. One option is to manage, treat or refer according to clinical signs and symptoms, in accordance with Dutch practice guidelines. The other option is to use laboratory tests to guide further patient management (treatment or referral). The choice depends on currently unknown factors, such as the pre-test probability of Lyme disease in patients presenting to general practitioners. Furthermore, clarity is required about how to proceed after a positive or negative test result. The consequences of a false test result will depend on the patient's status, possible alternative diagnoses and treatment options. Both physician and patient should be aware of the shortcomings of diagnostic tests.

Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial.

BACKGROUND: Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD) refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking. OBJECTIVES: To investigate long-term effectiveness, safety and drug survival of MTX and AZA. METHODS: In an open-label follow-up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves. RESULTS: Thirty-five of 43 originally included patients participated, of whom 27 completed the follow-up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1). CONCLUSIONS: Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD.

Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) is a promising non-invasive skin imaging technique that could facilitate early diagnosis of basal cell carcinoma (BCC) instead of routine punch biopsies. However, the clinical value and utility of RCM vs. a punch biopsy in diagnosing and subtyping BCC is unknown. OBJECTIVE: To assess diagnostic accuracy of RCM vs. punch biopsy for diagnosing and subtyping clinically suspected primary BCC. METHODS: A prospective, consecutive cohort of 100 patients with clinically suspected BCC were included at two tertiary hospitals in Amsterdam, the Netherlands, between 3 February 2015 and 2 October 2015. Patients were randomized between two test-treatment pathways: diagnosing and subtyping using RCM imaging followed by direct surgical excision (RCM one-stop-shop) or planned excision based upon the histological diagnosis and subtype of punch biopsy (standard care). The primary outcome was the agreement between the index tests (RCM vs. punch biopsy) and reference standard (excision specimen) in correctly diagnosing BCC. The secondary outcome was the agreement between the index tests and reference standard in correctly identifying the most aggressive BCC subtypes. RESULTS: Sensitivity to detect BCC was similar for RCM and punch biopsy (100% vs. 93.94%), but a punch biopsy was more specific than RCM (79% vs. 38%). RCM expert evaluation for diagnosing BCC had a sensitivity of 100% and a specificity of 75%. The agreement between RCM and excision specimen in identifying the most aggressive BCC subtype ranged from 50% to 85% vs. 77% by a punch biopsy. CONCLUSION: Reflectance confocal microscopy and punch biopsy have comparable diagnostic accuracy to diagnose and subtype BCC depending on RCM experience. Although experienced RCM users could accurately diagnose BCC at a distance, we found an important difference in subtyping BCC. Future RCM studies need to focus on diagnostic accuracy, reliability and specific criteria to improve BCC subtype differentiation.

The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis.

BACKGROUND: Interpretation of serological assays in Lyme borreliosis requires an understanding of the clinical indications and the limitations of the currently available tests. We therefore systematically reviewed the accuracy of serological tests for the diagnosis of Lyme borreliosis in Europe. METHODS: We searched EMBASE en MEDLINE and contacted experts. Studies evaluating the diagnostic accuracy of serological assays for Lyme borreliosis in Europe were eligible. Study selection and data-extraction were done by two authors independently. We assessed study quality using the QUADAS-2 checklist. We used a hierarchical summary ROC meta-regression method for the meta-analyses. Potential sources of heterogeneity were test-type, commercial or in-house, Ig-type, antigen type and study quality. These were added as covariates to the model, to assess their effect on test accuracy. RESULTS: Seventy-eight studies evaluating an Enzyme-Linked ImmunoSorbent assay (ELISA) or an immunoblot assay against a reference standard of clinical criteria were included. None of the studies had low risk of bias for all QUADAS-2 domains. Sensitivity was highly heterogeneous, with summary estimates: erythema migrans 50% (95% CI 40% to 61%); neuroborreliosis 77% (95% CI 67% to 85%); acrodermatitis chronica atrophicans 97% (95% CI 94% to 99%); unspecified Lyme borreliosis 73% (95% CI 53% to 87%). Specificity was around 95% in studies with healthy controls, but around 80% in cross-sectional studies. Two-tiered algorithms or antibody indices did not outperform single test approaches. CONCLUSIONS: The observed heterogeneity and risk of bias complicate the extrapolation of our results to clinical practice. The usefulness of the serological tests for Lyme disease depends on the pre-test probability and subsequent predictive values in the setting where the tests are being used. Future diagnostic accuracy studies should be prospectively planned cross-sectional studies, done in settings where the test will be used in practice.

In vivo confocal microscopy of basal cell carcinoma: a systematic review of diagnostic accuracy.

Basal cell carcinoma (BCC) is the most prevalent type of skin cancer. Histologic analysis of punch biopsy or direct excision specimen is used to confirm clinical diagnosis. In vivo reflectance confocal microscopy (RCM) is a non-invasive imaging modality that could facilitate early diagnosis and minimize unnecessary invasive procedures. We systematically reviewed diagnostic accuracy (sensitivity and specificity) of RCM in diagnosing primary BCCs to judge its usefulness. Eligible studies were reviewed for methodological quality using the QUADAS-2 tool. We used the bivariate random-effects model to calculate summary estimates of sensitivity and specificity. Six studies met the selection criteria and were included for analysis. The meta-analysis showed a summary estimate of sensitivity 0.97 (95% CI, 0.90-0.99) and specificity 0.93 (95% CI, 0.88-0.96). All but one of the QUADAS-2 items showed a high or unclear risk of bias with regards to patient selection. RCM may be a promising diagnostic tool, but the limited number of available studies and potential risk of bias of included studies do not allow us to draw firm conclusions. Future accuracy studies should take these limitations into account.

Molecular tools for diagnosis of visceral leishmaniasis: systematic review and meta-analysis of diagnostic test accuracy.

Molecular methods have been proposed as highly sensitive tools for the detection of Leishmania parasites in visceral leishmaniasis (VL) patients. Here, we evaluate the diagnostic accuracy of these tools in a meta-analysis of the published literature. The selection criteria were original studies that evaluate the sensitivities and specificities of molecular tests for diagnosis of VL, adequate classification of study participants, and the absolute numbers of true positives and negatives derivable from the data presented. Forty studies met the selection criteria, including PCR, real-time PCR, nucleic acid sequence-based amplification (NASBA), and loop-mediated isothermal amplification (LAMP). The sensitivities of the individual studies ranged from 29 to 100%, and the specificities ranged from 25 to 100%. The pooled sensitivity of PCR in whole blood was 93.1% (95% confidence interval [CI], 90.0 to 95.2), and the specificity was 95.6% (95% CI, 87.0 to 98.6). The specificity was significantly lower in consecutive studies, at 63.3% (95% CI, 53.9 to 71.8), due either to true-positive patients not being identified by parasitological methods or to the number of asymptomatic carriers in areas of endemicity. PCR for patients with HIV-VL coinfection showed high diagnostic accuracy in buffy coat and bone marrow, ranging from 93.1 to 96.9%. Molecular tools are highly sensitive assays for Leishmania detection and may contribute as an additional test in the algorithm, together with a clear clinical case definition. We observed wide variety in reference standards and study designs and now recommend consecutively designed studies.

Systematic reviews and meta-analyses of diagnostic test accuracy.

Systematic reviews of diagnostic test accuracy summarize the accuracy, e.g. the sensitivity and specificity, of diagnostic tests in a systematic and transparent way. The aim of such a review is to investigate whether a test is sufficiently specific or sensitive to fit its role in practice, to compare the accuracy of two or more diagnostic tests, or to investigate where existing variation in results comes from. The search strategy should be broad and preferably fully reported, to enable readers to assess the completeness of it. Included studies usually have a cross-sectional design in which the tests of interest, ideally both the index test and its comparator, are evaluated against the reference standard. They should be a reflection of the situation that the review question refers to. The quality of included studies is assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 checklist, containing items such as a consecutive and all-inclusive patient selection process, blinding of index test and reference standard assessment, a valid reference standard, and complete verification of all included participants. Studies recruiting cases separately from (healthy) controls are regarded as bearing a high risk of bias. For meta-analysis, the bivariate model or the hierarchical summary receiver operating characteristic model is used. These models take into account potential threshold effects and the correlation between sensitivity and specificity. They also allow addition of covariates for investigatation of potential sources of heterogeneity. Finally, the results from the meta-analyses should be explained and interpreted for the reader, to be well understood.

The prevalence of thyroid disease in patients with vitiligo: a systematic review.

BACKGROUND: Thyroid disease has been suggested to be associated with vitiligo. However, the outcomes of prevalence studies on thyroid disease in vitiligo vary widely. OBJECTIVES: To summarize and critically appraise current evidence of the prevalence of thyroid diseases in vitiligo. METHODS: A systematic review was performed searching the electronic databases OVID MEDLINE, OVID EMBASE and PubMed. Guidelines for the critical appraisal of studies on prevalence of a health problem were adapted to evaluate the methodological quality of the included studies. Results were analysed in a meta-analysis with a risk ratio (RR). RESULTS: Forty-eight studies published between 1968 and 2012 met the inclusion criteria. Most of the studies (50%) were of fair methodological quality, whereas 18 studies (38%) were of poor quality and six studies (12%) were of good quality. Thyroid disease, autoimmune thyroid disease and presence of thyroid-specific autoantibodies showed a mean prevalence of, respectively, 15·1%, 14·3% and 20·8% in patients with vitiligo and an RR of, respectively, 1·9, 2·5 and 5·2 (all statistically significant). This review shows an increased prevalence and an increased risk of (autoimmune) thyroid disease in patients with vitiligo compared with nonvitiligo. This risk seems to increase with age. CONCLUSIONS: Clinicians should be aware of this increased risk in patients with vitiligo and should be attentive for symptoms of thyroid disease. To make recommendations on screening for thyroid disease in patients with vitiligo future research of good methodological quality, including differentiation of vitiligo types and the use of standardized outcome measures, is needed.

EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference.

BACKGROUND: Demonstration of adequate reliability and validity is sufficient for concluding that an instrument is applicable for descriptive and predictive purposes, but before we can confidently use an outcome measure in clinical trials, the responsiveness (synonymous with sensitivity to change) and minimal clinically important difference (MCID) should be known. With this study, we aimed to assess responsiveness and MCID of four outcome measures used in atopic eczema: the Severity Scoring of Atopic Dermatitis (SCORAD), the objective SCORAD, Eczema Area and Severity Index (EASI), and the Patient-Oriented Eczema Measure (POEM). METHODS: Data of three randomized controlled trials were used. To demonstrate responsiveness, we plotted receiver operating characteristic (ROC) curves. MCID was estimated using mean change scores of patients that showed a relevant improvement. Bland and Altman methods were used to quantify the limits of agreement. RESULTS: Area under the ROC curve for the SCORAD was 0.70 [95% confidence interval (CI): 0.61-0.78], for the objective SCORAD, 0.73 (95% CI: 0.70-0.77), for the EASI, 0.67 (95% CI: 0.60-0.76), and for the POEM, 0.67 (95% CI: 0.59-0.75). Scores above 0.70 represent a fair responsiveness. The MCID was 8.7 points for the SCORAD, 8.2 for the objective SCORAD, 6.6 for the EASI, and 3.4 for the POEM. CONCLUSION: The objective SCORAD and SCORAD showed a fair responsiveness. The MCIDs are an important prerequisite for the interpretation of published eczema trials and for the planning/sample size estimation of future trials.

Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

OBJECTIVES: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia. DATA SOURCES: Major electronic databases were searched to January 2005 at least. REVIEW METHODS: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model. RESULTS: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case. CONCLUSIONS: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

Diagnostic criteria for atopic dermatitis: a systematic review.

BACKGROUND: Atopic dermatitis (AD) has a wide spectrum of dermatological manifestations and despite various validated sets of diagnostic criteria that have been developed over the past decades, there is disagreement about its definition. Nevertheless, clinical studies require valid diagnostic criteria for reliable and reproducible results. OBJECTIVE: To summarize the evidence concerning the validity of diagnostic criteria for AD. METHODS: All data sources were identified through searches on Medline, Embase and Cochrane databases. The Quality Assessment of Diagnostic Accuracy tool (QUADAS) was used. Results are presented in a receiver operating characteristic (ROC) plot. RESULTS: Out of the 20 articles that met the criteria, 27 validation studies were identified. In two studies concerning Hanifin and Rajka diagnostic criteria sensitivity and specificity ranged from 87.9% to 96.0% and from 77.6% to 93.8%, respectively. Nineteen validation studies of the U.K. diagnostic criteria showed sensitivity and specificity ranging from 10% to 100% and 89.3% to 99.1%, respectively. Three validation studies concerning the Schultz-Larsen criteria showed sensitivity from 88% to 94.4% and specificity from 77.6% to 95.9%. In one article concerning the criteria of Diepgen, the sensitivity ranged from 83.0% to 87.7% and the specificity from 83.9% to 87.0%. One article studied the Kang and Tian criteria and reported 95.5% sensitivity and 100% specificity. One article validating the International Study of Asthma and Allergies in Childhood (ISAAC) criteria showed a positive and negative predictive value of 48.8% and 91.1%, respectively. CONCLUSION: With this systematic review of the existing sets of diagnostic criteria for AD a varying number of validation studies with varying methodological quality was found. The U.K. diagnostic criteria are the most extensively validated. However, improvement of methodological design for validation studies and uniformity in well-validated and applicable diagnostic criteria are needed to improve future intervention studies and to compare study results.

Accuracy of body mass index in predicting pre-eclampsia: bivariate meta-analysis.

OBJECTIVE: The objective of this study was to determine the accuracy of body mass index (BMI) (pre-pregnancy or at booking) in predicting pre-eclampsia and to explore its potential for clinical application. DESIGN: Systematic review and bivariate meta-analysis. SETTING: Medline, Embase, Cochrane Library, MEDION, manual searching of reference lists of review articles and eligible primary articles, and contact with experts. POPULATION: Pregnant women at any level of risk in any healthcare setting. METHODS: Reviewers independently selected studies and extracted data on study characteristics, quality, and accuracy. No language restrictions. MAIN OUTCOME MEASURES: Pooled sensitivities and specificities (95% CI), a summary receiver operating characteristic curve, and corresponding likelihood ratios (LRs). The potential value of BMI was assessed by combining its predictive capacity for different prevalences of pre-eclampsia and the therapeutic effectiveness (relative risk 0.90) of aspirin. RESULTS: A total of 36 studies, testing 1,699,073 pregnant women (60,584 women with pre-eclampsia), met the selection criteria. The median incidence of pre-eclampsia was 3.9% (interquartile range 1.4-6.8). The area under the curve was 0.64 with 93% of heterogeneity explained by threshold differences. Pooled estimates (95% CI) for all studies with a BMI > or = 25 were 47% (33-61) for sensitivity and 73% (64-83) for specificity; and 21% (12-31) and 92% (89-95) for a BMI > or = 35. Corresponding LRs (95% CI) were 1.7 (0.3-11.9) for BMI > or = 25 and 0.73 (0.22-2.45) for BMI < 25, and 2.7 (1.0-7.3) for BMI > or = 35 and 0.86 (0.68-1.07) for BMI < 35. The number needed to treat with aspirin to prevent one case of pre-eclampsia ranges from 714 (no testing, low-risk women) to 37 (BMI > or = 35, high-risk women). CONCLUSIONS: BMI appears to be a fairly weak predictor for pre-eclampsia. Although BMI is virtually free of cost, noninvasive, and ubiquitously available, its usefulness as a stand-alone test for risk stratification must await formal cost-utility analysis. The findings of this review may serve as input for such analyses.