title: The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis.
abstract: 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.
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE, Amsterdam, The Netherlands. m.m.leeflang@amc.uva.nl.
authors.forename: M M G
authors.initials: MM
authors.lastname: Leeflang
authors.affiliation: VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Ang
authors.affiliation: Canisius-Wilhelmina Hospital, PO Box 9015, 6500 GS, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Berkhout
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, The Netherlands.
authors.forename: H A
authors.initials: HA
authors.lastname: Bijlmer
authors.affiliation: European Centre for Disease Prevention and Control (ECDC), 171 83, Stockholm, Sweden.
authors.forename: W
authors.initials: W
authors.lastname: Van Bortel
authors.affiliation: Izore Centre for Infectious Diseases Friesland, PO Box 21020, 8900 JA, Leeuwarden, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Brandenburg
authors.affiliation: HagaZiekenhuis, Leyweg 275, 2545 CH, The Hague, Netherlands.
authors.forename: N D
authors.initials: ND
authors.lastname: Van Burgel
authors.affiliation: Department of Medical Microbiology, Onze Lieve Vrouwe Gasthuis, P.O. Box 95500, 1090 HM, Amsterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Van Dam
authors.affiliation: Slagelse Hospital, Fælledvej 1, 4200, Slagelse, Region Zealand, Denmark.
authors.forename: R B
authors.initials: RB
authors.lastname: Dessau
authors.affiliation: German National Reference Centre for Borrelia, Bavarian Health and Food Safety Authority, Veterinärstraße 2, 85764, Oberschleißheim, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Fingerle
authors.affiliation: Centre for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J W R
authors.initials: JW
authors.lastname: Hovius
authors.affiliation: National Reference Centre for Borrelia, Department Laboratory of Bacteriology, Strasbourg University Hospital, 1 Place de l'Hôpital, Strasbourg, France.
authors.forename: B
authors.initials: B
authors.lastname: Jaulhac
authors.affiliation: Laboratory for Infectious Diseases, PO Box 30039, 9700 RM, Groningen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Meijer
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Van Pelt
authors.affiliation: Laboratory for Infectious Diseases, PO Box 30039, 9700 RM, Groningen, The Netherlands.
authors.forename: J F P
authors.initials: JF
authors.lastname: Schellekens
authors.affiliation: Dutch Cochrane Centre, Julius Center for Health Sciences and Primary Care/University Medical Center, PO Box 85500, 3508 GA, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Spijker
authors.affiliation: Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: F F
authors.initials: FF
authors.lastname: Stelma
authors.affiliation: Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Stanek
authors.affiliation: Department of Medical Microbiology University Medical Center Utrecht (UMC), P.O. Box 85500, 3508GA, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Verduyn-Lunel
authors.affiliation: European Centre for Disease Prevention and Control (ECDC), 171 83, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Zeller
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Sprong
mesh_terms: D019540:Area Under Curve; D016208:Databases, Factual; D004797:Enzyme-Linked Immunosorbent Assay; D005060:Europe / Q000453:epidemiology; D006801:Humans; D008193:Lyme Disease / Q000175:diagnosis* / Q000453:epidemiology; D012372:ROC Curve; D012680:Sensitivity and Specificity; D012698:Serologic Tests
keywords: Lyme borreliosis; meta-analysis; sensitivity and specificity; serology