Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis

Autoři: Daniel A. Pfeffer aff001;  Benedikt Ley aff001;  Rosalind E. Howes aff002;  Patrick Adu aff004;  Mohammad Shafiul Alam aff005;  Pooja Bansil aff006;  Yap Boum, II aff007;  Marcelo Brito aff009;  Pimlak Charoenkwan aff010;  Archie Clements aff011;  Liwang Cui aff013;  Zeshuai Deng aff014;  Ochaka Julie Egesie aff015;  Fe Esperanza Espino aff016;  Michael E. von Fricken aff017;  Muzamil Mahdi Abdel Hamid aff018;  Yongshu He aff014;  Gisela Henriques aff019;  Wasif Ali Khan aff005;  Nimol Khim aff020;  Saorin Kim aff020;  Marcus Lacerda aff009;  Chanthap Lon aff021;  Asrat Hailu Mekuria aff022;  Didier Menard aff023;  Wuelton Monteiro aff009;  Francois Nosten aff024;  Nwe Nwe Oo aff026;  Sampa Pal aff006;  Duangdao Palasuwan aff027;  Sunil Parikh aff028;  Ayodhia Pitaloka Pasaribu aff029;  Jeanne Rini Poespoprodjo aff030;  David J. Price aff031;  Arantxa Roca-Feltrer aff033;  Michelle E. Roh aff034;  David L. Saunders aff021;  Michele D. Spring aff021;  Inge Sutanto aff037;  Kamala Ley-Thriemer aff001;  Thomas A. Weppelmann aff038;  Lorenz von Seidlein aff024;  Ari Winasti Satyagraha aff040;  Germana Bancone aff024;  Gonzalo J. Domingo aff006;  Ric N. Price aff001
Působiště autorů: Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia aff001;  Malaria Atlas Project, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff002;  Foundation for Innovative New Diagnostics, Geneva, Switzerland aff003;  Department of Medical Laboratory Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana aff004;  Infectious Diseases Division, International Centre for Diarrheal Diseases Research, Bangladesh, Mohakhali, Dhaka, Bangladesh aff005;  Diagnostics Program, PATH, Seattle, Washington, United States of America aff006;  Médecins sans Frontières Epicentre, Mbarara Research Centre, Mbarara, Uganda aff007;  Mbarara University of Science and Technology, Mbarara, Uganda aff008;  Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Amazonas, Brasil aff009;  Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand aff010;  Faculty of Health Sciences, Curtin University, Bentley, Australia aff011;  Telethon Kids Institute, Nedlands, Australia aff012;  Department of Entomology, Pennsylvania State University, University Park, Pennsylvania, United States of America aff013;  Department of Cell Biology and Medical Genetics, Kunming Medical University, Kunming, Yunnan Province, China aff014;  Department of Hematology and Blood Transfusion, Faculty of Medical Sciences, University of Jos and Jos University Teaching Hospital, Jos, Plateau State, Nigeria aff015;  Department of Parasitology, Research Institute for Tropical Medicine, Department of Health, Alabang, Muntinlupa City, Philippines aff016;  Department of Global and Community Health, George Mason University, Fairfax, Virginia, United States of America aff017;  Department of Parasitology and Medical Entomology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Republic of the Sudan aff018;  Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom aff019;  Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia aff020;  Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand aff021;  School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia aff022;  Malaria Genetics and Resistance Group, Institut Pasteur, Paris, France aff023;  Shoklo Malaria Research Unit, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand aff024;  Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom aff025;  Department of Medical Research, Lower Myanmar, Yangon, Myanmar aff026;  Oxidation in Red Cell Disorders and Health Research Unit, Department of Clinical Microscopy, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand aff027;  Yale School of Public Health, New Haven, Connecticut, United States of America aff028;  Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia aff029;  Yayasan Pengembangan Kesehatan dan Masyarakat Papua (YPKMP), Papua, Indonesia aff030;  Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia aff031;  The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia aff032;  Malaria Consortium, Phnom Penh, Cambodia aff033;  Global Health Group, Malaria Elimination Initiative, University of California, San Francisco, San Francisco, United States of America aff034;  F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America aff035;  US Army Medical Materiel Development Activity, Fort Detrick, Maryland, United States of America aff036;  University of Indonesia, Jakarta, Indonesia aff037;  Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, United States of America aff038;  Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand aff039;  Eijkman Institute for Molecular Biology, Jakarta, Indonesia aff040
Vyšlo v časopise: Quantification of glucose-6-phosphate dehydrogenase activity by spectrophotometry: A systematic review and meta-analysis. PLoS Med 17(5): e32767. doi:10.1371/journal.pmed.1003084
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003084



The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold.

Methods and findings

Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (<70% G6PD activity), sensitivity fell to a minimum of 64% (95% CI: 52%–75%) and specificity to 35% (95% CI: 24%–46%). Our ability to identify underlying factors associated with study-level heterogeneity was limited by the lack of availability of covariate data and diverse study contexts and methodologies.


Our findings indicate that there is substantial variation in G6PD measurements by spectrophotometry between sites. This is likely due to variability in laboratory methods, with possible contribution of unmeasured population factors. While an assay-specific, universal quantitative threshold offers robust diagnosis at the 30% level, inter-study variability impedes performance of universal thresholds at the 70% level. Caution is advised in comparing findings based on absolute G6PD activity measurements across studies. Novel handheld quantitative G6PD diagnostics may allow greater standardisation in the future.

Klíčová slova:

Antimalarials – Glucose-6-phosphate dehydrogenase deficiency – Hematology – Malaria – Plasmodium – Primaquine – Quality control – Spectrophotometry


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