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Title Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs / prepared for Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services ; prepared by University of Ottawa Evidence-based Practice Centre. ; EPC director, David Moher ; investigators, Ronald A. Booth [and others].

Imprint Rockville, MD : Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services, [2010]


Location Call No. OPAC Message Status
 Axe Federal Documents Online  HE 20.6502:T 34    ---  Available
Description 1 online resource (PDF (1 volume)) : illustrations.
text txt rdacontent
computer c rdamedia
online resource cr rdacarrier
Series Evidence report/technology assessment ; no. 196
AHRQ publication ; no. 11-E002
Evidence report/technology assessment ; no. 196.
AHRQ publication ; no. 11-E002.
Note "Contract No. 290-2007-10059-I (EPCIII)."
""December 2010."
Bibliography Includes bibliographical references.
Summary OBJECTIVES: To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. DATA SOURCES: MEDLINE(r), EMBASE(r), and Healthstar were searched from inception to May 2010; the Cochrane Library(r) to October 2009; and BIOSIS(r), Genetics Abstracts, and EconLitTM to May 2009, for English language records. REVIEW METHODS: A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. RESULTS: 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. CONCLUSIONS: There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.
Funding Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, 540 Gaither Road, Rockville, MD 20850; Contract Number: 290-2007-10059-I (EPCIII), Prepared by: University of Ottawa Evidence-based Practice Centre, Ottawa, ON, Canada
Note Online resourse; title from PDF title page (viewed on Feb. 13, 2012).
Subject Medicine -- Research -- United States -- Evaluation.
Methyltransferases -- genetics.
Autoimmune Diseases -- enzymology.
Azathioprine -- therapeutic use.
Azathioprine -- adverse effects.
Genetic Association Studies.
Evidence-Based Practice.
United States.
Medicine -- Research -- Evaluation. (OCoLC)fst01015068
Meta-analysis. (OCoLC)fst01017463
Methyltransferases. (OCoLC)fst01018792
Purines. (OCoLC)fst01084343
United States. (OCoLC)fst01204155
Genre/Form Meta-Analysis.
Added Author Moher, David, 1957-
Booth, Ronald A.
United States. Agency for Healthcare Research and Quality.
University of Ottawa Evidence-based Practice Center.
Standard No. NLM 101570723
AU@ 000051461558
Gpo Item No. 0507-I-01 (online)
Sudoc No. HE 20.6502:T 34

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