Home > DARE Reviews > Diagnostic strategies using DNA testing...

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation

J Bryant, K Cooper, J Picot, P Clegg A. Roderick, W Rosenberg, and C Patch.

Review published: 2009.

Link to full article: [Journal publisher]

CRD summary

This review evaluated diagnostic accuracy and psychosocial outcomes of DNA testing for detecting hereditary haemochromatosis. The authors concluded that DNA testing was the preferred diagnostic strategy and this intervention can reduce anxiety with no adverse effects. This was a well-conducted review. The authors' conclusions reliably reflect the limited evidence base.

Authors' objectives

To evaluate diagnostic accuracy, clinical effectiveness and psychosocial outcomes of DNA testing for detecting hereditary haemochromatosis.

Searching

The Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS Previews, PsycLIT, MEDION, NHS EED, HTA database, DARE, EconLit, NRR, Current Controlled Trials and ClinicalTrials.gov were searched from inception to April 2007 for published English-language articles on DNA tests for C282Y mutations from 1996 onwards. Grey literature and conference proceedings were searched for unpublished material. Search terms were reported. Bibliographies of related papers were assessed for further studies.

Study selection

For evaluation of diagnostic accuracy, controlled cohort or case-control studies of DNA tests in north European Caucasians with iron overload that indicated haemochromatosis were eligible for inclusion in the review. Outcomes of interest were reported or calculable sensitivity (probability of individuals with an existing or potential primary iron overload phenotype having a positive test result for C282Y homozygosity) and specificity. Population screening studies were excluded. A range of definitions for the clinical phenotype was reported in the included studies.

For evaluation of clinical effectiveness, randomised controlled trials (RCTs), controlled cohort and case-control studies that compared DNA tests with any case identification strategy that did not involve DNA testing in the same population (as above) were eligible for inclusion. Outcomes of interest were treatment, morbidity and mortality.

For evaluation of psychosocial outcomes, any study that comprised diagnosed and at-risk individuals who underwent DNA testing were eligible. Studies that measured treatment compliance, psychological outcomes, legal implications, quality of life and discrimination/stigmatisation were eligible.

Two independent reviewers selected papers for inclusion in the review. Disagreements were resolved either by consensus or by involvement of a third reviewer.

Assessment of study quality

Validity assessment of diagnostic accuracy studies was carried out using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) tool combined with selected criteria from Spitzer and colleagues. Aspects considered were: description of patients, control group, tests and outcomes; definition of disease; sampling; comparability of groups; reporting of missing data; and generalisability of results. Observational studies were assessed on randomisation, sampling method and size, objectivity of outcome measures, attrition rates, comparability of groups and generalisability of results.

Two reviewers assessed study quality. Disagreements were resolved either by consensus or involvement of a third reviewer.

Data extraction

For diagnostic accuracy, data were extracted or calculated to enable reporting of sensitivity, specificity and positive predictive values (PPV) and negative predictive values (NPV). For psychosocial aspects, means, standard deviations and proportions of patients with the various outcomes were extracted.

Data were extracted by two reviewers. Disagreements were resolved either by consensus or involvement of a third reviewer.

Methods of synthesis

Studies were synthesised narratively. Differences were demonstrated in study tables. Sensitivity analyses were carried out to explore the effects of including only those studies with clearly defined haemochromatosis, clearly northern European studies and those that ruled out other causes of iron overload and in unrelated patients.

Results of the review

Diagnostic accuracy: Eleven cohort-controlled studies were included (n=3,577, sample size range 18 to 478). Study quality was reported to be variable (this was evident for the individual component scoring reported in the paper).

Sensitivity of DNA testing ranged from 28.4% to 100% (11 studies). In studies that were most likely to have correct definition of haemochromatosis, the range was 72.2% to 100% (seven studies). In studies that ruled out other causes of iron overload, and in unrelated patients, the range was 72.2% to 92.4% (four studies). When a small study conducted in southern Germany was excluded, the range was 91.3% to 92.4%.

Specificity ranged from 98.8% to 100% (11 studies). PPV ranged from 84.3% to 100%. NPV ranged from 46.3% to 100%. Further analysis with a narrower range of studies showed PPV ranges from 99% to 100% and NPV from 91% to 94.4%.

Clinical effectiveness: No studies assessed clinical effectiveness of DNA testing.

Psychosocial outcomes: Three cohort studies were included (n=355). All studies had methodological limitations. None reported any sampling method. Generalisability was difficult to determine.

Results suggested that DNA testing was generally well-accepted with few negative psychosocial outcomes and potentially reduced anxiety.

Cost information

A cost effectiveness evaluation reported that DNA testing in individuals suspected of having haemochromatosis was cost saving compared with liver biopsy (cost saved per case detected £123). When DNA testing was compared with baseline biochemical testing, family testing of offspring of individuals with hereditary haemochromatosis produced a cost saved per case detected of £7,982. There was no cost saving in the case of family testing of siblings.

Authors' conclusions

The authors concluded that DNA testing was the preferred diagnostic strategy for detecting hereditary haemochromatosis and this intervention can reduce anxiety with no adverse effects.

CRD commentary

The review addressed a clear question. Inclusion criteria were sufficiently detailed to allow replication. The search strategy was extensive and contained adequate attempts to minimise potential for publication bias. Language bias was a possibility. The restriction to English-language studies may mean that relevant data were missed. Appropriate validity assessment tools were used to evaluate the quality of included study designs and the results of this were used to illuminate the review findings. All aspects of the review process were conducted with satisfactory efforts to minimise errors and biases. The chosen method of synthesis was appropriate in light of the variable studies included. The authors acknowledged the limited evidence base. Their conclusions reflected the evidence presented and are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that DNA testing should be performed in conjunction with testing iron parameters when there was a clear clinical indication of suspicion of risk for haemochromatosis due to biochemical criteria or where there was a familial risk for hereditary haemochromatosis. Dissemination of guidelines in both primary and secondary care was advisable.

Research: The authors stated that prospective long-term follow-up studies were required to assess use of DNA testing for haemochromatosis. Further epidemiological research was needed on environmental and other genetic factors affecting the penetrance of genetic mutation, following which more research might be required on psychosocial aspects of testing.

Funding

National Institute of Health Research Health Technology Assessment Programme. Project number 05/07/04.

Bibliographic details

Bryant J, Cooper K, Picot J, Clegg A. Roderick P, Rosenberg W, Patch C. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation. Health Technology Assessment 2009; 13(23): 1-126. [PubMed: 19406046]

Other publications of related interest

Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, Patch C. Psychosocial aspects of DNA testing for hereditary haemochromatosis in at-risk individuals: a systematic review. Genetic Testing and Molecular Biomarkers. 2009; 13(1): 7-14.

Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, Patch C. A systematic review of the clinical validity and clinical utility of DNA testing for hereditary haemochromatosis type 1 in at-risk populations. J. Med. Genet. 2008; 45: 513-518

Indexing Status

Subject indexing assigned by NLM

MeSH

Genetic Predisposition to Disease; Genetic Testing /economics; Hemochromatosis /diagnosis /genetics; Homozygote; Humans

AccessionNumber

12009107063

Database entry date

31/03/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 19406046