Intended for healthcare professionals

Rapid response to:

Education And Debate

Evidence based diagnostics

BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7493.724 (Published 24 March 2005) Cite this as: BMJ 2005;330:724

Rapid Response:

Evidence based diagnostics and genetic testing

Gluud and Gluud have written an excellent article that emphasises the need for rigour in evaluating diagnostics, which we support(1). However, we disagree with their statement that “in some cases, the value of a diagnostic test is self-evident – for example, in genetic testing”. The term “genetic test” is shorthand to describe a test to detect (i) a particular genetic variant (or set of variants), (ii) for a particular disease, (iii) in a particular population and (iv) for a particular purpose(2). Genetic tests can be used for diagnosis, risk prediction, susceptibility testing or the detection of carrier status. A genetic test is therefore a complex intervention that is one component of an overall intervention. It is fundamental that evidence of a genetic test’s clinical utility should be obtained before its introduction into clinical practice; this should include clinical, economic and psychological measures of benefit and especially potential harms from testing.

Genetic tests may have certain perceived advantages compared to other types of diagnostic test, but the assumption that their value is self- evident is flawed. For example, the recent UK Government's White Paper on Genetics used the example of testing for gene variants that determine susceptibility to the adverse effects of warfarin(3). It was suggested that general practitioners might use genetic testing to identify individuals at high risk of bleeding before treating them with warfarin. Whilst this sounds like a good idea, there is no evidence showing that genetic testing improves clinical outcomes compared with routine management. Indeed, with the careful assessment of patients prior to treatment, the use of carefully controlled dosing regimens at initiation, regular monitoring of the INR, and computerised decision support systems controlling dose recommendations, patients on warfarin can be satisfactorily managed without a genetic test(4). There are already other genetic variants that could be tested for but which have doubtful utility (including ApoE and Alzheimer disease, HFE and haemochromatosis, and Factor V Leiden and venous thrombo-embolism)(5). A test that does not improve or alter clinical management should not be introduced into clinical practice.

It is our view that genetic tests must be evaluated as rigorously as possible in terms of their analytical validity (how well tests perform in the laboratory), clinical validity (how well they perform in patients), clinical utility (whether testing confers any net benefit to those tested), along with due consideration of their ethical, legal and social implications. These principles have been developed in the United States as part of the Centers for Disease Control’s ACCE programme and adopted by the United Kingdom’s Genetic Testing Network to produce a system for evaluating emerging genetic tests for use in the NHS(6;7). Although we believe that all genetic tests should be rigorously evaluated, we are not implying that a bureaucratic statutory system of regulation should be established because arguments that genetic tests require more statutory regulation than other diagnostics are generally weak(8).

Reference List

(1) Gluud C, Gluud LL. Evidence based diagnostics. BMJ. 2005;330:724 -26.

(2) Kroese M, Zimmern RL, and Sanderson SP. Genetic Tests and their Evaluation: Can we answer the key questions? Genet.Med. 6(6), 475-480. 2004.

(3) Department of Health. Our inheritance, our future - realising the potential of genetics in the NHS. 2004.

(4) Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med. 2005;7:97-104.

(5) Evans JP, Skrzynia C, Burke W. The complexities of predictive genetic testing. BMJ. 2001;322:1052-56.

(6) Haddow J, Palomaki G. ACCE: A Model Process for Evaluating Data on Emerging Genetic Tests. In: Khoury M, Little J, Burke W, eds. Human Genome Epidemiology. First ed. Oxford University Press; 2004: 217-33.

(7) Department of Health. United Kingdom Genetic Testing Network. www.ukgtn.org . 2004.

(8) Burke W, Zimmern RL. Ensuring the appropriate use of genetic tests. Nat Rev Genet. 2004;5:955-59.

Competing interests: None declared

Competing interests: No competing interests

15 April 2005
Simon P Sanderson
Clinical Lecturer Primary Care Genetics
Mark Kroese, Ron Zimmern
Public Health Genetics Unit and University of Cambridge