Abstract
Recent research into the human genome has generated a wealth of scientific knowledge and increased both public and professional interest in the concept of personalised medicine. Somewhat unexpectedly, in addition to increasing our understanding about the genetic basis for numerous diseases, these new discoveries have also spawned a burgeoning new industry of ‘consumer genetic testing’. In this paper, we present the principles learnt though the evaluation of tests for single gene disorders and suggest a comparable framework for the evaluation of genetic tests for susceptibility to common complex diseases. Both physicians and the general public will need to be able to assess the claims made by providers of genetic testing services, and ultimately policy-makers will need to decide if and when such tests should be offered through state funded healthcare systems.
Similar content being viewed by others
References
Altman D, Royston P (2000) What do we mean by validating a prognostic model? Stat Med 19:453–473
Altman DG, Vergouwe Y, Royston P, Moons KGM (2009) Prognosis and prognostic research: validating a prognostic model. BMJ 338:1432–1435
Anderson KM, Wilson PW, Odell PM, Kannel WB (1991) An updated coronary risk profile. A statement for health professionals. Circulation 83:356–362
Bundesrat (2009) Draft Human Genetic Examination Act (Genetic Diagnosis Act—GenDG)
Burke W, Zimmern RL (2007) Moving Beyond ACCE: an expanded framework for genetic test evaluation. PHG Foundation
Chanock S, NCI-NHGRI Working Group on Replication in Association Studies (2007) Replicating genotype-phenotype associations. Nature 447:655–660
Cook NR (2007) Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation 115:928–935
Cook NR (2008) Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem 54:17–23
Coop G, Wen X, Ober C, Pritchard JK, Przeworski M (2008) High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319:1395–1398
Drenos F, Whittaker J, Humphries SE (2007) The use of meta-analysis risk estimates for candidate genes in combination to predict coronary heart disease risk. Ann Hum Genet 71:611–619
Dupont WD, Plummer WD (1996) Understanding the relationship between relative and absolute risk. Cancer 77:2193–2199
Editorial (2009) Genetic testing for susceptibility: a risky business. Lancet Neurol 8:775
EGAPP Working Group (2007) Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Genetics in Medicine 9(12):819–825
EGAPP Working Group (2009a) Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genet Med 11:66–73
EGAPP Working Group (2009b) Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med 11:15–20
EGAPP Working Group (2009c) Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11:35–41
European Society for Human Genetics (2009) Genetic testing in asymptomatic minors: recommendations of the European Society of Human Genetics. Eur J Hum Genet 17:720–721
Evans JP, Green RC (2009) Direct to consumer genetic testing: avoiding a culture war. Genet Med 11(8):568–569
Fawcett T (2006) An introduction to ROC analysis. Pattern Recogn Lett 27:861–874
Foster MW, Mulvihill JJ, Sharp RR (2009) Evaluating the utility of personal genomic information. Genet Med 11(8):570–574
Fulda KG, Lykens K (2006) Ethical issues in predictive genetic testing: a public health perspective. J Med Ethics 32:143–147
Gail MH, Pfeiffer RM (2005) On criteria for evaluating models of absolute risk. Biostat 6:227–239
GeneTests (2009) Medical genetics information resource (database online). Available at http://www.genetests.org. Accessed 3 July 2009
Grosse SD, McBride CM, Evans JP, Khoury MJ (2009) Personal utility and genomic information: look before you leap. Genet Med 11(8):575–576
Gu S, Pakstis AJ, Li H, Speed WC, Kidd JR, Kidd KK (2007) Significant variation in haplotype block structure but conservation in tagSNP patterns among global populations. Eur J Hum Genet 15:302–312
Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, Smith-Gamble V, Lane KA, Gao S, Hall KS, Hendrie HC, Murrell JR (1996) APOE epsilon4 is not associated with Alzheimer’s disease in elderly Nigerians. Science 273:1516–1517
Gurwitz D, Bregman-Eschet Y (2009) Personal genomics services: whose genomes? Eur J Hum Genet 17:883–889
Haddow JE, Palomaki GE (2004) ACCE: A model process for evaluating data on emerging genetic tests. In: Khoury MJ, Little J, Burke W (eds) Human genome epidemiology. Oxford University Press, New York, pp 217–233
HGC (2002) Inside Information; balancing interests in the use of personal genetic data. A report by the Human Genetics Commission
HGC (2007) More genes direct: a report on developments in the availability marketing and regulation of genetic tests supplied directly to the public
HGC (2009) Common framework of principles for direct-to-consumer genetic testing services. http://www.hgc.gov.uk/Client/Content.asp?ContentId=816. Accessed 24 Oct 2009
Hindorff L, Junkins H, Mehta J, Manolio T (2009a) A catalogue of published genome-wide association studies. www.genome.gov/gwastudies. Accessed 3 July 2009
Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009b) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Nat Acad Sci 106:9362–9367
Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, May M, Brindle P (2007) Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study. BMJ 335:136
Hogarth S, Javitt G, Melzer D (2008) The current landscape for direct-to-consumer genetic testing: legal, ethical, and policy issues. Annu Rev Genomics Hum Genet 9:161–182
House of Lords Science and Technology Committee (2009) Genomic Medicine. HL paper no 107-I and 107-II
Ioannidis JPA (2009) Personalized genetic prediction: too limited, too expensive, or too soon? Ann Intern Med 150:139–141
Ioannidis JPA, Ntzani EE, Trikalinos TA (2004) ‘Racial’ differences in genetic effects for complex diseases. Nat Genet 36:1312–1318
Janssens ACJW, van Duijn CM (2008) Genome-based prediction of common diseases: advances and prospects. Hum Mol Genet 17:R166–R173
Janssens ACJW, Gwinn M, Bradley L, Oostra BA, van Duijn CM, Khoury MJ (2008) A crical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. Am J Med Genet 82:593–599
Kaye J (2008) The regulation of direct-to-consumer genetic tests. Hum Mol Genet 17:R180–R183
Khoury MJ, Feero WG, Reyes M, Citrin T, Freedman A, Leonard D, Burke W, Coates R, Croyle RT, Edwards K, Kardia S, McBride C, Manolio T, Randhawa G, Rasooly R, St.Pierre J, Terry S, the GAPPNet Planning Group (2009a) The genomic applications in practice and prevention network. Genet Med 11(7):488–494
Khoury MJ, Gwinn M, Yoon PW, Dowling N, Moore CA, Bradley L (2007) The continuum of translation research in genomic medicine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention? Genet Med 9:665–674
Khoury MJ, McBride CM, Schully SD, Ioannidis JPA, Feero WG, Janssens AC, Gwinn M, Simons-Morton DG, Bernhardt JM, Cargill M, Chanock SJ, Church GM, Coates RJ, Collins FS, Croyle RT, Davis BR, Downing GJ, DuRoss A, Friedman S, Gail MH, Ginsburg GS, Green RC, Greene MH, Greenland P, Gulcher JR, Hsu A, Hudson KL, Kardia SLR, Kimmel PL, Lauer MS, Miller AM, Offit K, Ransohoff DF, Roberts JS, Rasooly RS, Stefansson K, Terry SF, Teutsch SM, Trepanier A, Wanke KL, Witte JS, Xu J (2009b) The scientific foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention Multidisciplinary Workshop. Genet Med 11(8):559–567
Khoury MJ, Rich EC, Randhawa G, Teutsch SM, Niederhuber J (2009c) Comparative effectiveness research and genomic medicine: an evolving partnership for 21st century medicine. Genet Med 11(10):707–711
Kraft P, Hunter DJ (2009) Genetic risk prediction—are we there yet? N Engl J Med 360:1701–1703
Kraft P, Wacholder S, Cornelis MC, Hu FB, Hayes RB, Thomas G, Hoover R, Hunter DJ, Chanock S (2009) Beyond odds ratios—communicating disease risk based on genetic profiles. Nat Rev Genet 10:264–269
Kroese M, Zimmern RL, Farndon P, Stewart F, Whittaker J (2007) How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network. Eur J Hum Genet 15:917–921
Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von EE, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van DC, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett N (2009) STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 6:e22
Lunshof JE, Chadwick R, Vorhaus DB, Church GM (2008) From genetic privacy to open consent. Nat Rev Genet 9:406–411
Manolio T, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Investig 118:1590–1605
McBride CM, Alford SH, Reid RJ, Larson EB, Baxevanis AD, Brody LC (2008) Putting science over supposition in the arena of personalized genomics. Nat Genet 40:939–942
McGuire AL, Burke W (2008) An unwelcome side effect of direct-to-consumer personal genome testing: raiding the medical commons. JAMA 300:2669–2671
Mihaescu R, van Hoek M, Sijbrands EJG, Uitterlinden AG, Witteman JCM, Hofman A, van Duijn CM, Janssens AC (2009) Evaluation of risk prediction updates from commercial genome-wide scans. Genet Med 11
Ng PC, Murray SS, Levy S, Venter CJ (2009) An agenda for personalized medicine. Nature 461:724–726
Offit K (2008) Genomic profiles for disease risk: predictive or premature? JAMA 299:1353–1355
Panagiotakos D, Stavrinos V (2006) Methodological issues in cardiovascular epidemiology: the risk of determining absolute risk through statistical models. Vasc Health Risk Manag 2:309–315
Patch C, Sequeiros J, Cornel MC (2009) Genetic horoscopes: is it all in the genes? Points for regulatory control of direct-to-consumer genetic testing. Eur J Hum Genet 17:857–859
Pencina M, D’Agostino R Sr, D’Agostino R Jr, Vasan R (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172
Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P (2004) Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol 159:882–890
Personalized Medicine Coalition (2008) Personal genomics and industry standards: scientific validity. http://www.personalizedmedicinecoalition.org/sciencepolicy/publicpolicy_consumer-genomics.php
Pharoah PDP, Mackay J (1998) Absolute risk of breast cancer in women at increased risk: a more useful clinical measure than relative risk? The Breast 7:255–259
Pharoah PDP, Antoniou AC, Bobrow M, Zimmern RL, Easton DF, Ponder BAJ (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36
Pharoah PDP, Antoniou AC, Easton DF, Ponder BAJ (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358:2796–2803
Prainsack B, Reardon J, Hindmarsh R, Gottweis H, Naue U, Lunshof JE (2008) Personal genomes: misdirected precaution. Nature 456:34–35
Pushkarev D, Neff NF, Quake SR (2009) Single-molecule sequencing of an individual human genome. Nat Biotech 27:847–850
Sanderson S, Zimmern RL, Kroese M, Higgins J, Patch C, Emery J (2005) How can the evaluation of genetic tests be enhanced? Lessons learned from the ACCE framework and evaluating genetic tests in the United Kingdom. Genet Med 7:495–500
Schmidt C (2008) Regulators weigh risks of consumer genetic tests. Nat Biotech 26:145–146
Teutsh S, Bradley L, Palomaki G, Haddow J, Piper M, Calonge N, Dotson W, Douglas M, Berg A (2009) The evaluation of genomic applications in practice and prevention (EGAPP) initiative:methods of the EGAPP working group. Genet Med 11:3–14
UKGTN (2009) Gene Dossier. http://www.ukgtn.nhs.uk/gtn/Information/Services/Gene+Dossiers/Forms. Accessed 24 Oct 2009
United States of America (2008) Genetic information nondiscrimination act. Public Law110–233
Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW (2004) Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 6(5):387–391
Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97:1837–1847
Zimmern RL (2009) Testing challenges: evaluation of novel diagnostics and molecular biomarkers. Clin Med 9:68–73
Zimmern RL, Kroese M (2007) The evaluation of genetic tests. J Public Health 29:246–250
Acknowledgments
The authors with to thank Ron Zimmern for helpful discussions through which many of the concepts in this paper were developed. CW is funded by the PHG Foundation, which is the working name of the Foundation for Genomics and Population Health, a charitable company registered in England and Wales: Charity No 118664, Company No 5823194. MK is funded by the UK Genetic Testing Network.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wright, C.F., Kroese, M. Evaluation of genetic tests for susceptibility to common complex diseases: why, when and how?. Hum Genet 127, 125–134 (2010). https://doi.org/10.1007/s00439-009-0767-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-009-0767-x