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Research and Reporting Methods |

Measuring the Performance of Markers for Guiding Treatment Decisions

Holly Janes, PhD; Margaret S. Pepe, PhD; Patrick M. Bossuyt, PhD; and William E. Barlow, PhD
[+] Article and Author Information

From Fred Hutchinson Cancer Research Center, Seattle, Washington; Academic Medical Center, Amsterdam, the Netherlands; and Cancer Research and Biostatistics, Seattle, Washington.


Grant Support: By the National Institutes of Health (grant R01CA152089).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1272.

Requests for Single Reprints: Holly Janes, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2 C200, Seattle, WA 98109; e-mail, hjanes@fhcrc.org.

Current Author Addresses: Dr. Janes: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2 C200, Seattle, WA 98109.

Dr. Pepe: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2 B500, Seattle, WA 98109.

Dr. Bossuyt: Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Room J1b-21, Box 22700, 1100 DE, Amsterdam, the Netherlands.

Dr. Barlow: Cancer Research and Biostatistics, 1730 Minor Avenue, Suite 1900, Seattle, WA 98101.

Author Contributions: Conception and design: H. Janes, M.S. Pepe, P.M. Bossuyt, W.E. Barlow.

Analysis and interpretation of the data: H. Janes, W.E. Barlow.

Drafting of the article: H. Janes, W.E. Barlow.

Critical revision of the article for important intellectual content: H. Janes, M.S. Pepe, P.M. Bossuyt, W.E. Barlow.

Final approval of the article: H. Janes, M.S. Pepe, P.M. Bossuyt, W.E. Barlow.

Statistical expertise: H. Janes, M.S. Pepe, W.E. Barlow.

Obtaining of funding: H. Janes.

Collection and assembly of data: H. Janes.


Ann Intern Med. 2011;154(4):253-259. doi:10.7326/0003-4819-154-4-201102150-00006
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Treatment selection markers, sometimes called predictive markers, are factors that help clinicians select therapies that maximize good outcomes and minimize adverse outcomes for patients. Existing statistical methods for evaluating a treatment selection marker include assessing its prognostic value, evaluating treatment effects in patients with a restricted range of marker values, and testing for a statistical interaction between marker value and treatment. These methods are inadequate, because they give misleading measures of performance that do not answer key clinical questions about how the marker might help patients choose treatment, how treatment decisions should be made on the basis of a continuous marker measurement, what effect using the marker to select treatment would have on the population, or what proportion of patients would have treatment changes on the basis of marker measurement. Marker-by-treatment predictiveness curves are proposed as a more useful aid to answering these clinically relevant questions, because they illustrate treatment effects as a function of marker value, outcomes when using or not using the marker to select treatment, and the proportion of patients for whom treatment recommendations change after marker measurement. Randomized therapeutic clinical trials, in which entry criteria and treatment regimens are not restricted by the marker, are also proposed as the basis for constructing the curves and evaluating and comparing markers.

Figures

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Figure.
Marker-by-treatment predictiveness curves for 6 candidate treatment selection markers.

The 5-year DFS rate is plotted as a function of marker percentile, with raw marker values shown in parentheses. The overall DFS rate with use of the marker for guiding treatment is shown, as well as the percentage of women who have higher DFS rates with tamoxifen alone (marker-negative). In the absence of the marker, chemotherapy would be recommended for all women (overall DFS rate, 79%). Markers A and D are prognostic but not useful for selecting treatment, because all patients are recommended chemotherapy regardless of marker value. Marker B is not prognostic on tamoxifen plus chemotherapy but is useful for selecting treatment. Marker C performs similarly to the 21-gene recurrence score, an existing treatment selection marker (11). Marker D has the same interaction with treatment as marker C. Marker E is a very good marker for treatment selection. Marker F has the same association with response to each treatment as marker E, but a different distribution; marker F has a worse performance for treatment selection than marker E. DFS = disease-free survival.

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