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Validity of Models for Predicting BRCA1 and BRCA2 Mutations

Giovanni Parmigiani, PhD; Sining Chen, PhD; Edwin S. Iversen Jr, PhD; Tara M. Friebel, MPH; Dianne M. Finkelstein, PhD; Hoda Anton-Culver, PhD; Argyrios Ziogas, PhD; Barbara L. Weber, MD; Andrea Eisen, MD; Kathleen E. Malone, PhD; Janet R. Daling, PhD; Li Hsu, PhD; Elaine A. Ostrander, PhD; Leif E. Peterson, PhD; Joellen M. Schildkraut, PhD; Claudine Isaacs, MD; Camille Corio, MA; Leoni Leondaridis, MS; Gail Tomlinson, MD; Christopher I. Amos, PhD; Louise C. Strong, MD; Donald A. Berry, PhD; Jeffrey N. Weitzel, MD; Sharon Sand, CCRP; Debra Dutson, MA; Rich Kerber, PhD; Beth N. Peshkin, MS, CGC; and David M. Euhus, MD
[+] Article and Author Information

From Johns Hopkins University, Baltimore, Maryland; Center for Clinical Epidemiology and Biostatistics and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; Duke University, Durham, North Carolina; Massachusetts General Hospital, Boston, Massachusetts; University of California, Irvine, Irvine, California; University of Toronto, Toronto, Ontario, Canada; Fred Hutchinson Cancer Research Center, Seattle, Washington; Baylor College of Medicine and University of Texas M.D. Anderson Cancer Center, Houston, Texas; Lombardi Cancer Center, Georgetown University; University of Texas Southwestern Medical Center, Dallas, Texas; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.


Acknowledgments: Data were collected within the framework of the NCI's Cancer Genetics Network, combining data previously collected at each Cancer Genetics Network center and at City of Hope National Medical Center. Most data predated Cancer Genetics Network activities, but the Cancer Genetics Network provided the venue for the pooled analysis. The authors thank Connie Griffin for her Cancer Genetics Network leadership at the Johns Hopkins University, Kelly Qu for support with database management at Johns Hopkins University, Jihong Zong for collecting and transmitting data at M.D. Anderson Cancer Center, and Neil Malloy for assistance with data coordination at Massachusetts General Hospital.

Grant Support: In part by the NCI Cancer Genetics Network. Work of the Cancer Genetics Network Statistical Coordinating Center was supported by National Cancer Institute grant CA78284. Work of Drs. Parmigiani and Chen and Ms. Friebel was also supported in part by National Cancer Institute grants P50CA88843, P50CA62924-05, and 5P30 CA06973-39, R01CA105090-01A1; National Institutes of Health grant HL 99-024; and the Hecht Fund. Work of investigators at the Fred Hutchinson Cancer Research Center was supported in part by National Institutes of Health grants R01 CA 36397, R01 CA 63705, and K05 CA-90754. The work of Dr. Weitzel and Ms. Sand was supported in part by California Cancer Research Program of the University of California (grant no. 99-86874) and in part by a General Clinical Research Center grant from National Institutes of Health (M01 RR00043) awarded to the City of Hope National Medical Center. Data from Georgetown University were provided by the Familial Cancer Registry Shared Resource of Lombardi Comprehensive Cancer Center, which is supported in part by the National Institutes of Health (grant P30-CA-51008).

Potential Financial Conflicts of Interest: Employment: B.L. Weber (GlaxoSmithKline). Stock ownership or options (other than mutual funds): B.L. Weber (GlaxoSmithKline).

Requests for Single Reprints: Giovanni Parmigiani, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 550 North Broadway, Suite 1103, Baltimore, MD 21205-2011; e-mail, gp@jhu.edu.

Current Author Addresses: Dr. Parmigiani: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 550 North Broadway, Suite 1103, Baltimore, MD 21205-2011.

Dr. Chen: Department of Environmental Health Sciences, Johns Hopkins School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.

Dr. Iversen: Department of Statistical Sciences, Duke University, Box 90251, Durham, NC 27708.

Ms. Friebel: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 909 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021.

Dr. Finkelstein: Biostatistics Center, Massachusetts General Hospital, 50 Staniford Street, Suite 560, Boston, MA 02114.

Drs. Anton-Culver and Ziogas: University of California, 224 IH, Mail Code 7550, Irvine, CA 92697-7550.

Dr. Weber: GlaxoSmithKline, 2301 Renaissance Boulevard, Building 510, Mailcode RN0510, King of Prussia, PA 19406-2772.

Dr. Eisen: Department of Medicine, University of Toronto, Suite RFE 3-805, 190 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.

Drs. Malone, Daling, and Hsu: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024.

Dr. Ostrander: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, MSC 8000, Building 50, Room 5351, Bethesda, MD 20892-8000.

Dr. Peterson: The Methodist Hospital, 6550 Fannin Street, SM-1299, Houston, TX 77030.

Dr. Schildkraut: Duke University Medical Center, Box 2949, Durham, NC 27510.

Dr. Isaacs, Ms. Corio, Ms. Leondaridis, and Ms. Peshkin: Georgetown University, 2233 Wisconsin Avenue NW, Suite 317, Washington, DC 20007.

Drs. Tomlinson and Euhus: University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9155.

Drs. Amos, Strong, and Berry: M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 189, Houston, TX 77030.

Dr. Weitzel and Ms. Sand: City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91001.

Ms. Dutson and Dr. Kerber: Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550.

Author Contributions: Conception and design: G. Parmigiani, D.M. Finkelstein, H. Anton-Culver, B.L. Weber, G. Tomlinson, D.M. Euhus.

Analysis and interpretation of the data: G. Parmigiani, S. Chen, E.S. Iversen Jr., A. Ziogas, B.L. Weber, L.E. Peterson, R. Kerber, B.N. Peshkin, D.M. Euhus.

Drafting of the article: G. Parmigiani, H. Anton-Culver, L.E. Peterson.

Critical revision of the article for important intellectual content: S. Chen, E.S. Iversen Jr., K.E. Malone, J.R. Daling, L. Hsu, E.A. Ostrander, C. Isaacs, C.I. Amos, D.A. Berry, J.N. Weitzel, B.N. Peshkin, D.M. Euhus.

Final approval of the article: G. Parmigiani, S. Chen, E.S. Iversen Jr., D.M. Finkelstein, B.L. Weber, A. Eisen, K.E. Malone, J.R. Daling, E.A. Ostrander, J.M. Schildkraut, C. Isaacs, C. Corio, G. Tomlinson, J.N. Weitzel, B.N. Peshkin.

Provision of study materials or patients: D.M. Finkelstein, B.L. Weber, A. Eisen, K.E. Malone, J.R. Daling, J.M. Schildkraut, C. Isaacs, C. Corio, G. Tomlinson, C.I. Amos, L.C. Strong, J.N. Weitzel, D. Dutson, B.N. Peshkin, D.M. Euhus.

Statistical expertise: G. Parmigiani, S. Chen, E.S. Iversen Jr., A. Ziogas, L. Hsu, L. Leondaridis, C.I. Amos, S. Sand, R. Kerber.

Obtaining of funding: G. Parmigiani, H. Anton-Culver, B.L. Weber, J.R. Daling, E.A. Ostrander, J.M. Schildkraut, L.C. Strong.

Administrative, technical, or logistic support: G. Parmigiani, T.M. Friebel, D.M. Finkelstein, A. Ziogas, B.L. Weber, J.R. Daling, D.A. Berry, J.N. Weitzel, D. Dutson, D.M. Euhus.

Collection and assembly of data: T.M. Friebel, D.M. Finkelstein, H. Anton-Culver, B.L. Weber, K.E. Malone, J.R. Daling, E.A. Ostrander, J.M. Schildkraut, C. Isaacs, C. Corio, L. Leondaridis, G. Tomlinson, L.C. Strong, D.M. Euhus.


Ann Intern Med. 2007;147(7):441-450. doi:10.7326/0003-4819-147-7-200710020-00002
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We provide a comprehensive view of the predictive performance of 7 commonly used, publicly available mutation carrier prediction models for the BRCA1 and BRCA2 genes, across a range of clinically relevant strata. As shown in Table 2, the c-statistic for the better-performing models clusters closely around 80%. Clinicians and counselors can use these results to identify the model that performs best in the strata most relevant to their activities and to weigh the differences in discrimination against practical implementation issues that are specific to their practice. BRCAPRO has the largest c-statistic overall and in all but 2 clinical strata, although the range of c-statistics across all models is too narrow to identify a clearly superior model. If used for referral outside of high-risk groups, all models have high rates of false-negative and false-positive results across a range of thresholds to refer for testing (Appendix Table 6).

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Figure 1.
C-statistic, by age of the counselee and model.Table 3

Points within age groups are slightly spaced horizontally for readability. Vertical bars are 95% CIs. A description of each model is given in . FHAT = family history assessment tool; NCI = National Cancer Institute; Penn = University of Pennsylvania; Yale = Yale University.

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Summary for Patients

Validity of Models for Predicting BRCA1 and BRCA2 Mutations

The summary below is from the full report titled “Validity of Models for Predicting BRCA1 and BRCA2 Mutations.” It is in the 2 October 2007 issue of Annals of Internal Medicine (volume 147, pages 441-450). The authors are G. Parmigiani, S. Chen, E.S. Iversen Jr., T.M. Friebel, D.M. Finkelstein, H. Anton-Culver, A. Ziogas, B.L. Weber, A. Eisen, K.E. Malone, J.R. Daling, L. Hsu, E.A. Ostrander, L.E. Peterson, J.M. Schildkraut, C. Isaacs, C. Corio, L. Leondaridis, G. Tomlinson, C.I. Amos, L.C. Strong, D.A. Berry, J.N. Weitzel, S. Sand, D. Dutson, R. Kerber, B.N. Peshkin, and D.M. Euhus.

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