Table 1.

Key parameters, assumptions, modeling approaches, and sources (full list may be found in the Appendix in the Supplementary Data)

Model parameter Assumptions and approaches List of sources
Colorectal Cancer Natural History in Lynch Syndrome
 Adenoma incidence, location, and growth-Adenoma development was assumed to follow a nonhomogenous Poisson distribution.Mecklin et al. (41), Liljegren et al. (42), Lindgren et al. (43), Rijcken et al. (44), de Jong et al. (45), Pino et al. (46)
-Adenoma growth was described by a log-linear growth equation.
-Anatomical distribution of adenomas in mutation carriers was derived from an author-conducted meta-analysis.
 Cancer risk/malignant transformation-Cancer risk as a function of age and gender in mutation carriers was derived from an author-conducted meta-analysis.Hendriks et al. (47), Buttin et al. (48), Dunlop et al. (49), Quehenberger et al. (50), Hampel et al. (40), Wagner et al. (51), Senter et al. (52), Barrow et al. (53), Stoffel et al. (54)
-The malignant transformation rate of adenomas was a function of age, gender, and adenoma location.
 Cancer location-Cancer location was based on an author-conducted meta-analysis.Mecklin et al. (41), Lindgren et al. (43), Aaltonen et al. (55), de Vos tot Nederveen Cappel et al. (37)
 Survival-Difference in colorectal cancer survival between noncarriers and carriers was characterized by a hazard ratio derived from an author-conducted meta-analysis.SEER (20), Gryfe et al. (56), Barnetson et al. (57), Watson et al. (58), Sankila et al. (59), Aarnio et al. (60), Barrow et al. (53)
Cancer recurrence-Second primary colorectal cancers occurred as they arose from new adenomas after treatment of primary cancer.Lin et al. (61), Mecklin and Jarvinen (62), Rodriguez-Bigas et al. (63)
Endometrial Cancer Natural History in Lynch Syndrome
 Endometrial cancer incidence-Risk of developing endometrial cancer in mutation carriers was based on an author-conducted meta-analysis.Hampel et al. (64), Senter et al. (52), Buttin et al. (48), Hendriks et al. (47), Stoffel et al. (54), Dunlop et al. (49), Quehenberger et al. (50), Aarnio et al. (65), Jenkins et al. (66), Schmeler et al. (67)
 Survival-Survival was assumed to be the same for sporadic and Lynch syndrome-associated endometrial cancer and was derived from the SEER database.SEER (20), Boks et al. (68)
Prevalence
 Lynch syndrome prevalence among all colorectal cancer diagnoses (used to estimate mutation prevalence)-On the basis of a conservative estimate of 2.2% from Hampel et al. (40) and on author estimates of rates of Lynch syndrome in families with no defined mutation, this value was set to 3.0%, in concordance with Table 13 in Palomaki (1).Hampel et al. (40), Palomaki et al. (1)
 Mutation type- The distribution of different mutation types was taken to be: 32% MLH1, 39% MSH2, 14% MSH6, and 15% PMS2.Palomaki et al. (1)
Tests and Procedures Values
 Genetic test analytic sensitivitya MLH1: 90%, MSH2: 90%, MSH6: 90%, PMS2: 62%Palomaki et al. (1), Senter et al. (52)
 Genetic test analytic specificity MLH1: 99.97%, MSH2: 99.97%, MSH6: 99.97%, PMS2: 99.97%Palomaki et al. (1)
 Immunohistochemistry analytic sensitivity, specificity83%, 88.8%Palomaki et al. (1)
 Colonoscopy: sensitivity, specificity of adenoma detectionAdenoma size 0–5 mm: sensitivity 75%, specificity 95% 6–10 mm: sensitivity 85%, specificity 95% >10 mm: sensitivity 95%, specificity 95%Rex et al. (69)
 Colonoscopy: segments screened 95% reach ascending colon, 70% reach cecumRex et al. (69)
 Endometrial cancer surveillanceEndometrial aspirate biopsy: sensitivity 91%, specificity 98%Dijkhuizen et al. (70), Dove-Edwin et al. (71)
Compliances and Practice Patterns
 Compliance to annual colonoscopy screening for known unaffected mutation carriers81%Palomaki et al. (1)
 Compliance to annual endometrial biopsy for known unaffected mutation carriers57%Stoffel et al. (72), Wagner et al. (73), Collins et al. (74)
 Compliance to genetic testing of first-degree relatives of mutation-positive probands60% for siblings 70% for children 60% for parents (Only one parent of a proband was tested. If negative, then the other parent was considered an obligate carrier.)Ramsey et al. (75)
 Percent of individuals with malignancy who are seen by a physician who considers Lynch syndrome and the clinical criteria for testing for Lynch syndrome17%Grover et al. (6)
Surgical Mortalities
 Mortality associated with colonoscopy (occurring within thirty days after the procedure)0.008%Palomaki et al. (1)
 Mortality associated with total colectomy with ileorectal anastomosis (occurring within thirty days after the procedure)0.9%Palomaki et al. (1)
 Mortality associated with TAHBSO (occurring within thirty days after the procedure)0.02%Palomaki et al. (1)
Costs
 Multiple-gene testing for MLH1, MSH2, MSH6, and PMS2 $3,495Calculated from a 2009 author survey of U.S. commercial genetic test providersb
 Multiple-gene testing for MLH1, MSH2, MSH6 $2,618Averaged from a 2009 author survey of U.S. commercial genetic test providersb
 Single-gene testing for MLH1 $860
 Single-gene testing for MSH2 $771
 Single-gene testing for MSH6 $933
 Single-gene testing for PMS2 $884
 Single-site testing$298
 Immunohistochemistry$2812009 Medicare reimbursement rate
 Biopsy/polypectomy$1602007 Centers for Medicare & Medicaid Services (CMS) reimbursement projected to 2009
 Colonoscopy$5322007 CMS reimbursement projected to 2009
 Total colectomy for mutation carriers with advanced adenomas (costs for colorectal surgery for those with carcinoma are accounted for in the cost of colorectal cancer treatment)$22,8002009 Medicare reimbursement rate
 Transvaginal ultrasound$110Kwon et al. (76)
 Endometrial biopsy$201Kwon et al. (76)
 Gynecology visit$154Kwon et al. (76)
 Prophylactic TAHBSO$20,445Kwon et al. (76)
 Treatment of endometrial cancer$24,291Kwon et al. (76)
 Treatment of colorectal cancer by stages and phases Stage I, Initial/Continuing/Terminal Stage II, Initial/Continuing/Terminal Stage III, Initial/Continuing/Terminal Stage IV, Initial/Continuing/Terminal$27,221 / $2,166 / $48,791 $37,563 / $2,024 / $48,662 $45,804 / $2,883 / $51,276 $59,812 / $8,945 / $68,8091998–2003 Medicare reimbursement rate (77)
Health Utility Parameters
 Colorectal cancer Stage I0.74Ness et al. (78)
 Colorectal cancer Stage II0.67Ness et al. (78)
 Colorectal cancer Stage III0.50Ness et al. (78)
 Colorectal cancer Stage IV0.25Ness et al. (78)
 Endometrial cancer0.83Kwon et al. (76)
 Total colectomy with ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis for individuals with advanced adenoma (Surgical disutility for those with colorectal cancer is accounted for in disutility due to colorectal cancer diagnosis)0.84van Duijvendijk et al. (79), SF-36 scores converted to health utility indices using the methods by Ara et al. (80)
 TAHBSO0.86Kwon et al. (76)
 Mismatch repair (MMR) mutation detected in an unaffected (tumor-naïve) individual1.0 Decrease in quality of life due to detection of MMR mutation in unaffected carriers was found to be transient, returning to baseline at 6–12 months posttest result disclosure.Gritz et al. (81)
  • aAnalytic sensitivity of genetic tests was set by the authors to a level conservatively below subjective values cited in the literature (see text).

  • bList prices were used for genetic tests, as in Mvundura et al. (82).