Volume 114, Issue 5, Pages 893-901 (May 1998) Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis  David M. Cromwell*,‡, Richard D. Moore*,‡,§, Jill D. Brensinger*, Gloria M. Petersen§, Eric B. Bass*,‡, Francis M. Giardiello*,∥  Gastroenterology  Volume 114, Issue 5, Pages 893-901 (May 1998) DOI: 10.1016/S0016-5085(98)70308-7 Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 1 The main decision model. From the economic perspective of a third-party payer, this model compares the average per-person costs of screening at-risk relatives for FAP for three different FAP screening strategies: conventional flexible sigmoidoscopic (Flex. Sig.) screening without gene testing, testing for a mutation of the APC gene beginning with the pedigree's proband, and screening guided by APC gene testing that begins with the at-risk relatives. For gene testing starting with the proband, at-risk relatives are gene tested only if the proband's test result indicates that the pedigree has an identifiable APC mutation. If the proband does not have an identifiable mutation, all of that pedigree's at-risk relatives skip gene testing and undergo flexible sigmoidoscopic screening. (M), Markov chains used to model the progression of patients from phenotypically negative (without colorectal adenomas) to phenotype-positive (with colorectal adenomas) FAP during serial flexible sigmoidoscopic examinations. (L), Logic nodes where only one branch is chosen depending on the specified pedigree size. □, Choice node, which represents point in time at which the decision maker can elect one of several alternative FAP screening strategies. ○, Chance node, which represents point in time at which the hypothetical patient moves to an outcome based on probability estimates of those outcomes. [+], Tree branch truncated for display. A sample subtree for gene testing starting with the at-risk relatives is shown in Figure 2. Gastroenterology 1998 114, 893-901DOI: (10.1016/S0016-5085(98)70308-7) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 2 This sample subtree depicts the structure used to model costs for a pedigree of 3 at-risk relatives. The probability of finding an APC mutation (APC-pos) in the first tested at-risk relative is 40% (= [50% for autosomal dominant] × [80% test sensitivity]). Bayes' theorem indicates that if no APC mutation is found in the first at-risk relative, the chance of subsequent at-risk relatives testing APC-pos continues to decrease with increasing numbers of at-risk relatives who all test “negative.” If the first tested relative is not APC-pos, the second relative's chance of testing APC-pos is 33%. If both the first and second relatives are not APC-pos, the third relative's chance of testing APC-pos is 25%. If none of the 3 relatives tests APC-pos, the proband's chance of having an identifiable APC mutation is 33%. Once an APC mutation is identified in a pedigree, all subsequently tested at-risk relatives have a 50% chance of testing APC-pos. For this screening strategy, the proband is only tested if none of the at-risk relatives is found to have an APC mutation. In this setting, the proband's gene test result is used to confirm that the at-risk relatives are normal (proband has an identifiable APC mutation) or that the gene test has no predictive value in the at-risk relatives (proband's APC mutation is not identifiable). See Figure 1 for symbols. Gastroenterology 1998 114, 893-901DOI: (10.1016/S0016-5085(98)70308-7) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 3 Impact of pedigree size on the model's selection of optimum FAP screening strategy. As the number of at-risk relatives in the pedigree increases, the cost advantage of both APC gene testing strategies increases compared with conventional flexible sigmoidoscopic screening without gene testing. In addition, increases in pedigree size confers a gradually increasing cost advantage of gene testing starting with the proband over gene testing starting with the at-risk relatives. ●, Conventional flexible sigmoidoscopic screening; ▴, genotype at-risk relatives first; , genotype proband first. Gastroenterology 1998 114, 893-901DOI: (10.1016/S0016-5085(98)70308-7) Copyright © 1998 American Gastroenterological Association Terms and Conditions

Fig. 4 The gene test vendor charges $500 when the pedigree's APC mutation is known and an extra charge of $250 (total gene test charge of $750) when the pedigree's APC mutation is not known. At the base-case charge of $500 for testing when the pedigree's APC mutation is known (y axis = $500), projected least costly screening choices would be “genotype at-risk relatives first” for an extra charge between $0 and $168.20, “genotype proband first” for an extra charge between $168.20 and $833.00, and “conventional flexible sigmoidoscopic screening” for an extra charge above $833.00. At the base-case extra charge of $250 for gene testing when the pedigree's APC mutation is unknown (x axis = $250), “genotype proband first” is the least costly strategy for mutation-known gene testing charges less than $745.30, “genotype at-risk relatives first” is least costly for mutation-known gene testing charges between $745.30 and $833.70, and “conventional flexible sigmoidoscopic screening” is the least costly strategy when mutation-known gene testing costs more than $833.70. Gastroenterology 1998 114, 893-901DOI: (10.1016/S0016-5085(98)70308-7) Copyright © 1998 American Gastroenterological Association Terms and Conditions