Supplementary Table I: Additional parameters utilised by the seven cost-effectiveness studies with recalculation of costs s

Paper / Screening costs / Discount rate / Clinical studies referenced / CRC treatment cost / fDNA cost / ICER
Leshno [28] / Cost of FOBT: 40 USD; Cost of SIG: 450 USD / 3% costs; 3% life-years / Dong et al., (2001); Ahlquist et al., (2000) / Lifetime cost of localised CRC treatment: 44,000 USD; lifetime cost of regional CRC treatment: 85,000 USD; Lifetime cost of distant CRC treatment: 170,000 USD / 91 USD (2010) / fDNA vs NS: not reported / COL (10y) and annual FOBT + FSIG (5y) dominate fDNA
Song [18] / Cost of FOBT: 20 USD, FSIG: 290 USD, FSIG W biopsy: 440 USD, COL: 820 USD, COL W polypectomy: 1,200 USD / 3% costs; 3% life-years / Dong et al., (2001); Ahlquist et al., (2000); Tagore et al., (2003), Brand et al., (2002); Syngal et al., (2003);Exact sciences (2003) / Colorectal cancer care by stage: 46,000 USD (localised), 68,000 USD (Regional), 71,000 USD (Distant) / 824 USD (2010) / fDNA (5y) vs NS: 56,541 USD (2010) per LYG / All other screening strategies dominate fDNA
Ladabaum [27] / Cost of FOBT: 20 USD, FSIG: 290 USD, FSIG W biopsy: 440 USD, COL: 820 USD, COL W polypectomy: 1,200 USD, CTC: 820 USD / Not stated / Imperiale et al., (2004), Song et al., (2004), Ahlquist et al., (2000), Dong et al., (2001), Tagore et al., (2003), Brand et al., (2002), Syngal et al., (2003), Exact sciences 2003 / Cost of CRC care: 46,000 USD (localised), 68,000 USD (regional), 71,000 USD (distant) / 825 USD (2010) / fDNA vs NS: 86,768 USD (2010) per LYG (higher than all the other screening types tested e.g. 9,601 USD (2010) per LYG for FOBT and 22,285 USD (2010) per LYG for COL (10y)) / optimized fDNA vs NS: 36,746 USD (2010) per LYG
Wu [25] / FOBT cost: 0.6 USD, FSIG: 35.3 USD, COL: 66.2 USD / 3% costs; 3% life-years / Ahlquist et al., (2000), Tagore et al., (2003), Loktionov et al., (1998), Imperiale et al., (2004) / Initial cost for early CRC treatment: 3,117.6 USD, Initial cost for late CRC treatment: 7,705.9 USD, Continuing cost for CRC: 176.5 USD, Terminal cost: 7,647.1 USD / 50.9 USD (2010) / fDNA (3y) vs NS: 11,307 USD (2010) per LYG / fDNA (5y) vs NS: 10,777 USD (2010) per LYG / fDNA (10y) vs NS: 8,909 USD (2010) per LYG / all other screening strategies dominated fDNA
Parekh [19] / FOBT cost: 15 USD, FIT: 22 USD, COL: 920 USD, COL W polypectomy: 1,350 USD / 3% costs; 3% life-years / Imperiale et al., (2004),Itzkowitx et al., (2007) / Cost of CRC care: 51,000 USD (localised), 98,000 USD (regional), 200,000 USD (distant) / 324 USD (2010) (for all versions) / fDNAv1.0 vs NS: 22,931 USD (2010) per LYG / all other screening strategies dominated fDNAv1.0 / fDNAv1.1 vs NS: 18,280 USD (2010) per LYG / all other screening strategies dominated fDNAv1.1 / fDNAv2.0 vs NS: 16,982 USD (2010) per LYG; vs fDNAv1.1: 2,921 USD (2010); vs annual FOBT: 723,637 USD (2010) / COL (10y) & annual FIT dominate all versions of fDNA
Lansdorp-Vogelaar [20] / Hemoccult II: 5 USD, Hemoccult SENSA: 5 USD, iFOBT: 22 USD, SIG WO Biopsy: 161 USD, SIG with Biopsy: 348 USD, COL WO polypectomy: 522 USD, COL W polypectomy 673 USD / 3% costs; 3% life-years / Whitney et al., (2004)., Imperiale et al., (2004), Syngal et al., (2006), Tagore et al., (2003) / Annual cost of CRC treatment: Stage 1 - 25,487 (initial), 2,028 (Continuing), 45,689 (Terminal); Stage II - 35,173 (Initial), 1,890 (continuing), 45,560 (Terminal); Stage III - 42,885 (initial), 2,702 (Continuing), 48,006 (Terminal); Stage IV - 56,000 (initial), 8,375 (Continuing), 64,428 (Terminal) / 368 USD (2010); Modified societal 386 USD (2010) / fDNA (3y & 5y) vs NS: <15,775 USD (2010) per LYG for both / current recommended screening options dominated fDNA (3y & 5y)
Telford JJ [26] / FOBT cost: 10 CAD, FIT: 25 CAD, SIG: 193 CAD, DCBE: 178 CAD, COL: 424 CAD, CTC: 590 CAD / 5% costs; 5% life-years / Imperiale et al., (2004), Syngal et al., (2003), Ahlquist et al., (2000), Tagore et al., (2003) / Stage I - 13,734 CAD (Year 1), 503 CAD (Year 2-5 annual); Stage II - 27,095 CAD (Year 1), 857 CAD (Year 2-5 annual); Stage III - 35,040 CAD (Year 1), 857 CAD (Year 2-5 annual); Stage IV - 72,869 CAD (Year 1), 670 CAD (Year 2-5 annual); Terminal care: 17,869 CAD / 297 USD (2010) / l-sFOBT (2y), annual h-sFOBT, annual FIT and COL (10y) dominate fDNA

Supplementary Table II: Summary of clinical studies sourced by seven fDNA cost-effectiveness studies

Author, year / Version / No. of citations / Gold standard / Sample size / No. of markers in panel / K-ras / APC / p53 / BAT26 / DIA / Vimentin methylation / Sensitivity for Cancer (%) / Sensitivity for Adenoma (%) / Specificity (%) / Type of patient
Loktionov et al.,[1] 1998 / Stool DNA index / 1 / N/R / 56 / N/R / Y / N/R / N/R / N/R / N/R / N / 100 / N/R / 81 / 17 CRC, 11 polyp, 28 NC
Ahlquist et al.,[2] 2000 / Mutli target fDNA assay / 5 / COL / 61 / 15 mutational hot spots / Y / Y / Y / Y / Y / N / 91 / 82 / 93 / 22 CRC, 11 adenomas, 28 healthy
Dong et al.,[3] 2001 / N/R / 3 / COL / 51 / N/R / Y / N / Y / Y / N / N / 71 / N/R / N/R / 51 colon cancer patients
Brand et al.,[4] 2002 / N/R / 2 / N/R / 17 / N/R / Y / Y / Y / Y / N / N / N/R / N/R / N/R / 17 CRC
Exact sciences,[5] 2003 / PreGen-Plus / 2 / N/R / N/R / N/R / N/R / N/R / N/R / N/R / N/R / N / 52 / N/R / 95 / Average risk, asymptomatic population
Syngal et al., [6] 2003 / PreGen-Plus / 2 / END / 72 / 21 mutations / Y / Y / Y / Y / Y / N / 62.5 / N/R / N/R / 56 CRC, 16 AA
Tagore et al.,[7] 2003 / MTAP (PreGen Plus) / 5 / COL / 292 / 21 point mutations / Y / Y / Y / Y / Y / N / 63.5 / 57.1 / 96.2 / 52 CRC,28 AA, 99 SP, 113 NC
Imperiale et al.,[8] 2004 / Prototype assay (version 1.0 Exact sciences) / 5 / COL / 2507 / 21 mutations / Y / Y / Y / Y / Y / N / 51.6 / 15.1 / 94.4 / 31 CRC , 403 advanced neoplasia, 648 minor polyps, NC 1423
Song et al.,[9] 2004 / PreGen-Plus / 1 / N/R / Unk / N/R / N/R / N/R / N/R / N/R / N/R / N / 65 / 40 / 95 / N/R
Whitney et al.,[10] 2004 / MTAP / 1 / COL / 186 / 21 specific mutations / Y / Y / Y / Y / Y / N / 70 / N/R / 96 / 86 CRC, 100 NC
Syngal et al.,[11] 2006 / MTAP / 2 / END / 91 / 23 markers / Y / Y / Y / Y / Y / N / 63 / 26 / N/R / 68 CRC, 23 adenoma
Itzkowitx et al.,[12] 2007 / Second generation assay (v2.0) / 2 / COL / 162 / 22 mutations, DIA & 2 promoter methylation markers / Y / Y / Y / Y / Y / Y / 87.5 / N/R / 82 / 40 CRC, 122 NC
Ahlquist et al.,[13] 2008 / Pre commercial DNA / 1 / COL / 2497 / 21 specific point mutations / Y / Y / N / N / N / N / 20 / N/R / 96 / 157 screen relevant neoplasia, 2340 NC
Stool DNA test 2 / 1 / COL / 217 / 3 tumour specific markers / Y / Y / N / N / N / Y / 40 / N/R / N/R / 142 screen relevant neoplasia, 75 NC

Abbreviations:CRC – Colorectal cancer,COL – colonoscopy, END– Endoscopy, NC – normal colon, N/R – Not recorded, SP – small polyp, Y- Yes, N – No, Unk - Unknown

References

1.Loktionov A, O'Neill IK, Silvester KR, et al. Quantitation of DNA from exfoliated colonocytes isolated from human stool surface as a novel noninvasive screening test for colorectal cancer.Clin Cancer Res 1998 Feb;4(2): 337-42

2. Ahlquist DA, Skoletsky JE, Boynton KA, et al. Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 2000 Nov; 119 (5): 1219-1227.

3.Dong SM, Traverso G, Johnson C, et al. Detecting colorectal cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst 2001 Jun 6; 93 (11): 858-65

4.Brand RE, Shuber AP, Laken SJ, et al. Reliability of a stool DNA mutation specific assay for colorectal cancer. Gastroenterology 2002;122:A479.

5. Exact Sciences Corporation Press Release, October 11, 2003. PreGen-Plus four times more sensitive than FOBT in Exact Sciences’ multi-center study. Available at:

6.Syngal S, Chung D, Willet C, et al. The loss of stool DNA mutation abnormalities in colorectal neoplasia after treatment. Gastroenterology 2003;124:A5.

7. Tagore KS, Lawson MJ, Yucaitis JA, et al. Sensitivity and specificity of a stool DNA multitarget assay panel for the detection of advanced colorectal neoplasia. Clin Colorectal Cancer 2003 May; 3 (1): 47-53

8. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med 2004 Dec 23; 351 (26): 2704-2714

9.Song K, Fendrick AM, Ladabaum U. Fecal DNA testing compared with conventional colorectal cancer screening methods: A decision analysis. Gastroenterology 2004 May;126(5):1270-9

10.Whitney D, Skoletsky J, Moore K. Enhanced retrieval of DNA from human fecal samples results in improved performance of colorectal cancer screening test. J Mol Diagn 2004 Nov;6(4):386-95

11.Syngal S, Stoffel E, Chung D. Detection of stool DNA mutations before and after treatment of colorectal neoplasia. Cancer 2006 Jan 15;106(2): 277-83

12.Itzkowitz SH, Jandorf L, Brand R. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol. 2007 Jan;5(1): 111-7

13. Ahlquist D, Sargent D, Loprinzi C, et al. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med 2008 Oct 7; 149 (7): 441-450

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Supplementary Table III:Quality assessment results for seven cost-effective studies comparing fDNA to other colorectal cancer screening testsa, b

Question / Leshno et al.,[27](2003) / Song et al.,[17](2004) / Ladabaum et al.,[26]
(2005) / Wu et al.,[24]
(2006) / Parekh et al.,[18]
(2008) / Lansdorp-Vogelaar et al.,[19]
(2010) / Telford et al.,[25]
(2010)
Study design
Is the economic importance of the study stated? / Y / Y / Y / Y / Y / N / Y
Is the clinical importance of the study stated? / Y / Y / Y / Y / Y / P / Y
Is the study objective clearly stated? / Y / Y / Y / Y / Y / Y / Y
Is the study perspective clearly stated? / N / P / Y / Y / Y / Y / Y
Has the choice of model been justified? / Y / N / N / N / N / N / N
Is the description of the model explicit and clear? / Y / Y / Y / Y / Y / Y / Y
Has the time horizon of the model been justified? / N / N / N / N / N / N / N
Has the way in which the disease process was simplified been justified? / N / Y / Y / Y / P / Y / Y
For Markov models, has the cycle length of the model been justified? / N / N / N / N / N / N / N
Data collection
Is the primary outcome measure clearly stated and justified? / Y / P / Y / P / P / P / Y
Are the sources of efficacy data justified and described in sufficient detail? / P / Y / Y / Y / Y / Y / P
Is resource use reported separately from cost data? / N / N / N / N / N / N / N
Is it clear the types of costs (direct, indirect, intangible) being considered? / Y / Y / Y / Y / Y / Y / Y
Is the year of valuation for all costs clearly stated and details provided of any adjustment for inflation/deflation? / P / Y / Y / Y / Y / Y / Y
Are the sources of costs and charges clearly stated? / Y / Y / Y / Y / Y / Y / Y
Have the details of the model validation and calibration testing been provided? / N / N / Y / P / Y / Y / Y
Analysis and interpretation of results
If relevant, has the rate of exchange of any currency conversion been provided? / Y / NA / NA / Y / NA / NA / NA
Has discounting been performed for costs and/or effects, where appropriate? / Y / Y / Y / Y / Y / Y / Y
Has a sensitivity analysis been performed and details provided? / Y / Y / Y / Y / Y / Y / Y
Have you included a table of key assumptions? / Y / Y / Y / Y / Y / Y / Y
For stochastic data, have you provided details of the statistical tests performed and confidence intervals computed? / N / Y / N / N / Y / N / Y
Has justification been provided for the choice of variable and the ranges employed in any sensitivity analysis? / N / Y / Y / Y / Y / Y / Y
Have costs and benefits been presented in a disaggregated form before being combined into a single ratio/index? / Y / Y / Y / Y / Y / Y / Y
Have the study limitations been discussed? / N / N / Y / Y / Y / Y / Y
Are the implications and the generalisability of the study results discussed? / N / Y / Y / P / P / Y / Y
If the study perspective is narrower then the societal perspective have the implications of broadening the study perspective been discussed? / N / N / N / Y / N / Y / N
Are the study conclusions appropriate for the data presented and accompanied with appropriate caveats? / P / P / Y / P / Y / Y / Y
Are all assumptions explicit and transparent? / N / P / Y / Y / P / Y / Y
Is the Reference Case explicit? / Y / Y / Y / Y / Y / Y / Y

aThe range of possible responses to each question was “Yes”, “No”, “Partial”, and “Not Applicable”. Question were only assigned a “Yes” response if the item was explicitly stated and the detail necessary to fully answer the question was provided in the article; where it was deemed that the question was dealt to some extent, we assigned a response of “Partial”.

b This checklist is an amended version incorporating additional questions from the Drummond checklist

Key: Y – Yes, N – No, P – Partial, NA – Not applicable

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