. Author manuscript; available in PMC: 2021 Nov 1.

Published in final edited form as: Clin Gastroenterol Hepatol. 2019 Oct 17;18(12):2760–2767.e12. doi: 10.1016/j.cgh.2019.10.021

Appendix Table 6.

Results of one-way sensitivity analyses per 1,000 LS positive first-degree relatives of CRC index cases.

Usual Care is 5-yearly Colonoscopy

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^a,b (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
5-yearly colonoscopy	293	105		1.514	61.690	63.204	362	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	4.237	53.048	67.747	722	12,617	D
2-yearly colonoscopy	235	66	10.462	5.669	51.441	67.573	741	11,516	11,516
1-yearly colonoscopy	228	66	10.462	9.932	49.743	70.138	753	17,728	218,647

No interval extensions for ages 60-80

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^a,b (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	229	63	10.462	4.798	51.845	67.105	739	7,672	D
2-yearly colonoscopy	207	59	10.462	6.970	49.078	66.510	772	5,741	5,741
1-yearly colonoscopy	176	55	10.462	13.557	45.493	69.513	802	11,785	100,826

No decreased dwelling time

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	354	157		0.221	64.196	64.417	-	-	-
No LS testing
10-yearly colonoscopy	245	93		1.380	55.624	57.005	363	-	Cost-Saving
LS Testing
3-yearly colonoscopy	150	50	10.462	4.613	43.341	58.417	727	3,880	3,880
2-yearly colonoscopy	140	49	10.462	6.131	41.932	58.525	742	4,010	7,111
1-yearly colonoscopy	131	48	10.462	10.483	40.627	61.572	753	11,716	284,648

Halved dwelling time

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	363	166		0.229	67.431	67.66	-	-	-
No LS testing
10-yearly colonoscopy	271	102		1.275	59.987	61.262	371	-	Cost-Saving
LS Testing
3-yearly colonoscopy	179	57	10.462	4.500	47.678	62.639	766	3,486	D
2-yearly colonoscopy	167	55	10.462	5.995	45.926	62.383	785	2,705	2,705
1-yearly colonoscopy	155	54	10.462	10.306	44.151	64.919	800	8,529	176,255

5x faster dwelling time

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	362	166		0.228	67.227	67.455	-	-	-
No LS testing
10-yearly colonoscopy	293	108		1.155	61.431	62.586	353	-	Cost-Saving
LS Testing
3-yearly colonoscopy	215	63	10.462	4.349	50.331	65.143	747	6,491	D
2-yearly colonoscopy	205	61	10.462	5.809	48.627	64.898	766	5,599	5,599
1-yearly colonoscopy	196	61	10.462	10.098	46.972	67.532	778	11,621	208,305

20x faster dwelling time

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	364	167		0.229	67.428	67.657	-	-	-
No LS testing
10-yearly colonoscopy	335	118		1.047	65.172	66.219	305	-	Cost-Saving
LS Testing
3-yearly colonoscopy	287	74	10.462	4.157	56.789	71.408	694	13,348	D
2-yearly colonoscopy	279	73	10.462	5.572	54.881	70.915	719	11,345	11,345
1-yearly colonoscopy	268	73	10.462	9.809	52.444	72.716	739	15,000	93,835

Lower Cumulative Incidence (30% at age 80)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	255	117		0.161	47.555	47.715	-	-	-
No LS testing
10-yearly colonoscopy	218	79		1.046	44.488	45.534	233	-	Cost-Saving
LS Testing
3-yearly colonoscopy	172	48	10.462	4.284	37.525	52.271	509	24,387	D
2-yearly colonoscopy	166	47	10.462	5.718	36.380	52.560	523	24,227	24,227
1-yearly colonoscopy	161	47	10.462	10.010	35.183	55.655	531	33,911	366,988

Higher Cumulative Incidence (60% at age 80)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	510	240		0.327	99.024	99.352	-	-	-
No LS testing
10-yearly colonoscopy	444	163		1.121	93.110	94.231	494	-	D
LS Testing
3-yearly colonoscopy	356	99	10.462	4.135	78.906	93.503	1072	Cost-Saving	D
2-yearly colonoscopy	344	97	10.462	5.562	76.476	92.501	1100	Cost-Saving	Cost-Saving
1-yearly colonoscopy	333	98	10.462	9.768	73.953	94.183	1118	Cost-Saving	95,197

Lower Hazard Ratio Overall Survival (0.59)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	158		0.227	69.302	69.529	-	-	-
No LS testing
10-yearly colonoscopy	308	106		1.082	64.677	65.758	321	-	Cost-Saving
LS Testing
3-yearly colonoscopy	243	64	10.462	4.228	54.406	69.096	692	9,009	D
2-yearly colonoscopy	235	63	10.462	5.657	52.778	68.898	710	8,080	8,080
1-yearly colonoscopy	228	63	10.462	9.910	51.071	71.443	721	14,236	235,800

Higher Hazard Ratio Overall Survival (0.71)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	360	173		0.228	65.423	65.65	-	-	-
No LS testing
10-yearly colonoscopy	309	117		1.086	61.341	62.427	344	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	71	10.462	4.246	51.848	66.556	749	10,203	D
2-yearly colonoscopy	236	70	10.462	5.681	50.259	66.402	770	9,345	9,345
1-yearly colonoscopy	228	70	10.462	9.952	48.566	68.980	782	14,958	203,055

LS Testing of Index CRC Cases: Combined proportion of possible LS cases −50%(2.25%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	18.007	4.237	53.048	75.292	722	29,097	D
2-yearly colonoscopy	235	66	18.007	5.669	51.441	75.117	741	27,292	27,292
1-yearly colonoscopy	228	66	18.007	9.932	49.743	77.682	753	32,645	218,647

LS Testing of Index CRC Cases: Combined proportion of possible LS cases +50%(6.75%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	7.948	4.237	53.048	65.233	722	3,194	D
2-yearly colonoscopy	235	66	7.948	5.669	51.441	65.058	741	2,615	2,615
1-yearly colonoscopy	228	66	7.948	9.932	49.743	67.623	753	8,658	218,647

Index Case Genetic Pathway: Proportion of patients accepting genetic counseling −50% (42%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	18.17	4.237	53.048	75.455	722	29,518	D
2-yearly colonoscopy	235	66	18.17	5.669	51.441	75.281	741	27,693	27,693
1-yearly colonoscopy	228	66	18.17	9.932	49.743	77.845	753	33,034	218,647

Index Case Genetic Pathway: Proportion of patients accepting genetic counseling +50% (100%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	9.229	4.237	53.048	66.514	722	6,494	D
2-yearly colonoscopy	235	66	9.229	5.669	51.441	66.340	741	5,759	5,759
1-yearly colonoscopy	228	66	9.229	9.932	49.743	68.905	753	11,714	218,647

Index Case Genetic Pathway: Proportion of patients that once seen by genetic counselor will undergo genetic testing −50% (40%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	18.495	4.237	53.048	75.780	722	30,354	D
2-yearly colonoscopy	235	66	18.495	5.669	51.441	75.606	741	28,490	28,490
1-yearly colonoscopy	228	66	18.495	9.932	49.743	78.170	753	33,809	218,647

Index Case Genetic Pathway: Proportion of patients that once seen by genetic counselor will undergo genetic testing +50% (100%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	8.856	4.237	53.048	66.141	722	5,533	D
2-yearly colonoscopy	235	66	8.856	5.669	51.441	65.967	741	4,844	4,844
1-yearly colonoscopy	228	66	8.856	9.932	49.743	68.531	753	10,824	218,647

Index Case Genetic Pathway: Proportion of patients undergoing genetic testing that are positive for LS −50% (33%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	20.124	4.237	53.048	77.409	722	34,549	D
2-yearly colonoscopy	235	66	20.124	5.669	51.441	77.234	741	32,486	32,486
1-yearly colonoscopy	228	66	20.124	9.932	49.743	79.799	753	37,693	218,647

Index Case Genetic Pathway: Proportion of patients undergoing genetic testing that are positive for LS +50% (100%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	7.242	4.237	53.048	64.527	722	1,377	D
2-yearly colonoscopy	235	66	7.242	5.669	51.441	64.353	741	884	884
1-yearly colonoscopy	228	66	7.242	9.932	49.743	66.917	753	6,975	218,647

FDRs LS cases: Average number of FDRs of identified LS case −50%(2.98)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	19.845	4.237	53.048	77.130	722	33,831	D
2-yearly colonoscopy	235	66	19.845	5.669	51.441	76.956	741	31,803	31,803
1-yearly colonoscopy	228	66	19.845	9.932	49.743	79.521	753	37,029	218,647

FDRs LS cases: Average number of FDRs of identified LS case +50%(8.94)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	7.335	4.237	53.048	64.620	722	1,616	D
2-yearly colonoscopy	235	66	7.335	5.669	51.441	64.445	741	1,112	1,112
1-yearly colonoscopy	228	66	7.335	9.932	49.743	67.010	753	7,197	218,647

FDRs LS cases: Proportion of FDRs that accept genetic counseling −50%(26%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	19.845	4.237	53.048	77.130	722	33,831	D
2-yearly colonoscopy	235	66	19.845	5.669	51.441	76.956	741	31,803	31,803
1-yearly colonoscopy	228	66	19.845	9.932	49.743	79.521	753	37,029	218,647

FDRs LS cases: Proportion of FDRs that accept genetic counseling +50%(78%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	7.335	4.237	53.048	64.620	722	1,616	D
2-yearly colonoscopy	235	66	7.335	5.669	51.441	64.445	741	1,112	1,112
1-yearly colonoscopy	228	66	7.335	9.932	49.743	67.010	753	7,197	218,647

FDRs LS cases: Proportion of FDRs that once seen by genetic counselor will undergo genetic testing −50%(47.5%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	20.035	4.237	53.048	77.320	722	34,319	D
2-yearly colonoscopy	235	66	20.035	5.669	51.441	77.145	741	32,268	32,268
1-yearly colonoscopy	228	66	20.035	9.932	49.743	79.710	753	37,481	218,647

FDRs LS cases: Proportion of FDRs that once seen by genetic counselor will undergo genetic testing +50%(100%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	9.984	4.237	53.048	67.269	722	8,437	D
2-yearly colonoscopy	235	66	9.984	5.669	51.441	67.094	741	7,610	7,610
1-yearly colonoscopy	228	66	9.984	9.932	49.743	69.659	753	13,513	218,647

FDRs LS cases: Proportion of FDRs testing positive on a germline test −50%(25%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	20.835	4.237	53.048	78.120	722	36,379	D
2-yearly colonoscopy	235	66	20.835	5.669	51.441	77.945	741	34,230	34,230
1-yearly colonoscopy	228	66	20.835	9.932	49.743	80.510	753	39,389	218,647

FDRs LS cases: Proportion of FDRs testing positive on a germline test +50%(75%)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	7.005	4.237	53.048	64.290	722	767	D
2-yearly colonoscopy	235	66	7.005	5.669	51.441	64.116	741	303	303
1-yearly colonoscopy	228	66	7.005	9.932	49.743	66.680	753	6,410	218,647

Colonoscopy screening participation not diagnosed with LS = 40%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	325	130		0.799	64.351	65.150	222	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	4.237	53.048	67.747	722	5,200	D
2-yearly colonoscopy	235	66	10.462	5.669	51.441	67.573	741	4,671	4,671
1-yearly colonoscopy	228	66	10.462	9.932	49.743	70.138	753	9,401	218,647

Colonoscopy screening participation not diagnosed with LS = 80%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	291	94		1.370	61.465	62.835	445	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	4.237	53.048	67.747	722	17,727	D
2-yearly colonoscopy	235	66	10.462	5.669	51.441	67.573	741	15,985	15,985
1-yearly colonoscopy	228	66	10.462	9.932	49.743	70.138	753	23,700	218,647

Colonoscopy surveillance participation diagnosed with LS = 70%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	258	80	10.462	3.736	54.822	69.020	632	16,866	D
2-yearly colonoscopy	251	79	10.462	4.989	53.416	68.867	649	15,478	15,478
1-yearly colonoscopy	244	79	10.462	8.719	51.930	71.111	659	21,890	218,647

Colonoscopy surveillance participation diagnosed with LS = 90%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	229	55	10.462	4.738	51.274	66.475	812	5,188	D
2-yearly colonoscopy	220	54	10.462	6.350	49.467	66.279	834	4,571	4,571
1-yearly colonoscopy	212	54	10.462	11.145	47.557	69.164	847	10,072	218,647

Related to genetic testing: Combined costs of lab testing in index CRC case −50%($112)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	D
LS Testing
3-yearly colonoscopy	244	67	6.69	4.237	53.048	63.975	722	Cost-Saving	D
2-yearly colonoscopy	235	66	6.69	5.669	51.441	63.801	741	Cost-Saving	Cost-Saving
1-yearly colonoscopy	228	66	6.69	9.932	49.743	66.366	753	5,660	218,647

Related to genetic testing: Combined costs of lab testing in index CRC case +50%($336)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	14.235	4.237	53.048	71.520	722	19,383	D
2-yearly colonoscopy	235	66	14.235	5.669	51.441	71.345	741	18,039	18,039
1-yearly colonoscopy	228	66	14.235	9.932	49.743	73.910	753	23,650	218,647

Related to genetic testing: Cost of patient navigator per individual referred to genetic counseling −50%($54)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.381	4.237	53.048	67.666	722	9,459	D
2-yearly colonoscopy	235	66	10.381	5.669	51.441	67.491	741	8,584	8,584
1-yearly colonoscopy	228	66	10.381	9.932	49.743	70.056	753	14,460	218,647

Related to genetic testing: Cost of patient navigator per individual referred to genetic counseling +50%($162)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.544	4.237	53.048	67.829	722	9,880	D
2-yearly colonoscopy	235	66	10.544	5.669	51.441	67.655	741	8,985	8,985
1-yearly colonoscopy	228	66	10.544	9.932	49.743	70.219	753	14,849	218,647

Related to genetic testing: Costs of pre-test genetic counseling in CRC index case −50%($128)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.3	4.237	53.048	67.585	722	9,252	D
2-yearly colonoscopy	235	66	10.3	5.669	51.441	67.411	741	8,386	8,386
1-yearly colonoscopy	228	66	10.3	9.932	49.743	69.975	753	14,267	218,647

Related to genetic testing: Costs of pre-test genetic counseling in CRC index case +50%($383)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.625	4.237	53.048	67.910	722	10,088	D
2-yearly colonoscopy	235	66	10.625	5.669	51.441	67.735	741	9,183	9,183
1-yearly colonoscopy	228	66	10.625	9.932	49.743	70.300	753	15,042	218,647

Related to genetic testing: Avg. cost of germline test in index CRC case −50%($550)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	9.903	4.237	53.048	67.188	722	8,228	D
2-yearly colonoscopy	235	66	9.903	5.669	51.441	67.013	741	7,411	7,411
1-yearly colonoscopy	228	66	9.903	9.932	49.743	69.578	753	13,320	218,647

Related to genetic testing: Avg. cost of germline test in index CRC case +50%($1,649)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	11.022	4.237	53.048	68.307	722	11,111	D
2-yearly colonoscopy	235	66	11.022	5.669	51.441	68.133	741	10,158	10,158
1-yearly colonoscopy	228	66	11.022	9.932	49.743	70.698	753	15,989	218,647

Related to genetic testing: Post-test genetic counseling and tracing FDRs for LS positive cases −50%($45)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.292	4.237	53.048	67.577	722	9,231	D
2-yearly colonoscopy	235	66	10.292	5.669	51.441	67.403	741	8,367	8,367
1-yearly colonoscopy	228	66	10.292	9.932	49.743	69.968	753	14,249	218,647

Related to genetic testing: Post-test genetic counseling and tracing FDRs for LS positive cases +50%($135)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.633	4.237	53.048	67.918	722	10,108	D
2-yearly colonoscopy	235	66	10.633	5.669	51.441	67.743	741	9,202	9,202
1-yearly colonoscopy	228	66	10.633	9.932	49.743	70.308	753	15,061	218,647

Related to genetic testing: Somatic testing for LS negative cases −50%($250)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.377	4.237	53.048	67.662	722	9,451	D
2-yearly colonoscopy	235	66	10.377	5.669	51.441	67.488	741	8,576	8,576
1-yearly colonoscopy	228	66	10.377	9.932	49.743	70.053	753	14,452	218,647

Related to genetic testing: Somatic testing for LS negative cases +50%($750)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.547	4.237	53.048	67.832	722	9,888	D
2-yearly colonoscopy	235	66	10.547	5.669	51.441	67.658	741	8,993	8,993
1-yearly colonoscopy	228	66	10.547	9.932	49.743	70.223	753	14,857	218,647

Related to genetic testing: Costs of germline testing for LS in a FDR with a known mutation −50%($200)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.062	4.237	53.048	67.347	722	8,640	D
2-yearly colonoscopy	235	66	10.062	5.669	51.441	67.173	741	7,803	7,803
1-yearly colonoscopy	228	66	10.062	9.932	49.743	69.738	753	13,701	218,647

Related to genetic testing: Costs of germline testing for LS in a FDR with a known mutation +50%($600)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	67.237	67.465	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	62.908	63.992	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.862	4.237	53.048	68.147	722	10,700	D
2-yearly colonoscopy	235	66	10.862	5.669	51.441	67.973	741	9,766	9,766
1-yearly colonoscopy	228	66	10.862	9.932	49.743	70.538	753	15,609	218,647

Related to Colonoscopies: Costs of colonoscopies −50%($474/$596^f)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.114	67.237	67.351	-	-	-
No LS testing
10-yearly colonoscopy	308	112		0.542	62.908	63.450	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	2.119	53.048	65.629	722	5,610	D
2-yearly colonoscopy	235	66	10.462	2.835	51.441	64.738	741	3,160	3,160
1-yearly colonoscopy	228	66	10.462	4.966	49.743	65.172	753	4,105	36,951

Related to Colonoscopies: Costs of colonoscopies +50%($1,472/$1,788^f)

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.341	67.237	67.578	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.626	62.908	64.534	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	6.356	53.048	69.866	722	13,729	D
2-yearly colonoscopy	235	66	10.462	8.504	51.441	70.408	741	14,409	28,093
1-yearly colonoscopy	228	66	10.462	14.898	49.743	75.104	753	25,204	400,343

Colorectal cancer care costs −50%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	33.619	33.846	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	31.454	32.538	334	-	Cost-Saving
LS Testing
3-yearly colonoscopy	244	67	10.462	4.237	26.524	41.223	722	22,365	D
2-yearly colonoscopy	235	66	10.462	5.669	25.721	41.852	741	22,850	32,610
1-yearly colonoscopy	228	66	10.462	9.932	24.872	45.266	753	30,351	291,020

Colorectal cancer care costs +50%

Strategy	CRC Cases^a	CRC Deaths^a	Costs LS Testing^b,c (million$)	Costs CRC screening^b,d (million$)	Costs CRC Care^b (million$)	Total costs^ab (million$)	LYG^b (y)	ACER^b,e ($)	ICER^b ($)

No LS Testing or CRC Screening	359	165		0.227	100.856	101.083	-	-	-
No LS testing
10-yearly colonoscopy	308	112		1.084	94.362	95.446	334	-	D
LS Testing
3-yearly colonoscopy	244	67	10.462	4.237	79.572	94.271	722	Cost-Saving	D
2-yearly colonoscopy	235	66	10.462	5.669	77.162	93.294	741	Cost-Saving	Cost-Saving
1-yearly colonoscopy	228	66	10.462	9.932	74.615	95.010	753	Cost-Saving	146,275

CRC= Colorectal Cancer, LS= Lynch Syndrome, LYG= Life-Years Gained, ACER= Average Cost-Effectiveness Ratio, ICER= Incremental Cost-Effectiveness Ratio, D= Dominated.

CRC cases and deaths include those from LS diagnosis until death.

Costs and life-years gained were discounted at an annual rate of 3%.

Include total costs of screening CRC index cases and their FDRs, including LS negative and non-participants.

Include costs of CRC screening, diagnosis and surveillance.

Compared to no LS screening.

Costs used for colonoscopies without polypectomy/with polypectomy.