Base-Case Values and Ranges for Variables in the Model
| Variable | Base-Case Value | Range in Sensitivity Analyses | Distributions for Monte Carlo Simulations | References |
|---|---|---|---|---|
| Proband and relative characteristics | ||||
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| Probability that proband is female | 0.5 | 0 to 1 | Not varied | |
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| Age of proband, y | 48 | 44 to 50 | Normal; mean, 48 (SD, 2) | 15, 26, 29–33 |
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| Age of relative, y | 25 | 25 to 70 | Normal; mean, 25 (SD, 2.5) | 34 |
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| Female relatives, n | 4 | 2 to 6 | Normal; mean, 4 (SD, 1) | 50, 67 |
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| Male relatives, n | 4 | 2 to 6 | Normal; mean, 4 (SD, 1) | 50, 67 |
| Disease and gene prevalence | ||||
| Prevalence of the Lynch syndrome | 0.03 | 0.01 to 0.05 | β; α= 8.73, β= 282.27 | 50 |
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| Prevalence of MLH1 mutation among persons with the Lynch syndrome who have an identifiable mutation | 0.32 | Not varied | Not varied | 50 |
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| Prevalence of MSH2 mutation among persons with the Lynch syndrome who have an identifiable mutation | 0.39 | Not varied | Not varied | 50 |
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| Prevalence of MSH6 mutation among persons with the Lynch syndrome who have an identifiable mutation | 0.14 | Not varied | Not varied | 50 |
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| Prevalence of PMS2 mutation among persons with the Lynch syndrome who have an identifiable mutation | 0.15 | Not varied | Not varied | 50 |
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| Prevalence of no known germline mutations among persons with the Lynch syndrome | 0.15 | 0.05 to 0.25 | β; α= 5.31, β= 30.10 | Expert opinion |
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| Probability of germline mutation in a relative | 0.5 | 0 to 1 | Not varied | Assumed |
| Clinical criteria | ||||
| Amsterdam II criteria | ||||
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| Sensitivity | 0.22 | 0.13 to 0.67 | β; α= 4, β= 14 | 15, 17, 40 |
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| Specificity | 0.98 | 0.97 to 1 | β; α= 3218, β= 60 | 14, 17, 38, 40 |
| MMRpredict model* | ||||
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| Sensitivity | 0.69 | 0.68 to 0.75 | β; α= 32, β= 14 | 14, 38 |
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| Specificity | 0.9 | 0.86 to 0.94 | β; α= 1861, β= 193 | 14, 38 |
| Revised Bethesda Guidelines | ||||
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| Sensitivity | 0.82 | 0.78 to 0.91 | β; α= 28, β= 6 | 15, 16 |
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| Specificity | 0.77 | 0.75 to 0.79 | β; α= 945, β= 277 | 16 |
| MMRpro model* | ||||
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| Sensitivity | 0.89 | 0.6 to 1 | β; α= 3.87, β= 0.48 | 40 |
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| Specificity | 0.85 | 0.6 to 1 | β; α= 4.82, β= 0.85 | 40 |
| PREMM(1,2,6) model* | ||||
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| Sensitivity | 0.9 | 0.6 to 1 | β; α= 3.60, β= 0.40 | 39 |
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| Specificity | 0.67 | 0.6 to 1 | β; α= 6.58, β= 3.24 | 39 |
| Tumor testing | ||||
| IHC | ||||
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| Sensitivity | 0.83 | 0.75 to 0.89 | β; α= 94.77, β= 9.41 | 50 |
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| Specificity | 0.89 | 0.68 to 0.95 | β; α= 18.21, β= 2.30 | 50 |
| MSI | ||||
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| Sensitivity | 0.85 | 0.75 to 0.93 | β; α= 59.15, β= 10.44 | 50 |
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| Specificity | 0.9 | 0.87 to 0.93 | β; α= 353.47, β= 38.40 | 50 |
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| Mean germline genes tested after IHC, n | 1.4 | 1 to 3 | Not varied | Expert opinion |
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| Proportion of false-positive IHC results correctly identified as sporadic MLH1 by BRAF testing | 0.4 | 0.1 to 0.7 | Not varied | 50 |
| Acceptance and adherence probabilities | ||||
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| Proband accepts germline test | 0.9 | 0.88 to 0.94 | β; α= 155, β= 18 | 68, 69 |
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| Relative accepts germline test | 0.52 | 0.34 to 0.69 | β; α= 17.96, β= 16.58 | 50 |
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| Probands and relatives with the Lynch syndrome adhere to Lynch syndrome screening recommendations | 0.8 | 0.67 to 0.87 | β; α= 526.758, β= 130.242 | 11, 12, 50, 70–72 |
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| Probands with family history suggestive of the Lynch syndrome adhere to Lynch syndrome screening recommendations | 0.58 | 0.38 to 0.78 | β; α= 18, β= 13 | 70 and expert opinion |
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| Probands and relatives who seem to be at average risk adhere to average screening recommendations | 0.63 | 0.53 to 0.73 | β; α= 58.74, β= 34.50 | 73 |
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| Probands with Lynch-like tumors adhere to Lynch syndrome screening recommendations | 0.7 | 0.5 to 0.9 | β; α= 3.68, β= 1.58 | Expert opinion |
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| At-risk relatives untested for the Lynch syndrome adhere to Lynch syndrome screening recommendations | 0.5 | 0.4 to 0.6 | β; α= 12.50, β= 12.50 | Expert opinion |
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| Screening | ||||
| Age to start screening average-risk relative for colorectal cancer, y | 50 | 40 to 60 | Normal; mean, 50 (SD, 2.5) | 41 |
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| Fraction of colonoscopies with lesion removal | 0.4 | 0.2 to 0.6 | β; α= 4.27, β= 6.40 | Expert opinion |
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| Colonoscopy complications | ||||
| Bleeding | 0.0016 | 0.0011 to 0.0021 | β; α= 28.40, β= 17720.93 | 74, 75 |
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| Perforation | 0.00085 | 0.00033 to 0.00330 | β; α= 0.32, β= 377.14 | 74–78 |
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| Death | 0.000064 | 0.00005 to 0.00014 | β; α= 2.56, β= 39994.88 | 74, 76, 78 |
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| Age to stop screening for colorectal or gynecologic cancer, y | 75 | Not varied | Not varied | 41 |
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| Risk-reducing surgery and complications | ||||
| Subtotal colectomy | ||||
| Accepted by proband with the Lynch syndrome | 0.01 | 0.00 to 0.04 | β; α= 3, β= 271 | 11, 50 |
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| Accepted by relative with the Lynch syndrome at diagnosis of colorectal cancer | 0.03 | 0.00 to 0.04 | β; α= 7, β= 235 | 11 |
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| Death rate | 0.01 | 0.004 to 0.020 | β; α= 3.96, β= 392.04 | 79–82 |
| TAH-BSO | ||||
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| Accepted by proband with the Lynch syndrome | 0.19 | 0.10 to 0.30 | β; α= 61, β= 254 | 8 |
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| Accepted by relative with the Lynch syndrome | 0.18 | 0.03 to 0.25 | β; α= 138, β= 642 | 8, 11, 71, 83–85 |
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| Death rate | 0.0003 | 0.0002 to 0.0004 | β; α= 2, β= 6681 | 50 |
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| Probability of developing colorectal cancer | ||||
| With average risk | ||||
| Women | Age-specific and calibrated (e.g., 2.5% by age 70 y) | Varied within =20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 86 |
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| Men | Age-specific and calibrated (e.g., 3% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 86 |
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| With the Lynch syndrome | ||||
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| Women | Age-specific and calibrated (e.g., 46% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 3, 86 |
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| Men | Age-specific and calibrated (e.g., 54% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 3, 86 |
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| Relative risk for colorectal cancer (compared with no screening) | ||||
| With average risk | ||||
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| Adheres to average-risk screening recommendations | 0.3 | 0.2 to 0.6 | Log-normal; μ= −1.20, σ= 0.28 | 42–45 |
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| Adheres to Lynch syndrome screening recommendations | 0.2 | 0.1 to 0.3 | Log-normal; μ= −1.61, σ= 0.50 | Expert opinion |
| With the Lynch syndrome | ||||
| Adheres to Lynch syndrome screening recommendations | 0.42 | 0.22 to 0.82 | Log-normal; μ= −0.87, σ= 0.34 | 7, 12 |
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| Adheres to average-risk screening recommendations | 0.9 | 0.8 to 1.0 | Log-normal; μ= −0.11, σ= 0.09 | Expert opinion |
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| Probability of probands and relatives with the Lynch syndrome dying of colorectal cancer, by year after cancer diagnosis | ||||
| 1 | 0.12872 | 0.10298 to 0.15446 | Not varied | 86, 87 |
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| 2 | 0.06153 | 0.04922 to 0.07384 | Not varied | 86, 87 |
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| 3 | 0.04563 | 0.03650 to 0.05476 | Not varied | 86, 87 |
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| 4 | 0.03301 | 0.02641 to 0.03961 | Not varied | 86, 87 |
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| 5 | 0.02813 | 0.02251 to 0.03376 | Not varied | 86, 87 |
| Probability of dying of sporadic colorectal cancer, by year after cancer diagnosis | ||||
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| 1 | 0.16875 | 0.13500 to 0.20250 | Not varied | 86 |
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| 2 | 0.08900 | 0.07120 to 0.10680 | Not varied | 86 |
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| 3 | 0.06539 | 0.05231 to 0.07847 | Not varied | 86 |
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| 4 | 0.04585 | 0.03668 to 0.05502 | Not varied | 86 |
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| 5 | 0.03742 | 0.02994 to 0.04490 | Not varied | 86 |
| Relative risk for dying of colorectal cancer after diagnosis (compared with no screening) | ||||
| With average risk | ||||
| Adheres to average-risk screening recommendations | 0.7 | 0.55 to 0.85 | Log-normal, μ= −0.36, σ= 0.15 | 42–45, 86 |
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| Adheres to Lynch syndrome screening recommendations | 0.7 | 0.55 to 0.85 | Log-normal, μ= −0.36, σ= 0.15 | 42–45, 86 |
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| With the Lynch syndrome | ||||
| Adheres to Lynch syndrome screening recommendations | 0.56 | 0.45 to 0.65 | Log-normal, μ= −0.58, σ= 0.14 | 7, 12 |
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| Adheres to average-risk screening recommendations | 1 | 0.9 to 1.0 | Log-normal, μ= −0.11, σ= 0.09 | Expert opinion |
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| Probability of woman developing ovarian cancer | ||||
| With average risk | Age-specific and calibrated (e.g., 0.8% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 86 |
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| With the Lynch syndrome | Age-specific and calibrated (e.g., 7.4% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 50, 86 |
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| Probability of dying of ovarian cancer, by year after cancer diagnosis | ||||
| 1 | 0.247 | 0.19760 to 0.29640 | Not varied | 86 |
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| 2 | 0.14741 | 0.11793 to 0.17689 | Not varied | 86 |
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| 3 | 0.13084 | 0.10467 to 0.15701 | Not varied | 86 |
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| 4 | 0.10573 | 0.08459 to 0.12688 | Not varied | 86 |
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| 5 | 0.08016 | 0.06413 to 0.09619 | Not varied | 86 |
| Probability of woman developing endometrial cancer | ||||
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| With average risk | Age-specific and calibrated (e.g., 1.7% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 86 |
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| With the Lynch syndrome | Age-specific and calibrated (e.g., 37% by age 70 y) | Varied within ±20% of base-case value | Multiplied by factor with normal distribution; mean, 1 (SD, 0.1) | 50, 86 |
| Probability of dying of endometrial cancer, by year after cancer diagnosis | ||||
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| 1 | 0.077 | 0.06160 to 0.09240 | Not varied | 86 |
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| 2 | 0.04659 | 0.03727 to 0.05590 | Not varied | 86 |
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| 3 | 0.02841 | 0.02273 to 0.03409 | Not varied | 86 |
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| 4 | 0.01871 | 0.01497 to 0.02246 | Not varied | 86 |
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| 5 | 0.01192 | 0.00954 to 0.01430 | Not varied | 86 |
| Probability of dying of all other causes | ||||
| Women | Age-specific | Not varied | Not varied | 88 |
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| Men | Age-specific | Not varied | Not varied | 88 |
IHC = immunohistochemistry; MSI = microsatellite instability; TAH-BSO = total abdominal hysterectomy and bilateral salpingo-oophorectomy.
*
This prediction model has reported sensitivity for MLH1, MSH2, and MSH6 mutations.