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. Author manuscript; available in PMC: 2013 Oct 9.
Published in final edited form as: Ann Intern Med. 2011 Jul 19;155(2):69–79. doi: 10.7326/0003-4819-155-2-201107190-00002

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

 Probability that proband is female 0.5 0 to 1 Not varied

 Age of proband, y 48 44 to 50 Normal; mean, 48 (SD, 2) 15, 26, 2933

 Age of relative, y 25 25 to 70 Normal; mean, 25 (SD, 2.5) 34

 Female relatives, n 4 2 to 6 Normal; mean, 4 (SD, 1) 50, 67

 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

 Prevalence of MLH1 mutation among persons with the Lynch syndrome who have an identifiable mutation 0.32 Not varied Not varied 50

 Prevalence of MSH2 mutation among persons with the Lynch syndrome who have an identifiable mutation 0.39 Not varied Not varied 50

 Prevalence of MSH6 mutation among persons with the Lynch syndrome who have an identifiable mutation 0.14 Not varied Not varied 50

 Prevalence of PMS2 mutation among persons with the Lynch syndrome who have an identifiable mutation 0.15 Not varied Not varied 50

 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

 Probability of germline mutation in a relative 0.5 0 to 1 Not varied Assumed
Clinical criteria
 Amsterdam II criteria

  Sensitivity 0.22 0.13 to 0.67 β; α= 4, β= 14 15, 17, 40

  Specificity 0.98 0.97 to 1 β; α= 3218, β= 60 14, 17, 38, 40
 MMRpredict model*

  Sensitivity 0.69 0.68 to 0.75 β; α= 32, β= 14 14, 38

  Specificity 0.9 0.86 to 0.94 β; α= 1861, β= 193 14, 38
 Revised Bethesda Guidelines

  Sensitivity 0.82 0.78 to 0.91 β; α= 28, β= 6 15, 16

  Specificity 0.77 0.75 to 0.79 β; α= 945, β= 277 16
 MMRpro model*

  Sensitivity 0.89 0.6 to 1 β; α= 3.87, β= 0.48 40

  Specificity 0.85 0.6 to 1 β; α= 4.82, β= 0.85 40
 PREMM(1,2,6) model*

  Sensitivity 0.9 0.6 to 1 β; α= 3.60, β= 0.40 39

  Specificity 0.67 0.6 to 1 β; α= 6.58, β= 3.24 39
Tumor testing
 IHC

  Sensitivity 0.83 0.75 to 0.89 β; α= 94.77, β= 9.41 50

  Specificity 0.89 0.68 to 0.95 β; α= 18.21, β= 2.30 50
 MSI

  Sensitivity 0.85 0.75 to 0.93 β; α= 59.15, β= 10.44 50

  Specificity 0.9 0.87 to 0.93 β; α= 353.47, β= 38.40 50

 Mean germline genes tested after IHC, n 1.4 1 to 3 Not varied Expert opinion

 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

 Proband accepts germline test 0.9 0.88 to 0.94 β; α= 155, β= 18 68, 69

 Relative accepts germline test 0.52 0.34 to 0.69 β; α= 17.96, β= 16.58 50

 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, 7072

 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

 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

 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

 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

Screening
 Age to start screening average-risk relative for colorectal cancer, y 50 40 to 60 Normal; mean, 50 (SD, 2.5) 41

 Fraction of colonoscopies with lesion removal 0.4 0.2 to 0.6 β; α= 4.27, β= 6.40 Expert opinion

 Colonoscopy complications
  Bleeding 0.0016 0.0011 to 0.0021 β; α= 28.40, β= 17720.93 74, 75

  Perforation 0.00085 0.00033 to 0.00330 β; α= 0.32, β= 377.14 7478

  Death 0.000064 0.00005 to 0.00014 β; α= 2.56, β= 39994.88 74, 76, 78

 Age to stop screening for colorectal or gynecologic cancer, y 75 Not varied Not varied 41

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

  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

  Death rate 0.01 0.004 to 0.020 β; α= 3.96, β= 392.04 7982
 TAH-BSO

  Accepted by proband with the Lynch syndrome 0.19 0.10 to 0.30 β; α= 61, β= 254 8

  Accepted by relative with the Lynch syndrome 0.18 0.03 to 0.25 β; α= 138, β= 642 8, 11, 71, 8385

  Death rate 0.0003 0.0002 to 0.0004 β; α= 2, β= 6681 50

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

  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

 With the Lynch syndrome

  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

  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

Relative risk for colorectal cancer (compared with no screening)
 With average risk

  Adheres to average-risk screening recommendations 0.3 0.2 to 0.6 Log-normal; μ= −1.20, σ= 0.28 4245

  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

  Adheres to average-risk screening recommendations 0.9 0.8 to 1.0 Log-normal; μ= −0.11, σ= 0.09 Expert opinion

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

 2 0.06153 0.04922 to 0.07384 Not varied 86, 87

 3 0.04563 0.03650 to 0.05476 Not varied 86, 87

 4 0.03301 0.02641 to 0.03961 Not varied 86, 87

 5 0.02813 0.02251 to 0.03376 Not varied 86, 87
Probability of dying of sporadic colorectal cancer, by year after cancer diagnosis

 1 0.16875 0.13500 to 0.20250 Not varied 86

 2 0.08900 0.07120 to 0.10680 Not varied 86

 3 0.06539 0.05231 to 0.07847 Not varied 86

 4 0.04585 0.03668 to 0.05502 Not varied 86

 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 4245, 86

  Adheres to Lynch syndrome screening recommendations 0.7 0.55 to 0.85 Log-normal, μ= −0.36, σ= 0.15 4245, 86

 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

  Adheres to average-risk screening recommendations 1 0.9 to 1.0 Log-normal, μ= −0.11, σ= 0.09 Expert opinion

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

 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

Probability of dying of ovarian cancer, by year after cancer diagnosis
 1 0.247 0.19760 to 0.29640 Not varied 86

 2 0.14741 0.11793 to 0.17689 Not varied 86

 3 0.13084 0.10467 to 0.15701 Not varied 86

 4 0.10573 0.08459 to 0.12688 Not varied 86

 5 0.08016 0.06413 to 0.09619 Not varied 86
Probability of woman developing endometrial cancer

 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

 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

 1 0.077 0.06160 to 0.09240 Not varied 86

 2 0.04659 0.03727 to 0.05590 Not varied 86

 3 0.02841 0.02273 to 0.03409 Not varied 86

 4 0.01871 0.01497 to 0.02246 Not varied 86

 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

 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.

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