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Cost-Effectiveness and Diagnostic Effectiveness Analyses of Multiple Algorithms for the Diagnosis of Lynch Syndrome

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Abstract

Background and Aims

The optimal algorithm to identify Lynch syndrome (LS) among patients with colorectal cancer (CRC) is unclear. The definitive test for LS, germline testing, is too expensive to be applied in all cases. Initial screening with the revised Bethesda Guidelines (RBG) cannot be applied in a considerable number of cases due to missing information.

Methods

We developed a model to evaluate the cost-effectiveness of 10 strategies for diagnosing LS. Three main issues are addressed: modeling estimates (20–40 %) of RBG applicability; comparing sequential or parallel use of microsatellite instability (MSI) and immunohistochemistry (IHC); and a threshold analysis of the charge value below which universal germline testing becomes the most cost-effective strategy.

Results

LS detection rates in RBG-based strategies decreased to 64.1–70.6 % with 20 % inapplicable RBG. The strategy that uses MSI alone had lower yield, but also lower cost than strategies that use MSI sequentially or in parallel with IHC. The use of MSI and IHC in parallel was less affected by variations in the sensitivity and specificity of these tests. Universal germline testing had the highest yield and the highest cost of all strategies. The model estimated that if charges for germline testing drop to $633–1,518, universal testing of all newly diagnosed CRC cases becomes the most cost-effective strategy.

Conclusions

The low applicability of RBG makes strategies employing initial laboratory-based testing more cost-effective. Of these strategies, parallel testing with MSI and IHC offers the most robust yield. With a considerable drop in cost, universal germline testing may become the most cost-effective strategy for the diagnosis of LS.

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Abbreviations

LS:

Lynch syndrome

CRC:

Colorectal cancer

RBG:

Revised Bethesda Guidelines

MSI:

Microsatellite instability

IHC:

Immunohistochemistry

MMR:

Mismatch repair

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Acknowledgments

This work was supported in part by the Texas Digestive Disease Center NIH DK58338 and Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413).

Conflict of interest

No conflict of interests exist.

Author information

Authors and Affiliations

  1. Sections of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Milena Gould-Suarez

  2. Sections of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA

    Hashem B. El-Serag

  3. Sections of Gastroenterology and Hepatology, Michael E DeBakey VA Medical Center, Houston, TX, USA

    Hashem B. El-Serag

  4. Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Houston, TX, USA

    Hashem B. El-Serag

  5. Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Benjamin Musher

  6. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Luis Miguel Franco & Guoqing J. Chen

  7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Luis Miguel Franco

  8. Sections of Health Services Research, Houston Center for Quality of Care and Utilization Studies, Baylor College of Medicine, Houston, TX, USA

    Guoqing J. Chen

Authors
  1. Milena Gould-Suarez
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  2. Hashem B. El-Serag
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  3. Benjamin Musher
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  4. Luis Miguel Franco
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  5. Guoqing J. Chen
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Corresponding author

Correspondence to Hashem B. El-Serag.

Appendices

Appendix 1

Costs of tests used in the model for the base case scenario. The italic numbers are the ones used in the base case analysis

Test

Cost ($)

Reference

RBG—cost of genetic consultation

150*

1

MLH1, MSH2, MSH6 and PMS2 full gene sequencing

4,000*

2

MLH1, MSH2, and MSH6 deletion/duplication analysis

2,200*

2

MLH1 full gene sequencing

1,150

2

1,018

3

1,200

4

900*

5

1,342

6

1,290

7

MLH1 deletion/duplication

1,500

2

300*

3

470

4

505

5

474

6

MLH1 hypermethylation analysis

439

3

MSH2 full gene sequencing

1,150

2

996

3

1,200–900*

4

1,342

5

1,090

67

MSH2 deletion/duplication

1,500

2

300*

3

470

4

505

5

474

6

MSH6 full gene sequencing

1,150

2

1,018

3

1,200

4

900*

5

1,102

6

1,050

7

MSH6 deletion/duplication

1,500

2

300*

3

470

4

505

5

474

6

PMS2 full gene sequencing

1,400

2

1,870

4

1,342

6

980*

7

PMS2 deletion/duplication

470*

4

474

6

IHC(MLK1, MSH2, MSH6, and PMS2)

500*

2

558

3

MSI

415*

2

493

3

BRAF mutation analysis

314*

3

Abbreviations: RBG Revised Bethesda Guidelines, IHC immunohistochemistry, MSI microsatellite instability

References for cost

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    Emory Genetics Labs

  3. 3.

    Mayo Medical Laboratories

  4. 4.

    BCM labs

  5. 5.

    Harvard Partners

  6. 6.

    University Hospitals Case Medical Center

  7. 7.

    Prevention Genetics

Appendix 2

Estimates of transition probabilities used in the model for the base case scenario

Parameter

Percentage (%)

Reference

Prevalence of LS in CRC

3

1

Proportion of LS with MSH2 mutation

39

20

Proportion of LS with MLH1 mutation

32

20

Proportion of LS with MSH6 mutation

14

20

Proportion of LS with PMS2 mutation

15

20

RBG sensitivity for LS

91

21

RBG specificity for LS

82

21

MSI specificity for LS

90.2

20

MSI sensitivity for LS MLH1/MSH2

91

20

MSI sensitivity for LS MSH6/PMS2

77

20

IHC specificity for LS

88.8

20

IHC sensitivity for LS

83

20

BRAF V600E sensitivity for LS

69

20

BRAF V600E specificity for LS

99.5

20

MMR sensitivity for LS

99.5

6

MMR specificity for LS

99.96

6

Abbreviations: LS Lynch syndrome, CRC colorectal cancer, RBG Revised Bethesda Guidelines, MSI microsatellite instability, IHC immunohistochemistry, MMR mismatch repair gene testing

Appendix 3

HNPCC Ten Screening Strategies (Decision Trees)

Abbreviations: CRC colorectal cancer, RBG revised Bethesda guidelines, MMR4 mismatch repair testing (gene sequencing, deletion, and duplication testing of all 4 LS genes), MSI microsatellite instability, IHC immunohistochemistry

IHC4—indicates abnormal IHC or absence of MMR proteins.

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Gould-Suarez, M., El-Serag, H.B., Musher, B. et al. Cost-Effectiveness and Diagnostic Effectiveness Analyses of Multiple Algorithms for the Diagnosis of Lynch Syndrome. Dig Dis Sci 59, 2913–2926 (2014). https://doi.org/10.1007/s10620-014-3248-6

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  • DOI: https://doi.org/10.1007/s10620-014-3248-6

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