Friday, June 2, 2023

Festival of AI: GPT4 Can Assess a Long, Complex MolDx LCD

On June 1, 2023, MolDx released a lengthy and complex proposed LCD (5000 words, 84 citations), proposing to non-cover a categorical oncology test.  My blog is here.  The draft LCD is here.   Genomeweb here.  

As a hobbyist with AI using GPT4, I asked it for three assessments.   These are presented only a curiosities, "what would AI say and how would it write it?" rather than as being good/bad or right/wrong.

In Topic One, I ask for an assessment of the LCD overall.   

In Topic Two, I ask for advice on what a hypothetical company would  do in response.  

In Topic Three, I note that the LCD uses some much-less-common terms (e.g. not just "false positives" or "sensitivity" but terms like"monotonicity") and ask for some AI clarification.

Finally, as an Appendix, I also give an AI-produced summary of the LCD evidence report (4000 words) and the LCD quality analysis (2000 words).   



The payor or health technology assessor appears to hold a cautious perspective towards the clinical evidence surrounding the 40-gene expression profile (40-GEP) test. While they acknowledge the potential of the 40-GEP to enhance risk stratification and contribute to individualized patient management plans, they express concerns over several key issues.

Integration into Clinical Practice: The assessor is concerned about the clarity of integrating the 40-GEP test into patient management plans. They mention that there's a lack of defined strategies based on 40-GEP results, indicating that this is a crucial factor in measuring patient outcomes.

Relative Value and Comparison to Existing Methods: They note that the test hasn't convincingly demonstrated superiority to current staging tools and clinicopathologic factors, implying that they don't see it as a stand-alone solution but rather a complementary tool.

Risk of Misinterpretation: The assessor points out the potential risk of under-treatment due to possible misinterpretation of Class 1 results, emphasizing the need for clinicians to be careful in interpreting and acting on the results.

Gaps in Current Research: They mention several limitations in the existing literature surrounding the 40-GEP test, including a lack of data addressing test performance in certain patient populations and insufficient examination of the test's statistical properties.

In conclusion, the payor or health technology assessor sees potential in the 40-GEP test but maintains a need for further data and research to fully validate its clinical utility and understand its role in patient management. They advocate for continuous monitoring of emerging evidence and adaptation based on new information.


The laboratory that has generated the evidence has several potential paths forward. Given the cautious, yet not outright negative, assessment by the payor or health technology assessor, it seems that there is an opportunity to address the concerns raised and strengthen the case for the 40-GEP test.

Further Research: The laboratory should invest in additional research, addressing the gaps and limitations pointed out by the assessor. More specifically:

  • Further comparative studies should be carried out to more convincingly demonstrate the superiority of the 40-GEP test over existing staging tools and clinicopathologic factors.
  • The lab might conduct specific studies to address the performance of the test in patient populations that were excluded in the previous studies.
  • Additional investigation should be done to better assess statistical properties like distinctiveness, homogeneity, monotonicity, and the concordance index (c-index) of the 40-GEP.
  • Prospective studies could be particularly valuable, to provide more evidence on how the test results influence clinical decision-making and how this translates into patient outcomes.

Clear Guidelines: The laboratory should work on establishing clearer guidelines for how to interpret and act on the 40-GEP test results, in order to minimize the risk of misinterpretation and under-treatment.

Collaboration with Clinicians: It could be beneficial to work closely with clinicians to understand their concerns and needs better, and to ensure that the test is effectively integrated into existing clinical workflows.

Advocate for the Test: It's also important to continue advocating for the potential benefits of the 40-GEP test, emphasizing that it is not meant to replace existing tools but to complement them, and pointing out that it could potentially enhance personalized treatment strategies and prognostic accuracy.

Rather than protesting the review as excessively harsh, the laboratory would likely be better off taking it as constructive feedback and an opportunity to further improve their product and evidence base. This approach is likely to be more productive and lead to a better outcome for all parties involved, including patients.


I am familiar with terms like sensitivity, specificity, false positives, positive predictive value, etc.   Please help me understand terms like "distinctiveness, homogeneity, monotonicity, c-index" in this setting.

Certainly, I'm happy to help explain these statistical terms in the context of evaluating a diagnostic test like the 40-Gene Expression Profile (40-GEP):

  • Distinctiveness: In the context of diagnostic testing, distinctiveness refers to the ability of the test to differentiate between different classes or risk groups. In the case of the 40-GEP, distinctiveness would refer to its ability to accurately and reliably distinguish between low, moderate, and high metastatic risk groups. A test with good distinctiveness will have a low likelihood of assigning patients to the wrong risk group.
  • Homogeneity: Homogeneity in this context refers to the consistency within each risk group identified by the test. For the 40-GEP, homogeneity would mean that patients within each risk group (low, moderate, and high risk) are similar in terms of their gene expression profiles and subsequent disease progression. If the test shows good homogeneity, it suggests that the test is grouping like patients together effectively, and that each risk group is relatively uniform.
  • Monotonicity: Monotonicity, in the context of risk stratification, refers to a consistent trend or pattern in the results when moving from one risk group to another. In the case of the 40-GEP, monotonicity would mean that as you move from low to moderate to high-risk groups, there should be a consistent increase in the characteristics associated with higher risk (such as certain gene expression patterns). A test demonstrating good monotonicity indicates that the risk classes are ordered properly and that there is a clear progression from low to high risk.
  • Concordance Index (c-index): The concordance index is a measure of the predictive accuracy of a model. In the context of a diagnostic test like the 40-GEP, it's a measure of how well the test predicts patient outcomes. A c-index of 0.5 indicates that the test's predictions are no better than chance, while a c-index of 1.0 indicates perfect prediction. It is indeed similar to the concept of correlation, but it's more specifically about prediction accuracy. For the 40-GEP, a high c-index would indicate strong predictive power in assessing metastatic risk in patients with cSCC.

It's important to note that each of these properties is connected to the validity and utility of the 40-GEP test, so understanding and optimizing them is a key part of refining the test and demonstrating its value to clinicians and payers.  [BQ: Venables et al., 2022, PMID 9315012 uses this set of terms. This is LCD Citation #29; it is cited 4 times, suggesting high interest of the MolDx authors.]

An ROC curve also goes from 0.5 to 1.0.


Indeed, the Receiver Operating Characteristic (ROC) curve and the Concordance Index (c-index) are similar in that they both measure the predictive accuracy of a model, and both provide a score between 0.5 (no better than chance) to 1.0 (perfect prediction).

However, there are differences between the two measures:

ROC Curve: An ROC curve is a plot that illustrates the diagnostic ability of a binary classifier system as its discrimination threshold is varied. The curve is created by plotting the true positive rate (TPR) against the false positive rate (FPR) at various threshold settings. The area under the ROC curve (AUC-ROC) provides a measure of the model's ability to distinguish between positive and negative classes.

Concordance Index (c-index): The c-index, on the other hand, is a measure often used in survival analysis. It quantifies the agreement between the predicted and observed risk. The c-index is equivalent to the area under the ROC curve when the outcome is binary, but it is particularly useful for censored or time-to-event data, which is often seen in clinical studies.

While similar in some respects, these two measures are used in different scenarios and for different types of data. It's also important to note that while both these measures are useful, neither of them is perfect, and it's often important to look at other metrics as well to fully understand the performance of a model or a test.


GPT4 Provides Simple Direct Summary of "Evidence" (4000 words) and "Quality Analysis" (2000 words).

EVIDENCE [from 4000 words to 450]

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Despite it generally being manageable, a subset of patients will develop metastatic disease. Traditional tumor staging, provided by American Joint Committee on Cancer (AJCC) and the Brigham and Women’s Hospital (BWH) systems, while being robust, fail to account for the heterogeneity in tumor behavior, leading to some patients being inaccurately classified in terms of their metastatic risk.

To address this, genomic tests like the 40-gene expression profile (40-GEP) test have been developed to better predict metastatic risk in cSCC patients. The 40-GEP test stratifies patients with one or more risk factors into low (Class 1), moderate (Class 2A), or high metastatic risk (Class 2B) groups. The test was developed using a discovery and development cohort and validated using archival tissue from a separate cohort of high-risk primary cSCC patients with known 3-year outcomes. In statistical analyses, the 40-GEP signature maintained predictive value and demonstrated significant capability of stratifying metastatic risk.

In the second study presented by Ibrahim et al, the expansion of the previous cohort to 420 patients showed a similar predictive capability of the 40-GEP in predicting metastatic risk. The median time to metastasis was 0.9 years, and the metastatic rates for Class 1, 2A, and 2B were consistent with previous findings.

Arron et al evaluated a subset of patients with cSCC of the head and neck, further confirming the predictive ability of the 40-GEP. Clinical utility of the 40-GEP lies in its potential to improve prognostic value and facilitate individualized risk assessment, treatment, and follow-up when incorporated into existing risk-assessment frameworks.

However, it is important to note that the 40-GEP should not be used as a surrogate for standard care but rather as an additional data point when determining individualized management plans for high-risk patients. Clinical vignettes and clinician surveys have demonstrated that the 40-GEP could influence decisions regarding treatment plans, yet outcomes data from prospective studies documenting specific changes in management are currently lacking.

The preliminary results from the Clinical Utility and Health Outcomes Study (UTILISE) showed the 40-GEP's potential impact on clinician perception of metastatic risk and on the intensity of management. It also demonstrated consistency with the increased risk associated with Class 2A and 2B results. However, the precise changes to management were not published and clinical patient outcomes are not available at the time of publication.

In conclusion, the 40-GEP is a promising tool that, when used alongside existing clinical staging systems and risk-assessment frameworks, could potentially enhance personalized treatment strategies and prognostic accuracy in cSCC. However, further data are required, particularly from prospective studies, to validate its clinical utility and determine the extent of its impact on management decisions and patient outcomes.' 

QUALITY ANALYSIS (CONCLUSIONS) (From 2000 words to 350)

The analysis concerns a molecular laboratory test known as the 40-Gene Expression Profile (40-GEP) for skin cancer (cutaneous squamous cell carcinoma, cSCC). The 40-GEP can stratify metastatic risk, but its consistent interpretation and integration into patient management plans remain unclear. There's also a lack of defined management strategies based on 40-GEP results, which are vital for measuring patient outcomes.

The majority of 40-GEP test results fall into Class 1 (low metastatic risk) or Class 2A (moderate risk), while Class 2B (high risk) results are relatively rare. Furthermore, it's noted that the test hasn't convincingly demonstrated superiority to current staging tools and clinicopathologic factors.

Interestingly, Class 2B results often occur in patients with multiple risk factors, who would already be identified as high-risk using current tools. The analysis suggests further exploration into patients with Class 2B results who aren't identified as very high-risk by other methods, but could benefit from intensified management due to 40-GEP results.

One of the key concerns is the risk of patients being under-treated as a result of 40-GEP, as some clinicians may interpret a Class 1 result as a very low metastatic risk, leading to potential de-escalation of care that may not be warranted. The clinical validity and utility of 40-GEP could be improved by integrating it with other clinicopathologic factors within existing guideline frameworks.

There are also some limitations in the 40-GEP literature. Most notably, the literature does not address test performance in patient populations with certain exclusion criteria proposed by the test manufacturer. Moreover, it doesn't thoroughly examine distinctiveness, homogeneity, and monotonicity, and c-index of the 40-GEP to better assess its overall performance.

The analysis concludes that although molecular markers like the 40-GEP could enhance cSCC risk stratification, their clinical validity and utility over current methods have not yet been established. As such, continued monitoring of emerging evidence and updates to coverage based on new information are recommended


While cutaneous squamous cell carcinoma (cSCC) is generally manageable, traditional staging systems fail to adequately account for heterogeneity in tumor behavior, leading to a subset of patients being inaccurately classified in terms of metastatic risk. The 40-gene expression profile (40-GEP) test, a molecular laboratory tool, has been developed to enhance risk stratification by categorizing patients into low (Class 1), moderate (Class 2A), or high (Class 2B) metastatic risk groups. Multiple studies have validated the predictive capability of the 40-GEP, demonstrating its potential to improve prognostic value and facilitate individualized risk assessment, treatment, and follow-up.

However, it's crucial to understand that the 40-GEP isn't a replacement for standard care, but an additional element for personalized management plans. Its interpretation and integration into care remain unclear, as outcomes data from prospective studies and defined management strategies based on 40-GEP results are currently lacking. Furthermore, there's concern about the risk of under-treatment due to possible misinterpretation of Class 1 results leading to unwarranted de-escalation of care.

The test's clinical validity and utility could be improved by integration with other clinicopathologic factors within existing guideline frameworks. Although the 40-GEP can enhance cSCC risk stratification, its superiority to current methods hasn't been convincingly demonstrated. Limitations within the 40-GEP literature, such as not addressing test performance in patient populations with certain exclusion criteria and not thoroughly examining key statistical properties, need to be addressed for better overall assessment.

In conclusion, while the 40-GEP shows promise, it's evident that further data and research are required, especially from prospective studies, to validate its clinical utility and better define its role in patient management. Continued monitoring of emerging evidence and adaptation based on new information are recommended.



In a "hall of mirrors" supplement, I give GPT4 "THIS BLOG" above, and ask GPT4 to analyze what is going on.