Friday, June 9, 2023

AMP Announces Economics Summit 2023: September 13, 2023

The Association for Molecular Pathology has announced its third-annual summit on MoPath economics.  It will be held on September 13, 2023, in Washington DC.  I've clipped the webpage below and some key bullet points.

AMP’s Molecular Pathology Economics Summit will be a highly interactive one-day gathering focused on:

  • Identifying barriers to appropriate reimbursement for molecular pathology procedures;
  • Identifying the impact of these barriers on various stakeholders and patient access to care; and
  • Identifying potential solutions and/or novel approaches to overcoming barriers, with a goal of identifying shared policy agendas for the participating stakeholders in oncology, infectious diseases, and inherited conditions
Registration is in the range of $400 for non profits and $1000 for for-profits; see details and early bird deals.

Thursday, June 8, 2023

Learning AI with Humorous Examples: A PhD Job Talk and GPT4

From time to time, I post examples of using AI outside of biotechnology and genomics.  Here is a whimsical one.

A Yale graduate student is doing her PhD on Mark Twain, specifically, the influence of Charles Dickens on Mark Twain.

  • GPT4 gives her help planning her thesis framework.
  • GPT4 gives her help planning her Orals Thesis Defense.
  • GPT4 gives her help planning her first job talk, at another college.
  • As a bonus, GPT4 helps her navigate some "difficult politics" at her new job.
I've set it up as a white paper.  Almost all the text (except prompts in red) are GPT4 AI text.  This includes the introductory summary, and includes a script at the end for a video.

Some of the issues are humorous, but the ability of GPT4 to assess a problem, write an explanation, and debate alternatives is real and can be applied to numerous other kinds of problems and challenges.

Wednesday, June 7, 2023

Flashback: NCI Held 3-Hour Workshop on MCED R&D Plans, May 2023

The National Cancer Institute is planning a major study of multiple cancer early detection tests / MCED.  For example, there was a panel discussion on this topic at the "TRICON" conference in San Diego in February 2023.


The NCI has a web page here and 33 slide deck from 2022, here.

May 2023 Long Webinar

On May 3, 2023, NCI held a nearly three-hour webinar on the topic ("NCI Virtual Workshop to Engage MCD Assay Developers."  They archived the video, plus links to several PDF documents.

Find it all here:

I posted an "auto transcript," for what it's worth:


Tuesday, June 6, 2023

Novitas/FCSO: To Hold Webinar and Explain Confusing Oncology LCD

See the LCD

On June 2, 2023, First Coast and Novitas MACs released a massive oncology genomic testing LCD - about 40,000 words and circa 70-90 pages when printed.  My blog and links here.  Genomeweb here.

Watch the Webinar!

The MACs will hold webinars to "explain the LCD," on Wednesday June 21 and Thursday June 29, the first at 3-430 ET and the second at 12-130 ET.

Find the web page with registration and a chance to submit written questions:

I'll cut and paste the full text below.  Check the web site above to register or see updates.  They note the language of the webinar is English, which may reassure some skeptics who wondered whether the original complex. challenging to absorb, and multifaceted LCD was written in what language.  The webinar materials include the several-hundred-page LCA or billing article. 



"New Local Coverage Determination (LCD): 

Genetic Testing for Oncology" (Part A/B)

A Novitas and First Coast collaborative event

Delivery language: English

With advancement in science and technology comes the ability to incorporate genetic testing for oncology biomarkers into clinical care, with the goal of improved patient outcomes. 
A new local coverage determination (LCD) has been created to provide the coverage criteria and limitations, effective July 16. The scope of this LCD is DNA and RNA genetic testing in the practice of oncology in the Medicare population.
This multi-contractor collaborative session will include an overview of the new LCD: Genetic Testing for Oncology. We'll highlight the coverage indications and limitations within the LCD and review utilization parameters and documentation requirements within the companion local coverage article (LCA), while also:
 Reviewing the integral components of the LCD
 Determining the purpose of the LCA
 Examining the LCA to discover the CPT and ICD-10 coding guidelines
Target Audience: This webcast is intended for any oncology-focused providers, ordering providers and laboratories who perform, order or bill for these services, as well as their coding and billing staff.
Click on ‘Register now’ and follow the instructions.

Wednesday, June 21

3-4:30 p.m. ET

Thursday, June 29

12-1:30 p.m. ET

We offer continuing education credits, click here for more information. Also, want to submit questions prior to this event? Email us at no later than Friday, June 16..  


This is my table of the LCD organization.   In the Introduction, they mention their interest in Knowledge Databases, such as NCCN Biomarkers.  Then, they discussed these in "covered indications," for 6 pages.  Then they discuss these databases in the Evidence section for 7 pages, and in the Analysis section for 9 pages.   Overall, about 21% of the text (by word count) is about these knowledge databases.  See below:

click to enlarge

Evidence versus Analysis - the CMS LCD Template

About 12% of the document is a reporting of text-specific data (e.g. evidence) and about 38% of the document (by word count is test-specific analysis or judgement.   For example, "Test A was validated in 100 patients with 80% accuracy" is the Evidence section.  They might return to the same study again in the Analysis section, but this time saying, "80% accuracy is not good enough for Medicare coverage.50% of the document text (12% + 38%) is test-specific for about a dozen proprietary branded tests.

Friday, June 2, 2023

Novitas Releases Anxiously Awaited Oncology LCD (L39365)

The Fast Summary

Novitas released a long-awaited massive omnibus LCD for cancer testing.  It includes (1) very complex rules, (2) a list of non covered tests (including from some publicly-held labs), and (3) a very very long "billing article."


What Happened?

Rarely, an LCD or NCD is so talked-but that it's known by its number - "NCD 90.2," the CMS NGS NCD, being one example.  A nominee from the LCD side is Novitas' massive and important LCD for oncology - L39365.  

I should say, it's massive "now" - the draft was 14 pages, 6000 words, and the final is 68 pages, 30,000 words.  

There are now 230 citations (up from only 19).   

A lengthy section of definitions, some quirky, have been added.  A billing article runs hundreds of pages.  In all about 400 pages of reimbursement documentation was just released!

  • Billing & Coding, A59125, 283 pages.
  • LCD, L39365, 68 pages.
  • Response to Comments, A59417, 44 pages.  
    • I get 395 pp.

June 2022 to June 2023

Last June, 2022, Novitas put out a major revision of this complicated LCD.   I would say, charitably, that it "defies easy summary" even in its original 14 page form.  But, it was founded on a heavy reliance on NCCN guidelines and similar sources for its coverage rules.   

Novitas went right to the wire on this one, chased by the legal one-year deadline that CMS imposes between a draft and a final LCD.   

A Rare One-Off Release Date

For one oddity, whereas LCDs normally are issued nationally on Thursdays - e.g. June 1 - this one came out on Friday, June 2, after market close.  Genomeweb here.

Look It Up!

Find the 2022 draft version here and its tracking sheet here.   

  • The revisions include, "literature reviews added for 13 specific tests (Cxbladder, ThyroSeq® CRC, PancraGEN®, DecisionDX-Melanoma, DecisionDX-SCC, UroVysion® FISH, Colvera™, PancreaSeq® Genomic Classifier)."  
    • And also, "Updates to the Analysis of Evidence including Technology Assessment of knowledge bases and literature reviews added for 13 specific tests (Cxbladder, ThyroSeq CRC, PancraGEN, DecisionDX-Melanoma, DecisionDX-SCC, UroVysion FISH, Colvera, PancreaSeq Genomic Classifier)."

The responses to comments are here, A59417:

The FINAL LCD, L39365 2023, is HERE:

The billing and coding article is here, A59125:

Tier 2 Codes Handled?

Novitas has paid out a billion dollars in the last couple years for Tier 2 codes, at least a good part of which, to labs indicted or pled guilty in court.  

In this billing article, only two of the Tier 2 81408 genes are eligible for coverage, which are ataxia telangiectasia and neurofibromatosis.  Folks requiring either of this two genes will be rare as hen's teeth in the nursing homes of Texas and Florida.  Novitas has paid zillions of dollars for 81408 in multiples of 2 per patient per day, for several years (!!!!!)  It's impossible to imagine anyone needed both ataxia telangiectasia and neurofibromatosis testing on the same day for $4000 again.    

81493 - Proteomic

I don't see (by search) a reference to 81493, the CardioDx test I recently wrote about.  It doesn't seem to be in Group 1 of this LCD, where it had been just recently.  I'll keep looking. It might be dropped for being a "proteomic" test as the LCD re-emphasizes it is for DNA/RNA tests aka "genetic" tests (for Novitas).

81455 - CGP

The LCD doesn't really discuss one of the biggest areas in oncology, large tumor gene profiles.  In one place, the billing article says these are covered "when they meet the criteria of the LCD," as if the provider is suppose to guess at that, by reading the 68 page LCD.   However, sections 7 and 8 seem to provide nearly unlimited coverage of CGP as long as the patient has a cancer diagnosis code in the solid tumor series (#7) or the hematopoeitic series (#8).

Hot topics like liquid biopsy in lieu of paraffin, or MRD testing for relapse, or MRD testing for drug response, don't seem to be mentioned.  In contrast, in the MolDx policy system, these are among the most actively and vigorously discussed and updated areas.

Large Changes in Content, w/o Public Review

The increase in LCD content, from about 14 pages to 68 pages or 5X, means that much of the text that is now effective on July 13, 2023, was not prior reviewed by the public or commented on by the public.

My own draft-to-final comparison or redline is in the cloud here.

Not Medically Necessary

This section of the LCD is clipped and pasted below.


The following are considered not medically reasonable and necessary:

  • DecisionDx-Melanoma*
  • DecisionDx-SCC* [see 5/23/2022 press release re Pittsburgh investments]

  • Cxbladder Detect*
  • Enhanced Cxbladder Detect*
  • Cxbladder Monitor*
  • Cxbladder Triage*
  • Enhanced Cxbladder Triage*
  • Cxbladder Resolve*
  • [BQ: Discussion of both Castle and CX products are about 5000 words long.  Each has one initial discussion called "evidence" and a later discussion called "evaluation." Clipped here, here.  For example, the statement "The study has 100 patients and 80% accuracy" is "evidence" while the statement "80% accuracy is too low for coverage" is "evaluation."]
  • Colvera*
  • PancreaSeq Genomic Classifier*
  • PancraGEN*
  • ThyroSeq CRC
  • UroVysion fluorescence in situ hybridization (FISH)*

Noncoverage principles include:
  • A genetic test with unestablished analytical validity, clinical validity, and/or clinical utility.
  • Interventions with levels of evidence not identified by ClinGen24, NCCN25, or OncoKB26 as demonstrating actionability in clinical decision making OR interventions that are non-covered per MAC review.
  • Genetic testing in patients who do not have either an established diagnosis of cancer or substantiated suspicion of cancer as determined by a clinical evaluation and abnormal results (cancer or suspicious for cancer) from histologic, cytologic, and/or flow cytometric examination. (Except where otherwise specified in the Covered Indications as reasonable and necessary) (See SSA Section 1862(a)(1)(A))
  • Genetic testing of asymptomatic patients for the purposes of screening the patient or their relatives. (See SSA Section 1862(a)(1)(A))
  • Repetitions of the same genetic test on the same genetic material. (see Medicare NCCI Policy Manual, Chapter 10, Section A Introduction)

See also additional comments and rules in the lengthy billing article.

The LCD - A "Quant" View

It took me a while to wrap my head around what's going on in this lengthy document.  I cut/pasted parts into Word for this analysis: 



4 pp, 1680 words


Coverage Rules & Authorities

9 pp, 1800 words


Authority Sources Analysis

17 pp, 7400 words


Specific Tests: Evidence & Analysis

40 pp, 19,000 words



Of the above, first 8 pp and 4500 words are “Evidence,” the rest,  “Analysis”


Bibliography – Final

17 pp, 7250 words, 230 citations


Bibliography – Proposed

3 pp, 520 words, 19 citations

 Part 03 is an extensive analysis of how authorities, such as NCCN, do or do not meet 8 criteria for valid authorities (e.g. "transparency of process.")

Wild Swings

Numerous payers (Medicare or commercial) issue policies that one or another MAAA test isn't yet proven essential.   So that's not surprising in itself.  However, it seems to me the author of the LCD takes some pretty wild swings that are too picky or simply odd to make sense scientifically in the context of an HTA.  Often generalistic paragraphs about measuring the cell biology of RNA are cut-and-pasted repeatedly into different product reviews in this LCD. 

Can AI Help Us Understand This Massive LCD?

Can AI help understand this?  Maybe.  In a separate appended blog, for the AI-curious, I ask GPT4 a half dozen questions about different parts of the L39365 LCD.

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.

Book Notice: Covington on Device and Drug Reimbursement

The national law firm Covington has a strong team on reimbursement for drugs and devices - here.  

They now have a new book, Market Access, Pricing and Reimbursement of Drugs and Devices: Legal Principles and Practice, Desai et al. 2023.   It's on sale at American Health Law Association (AHLA; around $200), here.

See also a Covington web page offering an excerpt and a discount code - here.

Thursday, June 1, 2023

United Healthcare to Require Z Codes in 8 Weeks

United Healthcare has announced it will require "Z codes" on molecular test claims, and effective August 1, 2023

See the announcement here:

click to enlarge

Like CPT codes, Z-Codes are copyrighted.  Unlike CPT codes, they aren't generally circulated but are submitted as private codes between lab and payer.   Unlike CPT codes, or ICD-10 codes, Z-Codes are submitted via comment fields.  Unlike CPT codes, there is no overall organization to Z codes and there are no "descriptors" but there are paragraph-like test descriptions.    Unlike CPT codes, Z codes are mapped to labs and the lab's own test numbers.

Unlike CPT codes, modifiers are not appended to Z-codes (yet?)


Prior, there were multiple announcements of use of Z codes in United Medicare Advantage (vintage 2021) which would be pre-tested to match Medicare Part B policies, at least those of MolDx.  Here, here, here.

The DEX registry that's publicly available lists 2659 lab entities and 16,222 tests.

See an announcement of the same issue, dated May 2, 2023, at Palmetto, here.



MolDx Draft LCD: L39614, Non Coverage of Squamous Cell Carcinoma Risk Stratification

 MolDx has released a draft non coverage LCD on "risk stratification of cutaneous squamous cell carcinoma," DL39614.

The draft LCD is posted here.


The coverage request, 2 pages long, seems to be dated June 1, 2020.   Find it here.

There are 84 citations.  Comment runs to July 15, 2023.  At the bottom of the LCD, there is a link to WPS Open Meetings, referring to one on June 15.

There is a link to a draft article, DA59429. This is concise with "instructions how to receive a denial."

The Dex Registry here currently lists the Castle DxSCC test as "non covered."


CSTL share price slipped this morning from around $24 to $19 before recovering to $21.  (The one year high is $34).  Against a $600M market cap, a 10% drop is around $60M value. Someone who shorted the stock at 10 am, well into the public knowledge phase, would have been well ahead at 10:30 but behind at noon.

There wasn't an immediate Castle response that I could find.  In press, they recently presented data on pharmacogenetics in depression and opened a state-of-the-art lab in Pittsburgh, giving them access to both MolDx LCDs and Novitas LCDs.  (Press.) 2022 had revenue around $137M, COGS at $32M, and net income around (-$67).  They list 2022 R&D at $45M.

Coverage at Genomeweb here.


Here, I quote directly from the "RATIONALE FOR DETERMINATION" in part.

Analysis of Evidence (Rationale for Determination)

  • While the 40-GEP is capable of metastatic risk stratification, it is unclear how GEP-results can be consistently or accurately interpreted in the context of baseline clinicopathologic risk as part of a comprehensive risk assessment to change patient management. 
  • Along these lines, the literature presented to date suggests, but does not adopt, a consistent and recommended patient management strategy with regard to follow-up frequency, nodal assessment, and adjuvant therapy for Class 1, 2A, and 2B tumors according to which outcomes could be measured. Most patients receive a Class 1 or 2A result while Class 2B results are rare; therefore, it is important to clearly define the difference in management of patients with a Class 1 vs 2A result and the net benefit. 
  • To date, this has not been done
  • It is also important to examine the impact of changes in patient management as a result on the 40-GEP on clinical outcomes from larger real-world trials (rather than anecdotal case reports), as misclassification can cause patient harm. 
  • Finally, test performance has not convincingly demonstrated superiority to currently available staging tools and clinicopathologic factors in the intended use population. The main concerns are further outlined below....[continues]


AI Supplement.

Separate from this blog, and only for curiosity purposes, I provide a GPT4 summary of #1 the MolDx evidence review and #2 the MolDx decision analysis - here.  

These AI summaries are not endorsed by me or anyone and are presented for those curious about AI approaches.  

For the evidence review the AI compresses 4300 words (omitting tables) to 450.  For the analysis and conclusion, the AI condenses 2000 words to 300.

Analysis of the Analysis

Here, I am paraphrasing from remarks that MolDx made at a California meeting last winter.   It's my interpretation.   I would think about three classes of test or service.

1.  Class 1.   The new test (or service) is a standard of care.  Nearly all payers and guidelines or reviews endorse it.  If you have to start arguing whether it is a standard of care, you can stop, because it is not a standard of care.

2.  Class 2.  The new test fits into a standard of care goal or care pathway, but is better.   I believe this is how MolDx gave coverage to the CareDx donor DNA test for renal transplants.  We know we have to manage transplants, we know we have to detect early rejection, the test does this better than a standard, like eGFR.  So it is covered.   MolDx would readily admit there is a judgment factor in assessing Class 2.

3.  Class 3.  The test is a new test without a clear similar standard that is covered and that has an established risk benefit (unlike #2).   The new test will not be covered until basic uncertainties about net risk and net benefit (real world) are resolved.   MolDx would also readily admit there is a judgement factor whether a test fails the #3 standard or has enough new evidence to pass the #3 standard.

While these are my interpretations, they provide some guiderails for reading the MolDx assessment (which puts this test in group #3).   Decisions over new tests are basically whether they are a better fit in Class 2 or in Class 3. 

Friday, May 26, 2023

NASEM Meeting Video and Decks: "Integrated Diagnostics and Oncology"

 In April 2023, National Academies held a two-day workshop on the topic, Incorporating Integrated Diagnostics into Precision Oncology Care: A Workshop.

This workshops usually produce a 50 or 100 page book after about nine months.  For now, we have all the posted presentations and the speakers in video archive.  Find the meeting here:

For example, see Lennerz' deck on integrated diagnostics at MGH, here.  There was also an AMP webinar by this group a few months back.

A publication from MGH is listed as pending as Bredella  et al.   For other peer-reviewed perspectives, see Volkov, Bredella, et al., 2023, Developing adaptive capacity and preparedness in clinical and translational science (PMID 37008599).   See Carobene et al., 2022, Where is laboratory medicine headed in the next decade? Partnership model for efficient integration and adoption of artificial intelligence into medical laboratories (PMID 36327445). 

I recently highlighted a special issue of Clin Chem Lab Med on AI & Clin Lab, 10/2022, here.

Annual Meeting: Pathology Innovation Collaborative Community: Washington DC June 27-28, 2023

"Collaborative Community" is a term of art used by FDA to designation public private partnerships (and often academic-industry) to help forge and communicate healthcare innovation.  FDA devotes a website to this topic - here.

A great example is PICC - the Pathology Innovation Collaborative Community, PICC.   It will hold the annual in person meeting June 27-28, 2023, in Washington DC.  Find them at Le Meridien, Arlington.  Fee circa $500.   PICC falls under the auspices of the broader MDIC, Medical Device Innovation Consortium.

Gotta love the subtitle: Unlocking the Potential of Digital Pathology and AI through Regulatory Science.

Find the meeting here:

The website includes a 3 minute video promo.

Here is some text from the description:

"Unlocking the Potential of Digital Pathology and Artificial Intelligence (AI) through Regulatory Science. “

Why you should attend: 

  • Network with domain experts with keen interest in moving regulatory science forward through in-person interactive working sessions 
  • The most comprehensive overview from a multistakeholder organization on digital pathology and AI 
  • Opportunities to share your unique point of view with the entire community  
  • Synergize to large scale project(s) to create practically relevant regulatory science tools and templates  

Topics Covered: 

During PIcc23, thought-leaders, regulators and pioneers in digital pathology will network and discuss: 

  • Advances in digital pathology and AI applications 
  • How these advances create new incentives to tackle the next big hurdle, to broadly implement digital pathology and AI/machine learning (ML) 
  • Impact of regulatory and legislative developments digital pathology and AI tools in diagnostics due to the end of covid pandemic public health emergency  
  • Perspectives from patient advocates about the potential of digital pathology  


CMS Publishes Annual Lab Meeting Code List, Adds Final Updates


This adds codes from the May 2023 AMA CPT meeting.   This includes several for Acetylcholine receptor antibodies, a muscle-kinase antibody, and Hep D quantification.  Plus, 18 PLA codes, plus one Admin MAAA code (---M).

At CMS, you might have to refresh or reboot your browser to "see" the updated 5/26 file at the far bottom of the web page.


The Lab Pricing Public Meeting

Every summer, CMS holds "Crosswalk/Gapfill" meetings to assist it in pricing new lab tests.  This year, the meeting is Thursday, June 22, 2023, public comments due June 1.  The meeting does not require registration and is streaming-only, unless you want to submit a public comment and register to speak.

April Agenda Versus Bigger, Last-Minute Agenda

For years, CMS publishes the test code agenda twice.  One version comes out around May 1, and includes codes passing AMA review through the first quarter.   Then a second version comes out, sometime circa June 1, which includes last minute codes finalized by AMA in early May.

The April Agenda Assessed

CMS issued the prelimary agenda on April 27.   I missed it because it is at the far-bottom of the relevant webpage.   Here's the link to the webpage, scroll to the far bottom, and see the 2024 code list.  (I'm giving the way page rather than a specific link, to allow for unpredictable CMS updates).

At this web page, click on the meeting notice heading, and then ALSO when that opens, scroll to the far bottom. 

In this April 27 version, there are 64 items.

  • Six PLA codes submitted for reconsideration.  Four are items 1-4 - 0326U, 0324U, 0348U, 0350U.  Later, items 39 and 41 are also reconsidered PLA codes (0329U, 0334U).
  • One regular CPT code is also reconsidered, 87467, microbiology, HepB SAg, quantitative.
  • Two PLA codes are on the agenda for "substantial revisions" which are 0022U and 0095U.
  • NEW PLA codes run from 355U to 401U.   
    • Again, we would normally expect CMS to add a couple dozen last minute PLA codes around June 1.
  • There are 8 new Category I PLA codes.  
    • 2 of them are not genomic.  8X016 is anti mullerian hormone chemistry, 8X025 is liver disease, 3 biomarkers, risk score.
    • 6 of them are genomic sequencing procedures.   3 are for solid organ sequencing, 3 are for solid organ sequencing specifying liquid biopsy (cell free nucleic acid).
These six codes that revamp genomic tumor sequencing are a big deal and will have a lot of impact when active beginning in January 2024.

The three genomic codes (show in orange below) are three tiers of test functions.   The first is sequence variants, DNA analysis, microsatellite instability.   The second is sequence variants, DNA analysis, copy number variants and microsatellite instability.   The third is sequence variants, DNA analysis OR DNA/RNA analysis, vopy number variants, microsatellite instability, AND tumor mutation burden and rearrangements.   The three tiers of liquid biopsy codes have a similar but not identical pattern of added features row by row.

Click to enlarge.

AMA 2024 Copyright

The CMS April Agenda is the first chance to see the full code names for the new codes. Otherwise AMA CPT doesn't release them til around September 1.

Will There Be More Codes?

Consistently, year on year, CMS has added about 20  codes at the last minute (e.g. now) to the agenda.  That doesn't mean they must do so this year.  The 65-item agenda we today have "could" be the final agenda.

Appeals Cryptic

After last years crosswalk and "turf to gapfill" decisions were announced, labs had 60 days to request reconsideration.  This basically means the code appears on this summer's schedule again.   Labs are required to submit justification and rationale for reconsideration, but CMS doesn't publish that, so we are in the dark as to what exactly was in dispute for the 7 reconsidered codes.   

We do know this.  If the code is in crosswalk, the issue may be either a different crosswalk or turf-to-gapfill instead.   If the code is in gapfill, the only appeal is to request it be assigned some crosswalk.   Every year in January, the fee schedule expands, so it's possible a stakeholder may recommend a crosswalk in June 2023 that didn't exist the last time around in June 2022.

Thursday, May 25, 2023

Welcome to the Madhouse: CardioDx Long Gone, but Novitas Continues Millions in Annual Payments

Recently, someone had me look at CPT code 81493, which represents solely the CardioDx CorusCAD test ($1050).  The company went bankrupt and closed in 2019 after Moldx withdrew coverage.  Prior to Medicare cancelling the CorusCAD test coverage, annual payments were substantial ($30M in 2018, a top-ten test).  The April 2023 coverage listing from Florida BCBS lists 81493 as experimental.

The proprietary, single-lab CPT code is still alive, and as of 2023, the AMA shows the code as being still registered to CardioDx.  AMA writes that the PLA MAAA tests are "unique to a single laboratory," the laboratory here, for AMA, for the year 2023, is CardioDx.  

Payments continue only from the Novitas MAC and only to a few labs in Texas.  This suggests the test may be re-licensed as an asset, but, the AMA still shows it as the first owner, CardioDx.  Novitas's 2020 payments for the test were $2M; Novitas's 2021 payments were $1.6M, or a two-year total of $3.6M.  

2021 payments were divided among 3 labs; one was a high biller of code 81408 (rare, full-sequence genes), another got half its revenue from 81493.

Novitas' current billing article A58917 specifically lists 81493 as Category I, payable. And a future update of the same article at FCSO (A58918) continues the coverage.   MolD's negative LCD, which killed the company in 2019, was retired in late 2022 (L37770).  


Coverage began in 2012.

Nerd Corner: IHC/Algorithm Test Gets ADLT Status, New OPPS Payment Code

CMS released new quarterly instructions for hospital outpatient claims porcessing on May 18, 2023, and it includes an obscure paragraph highlighting some details of hospital lab-test claims processing.  Code 0295U (Prelude) gets ADLT status, new claims processing indicator.  Here's why, and we show how test pricing jumped from $1897 to $5435, or 2.9X.


Conditional Bundling: Q4, versus A

Since about 2014, Medicare has bundled almost all hospital outpatient lab tests "conditionally," meaning they are bundled if there is any same-day event to bundle them to (like an office visit or surgery).  If there is no same-day service but the lab test, it's payable.  This is outpatient payment status Q4.  Every CPT and HCPCS codes on CMS Outpatient Appendix B has a payment indicator.  Q4 is conditionally bundled; "A" is payable but on a different basis than the outpatient APC system.

Most Lab Tests are Q4! Conditionally Bundled

Almost all lab tests are Q4.  However, exempt are "molecular pathology" tests which CMS defines in its practice as human DNA RNA tests.  These are "status A."  Also Status A are "ADLT" tests of the MAAA type.  To be an ADLT test of the MAAA type, you must be covered by CMS and be a clinically unique test ("provide information not available from any other test.")

Why Most ADLTs were Already "A"

Now and then, a test is converted from normal status to ADLT status, and that has the potential to change its payment indicator from Q4 bundled to A separately payable.   However, this status change is rare, because most ADLT tests are ALREADY genomic tests, so they start out in status "A".

A Rare Day, Like a Solar Eclipse: ADLT Status FlipFlops Payment Indicator

So May 18, 2023, is a rare day.   The most recent ADLT test is the Prelude test, 0295U, which became an ADLT basedon a March 23, 2023 decision, effective April 1, 2023.  The Prelude test is a recurrence risk score based on 7 proteins (via slides = immunohistochemistry) and 4 clinical variables (like size and margin status.)  It's the first ADLT since March 2022, which was the first ADLT since June 2021.  So new ADLT decisions have been seldom.

But most ADLT decisions don't change the hospital status indicator, because most ADLTs were genomic tests from the get-go.  But not 0295U, which is immunohistochemical slides plus an algorithm.  So it's a proteomic test at heart, and was classifed Q4.   Now that it is an ADLT of the MAAA type, its outpatient payment indicator is upgraded from Q4 bundled to A, separately payable.  

I Think It's a Big Deal - to Avoid Bundling Here

I think this is a fairly big deal, because clinical chemistry tests are bundled if there's an event, like a lumpectomy, to bundle them to, in the hospital outpatient setting.   (I don't think that rule applies in the ASC setting).   And while 0295U could have been separately payable as pathology and immunohistochemistry (under an APC for pathology), 0295U was placed on the Clinical Lab Fee Schedule, so it wouldn't be eligible for APC coding and processing as a physician service.

So, in transmittal CR13210, T12053, May 18, 2023, effective July 1, 2023, 0295U has "A" hospital outpatient status, effective backwards to April 1, 2023, the first quarterly date that follows its March 23, 2023 classification as an ADLT.

But Hospitals Won't Get Paid Directly, Prelude Will

For hospital outpatient lumpectomy specimens whose slides go to Prelude for staining and algorithm, only Prelude (not the hospital) will bill for it.   That's because based on circa 2018 rules, when hospital outpatient tests (like genetic tests) are separately payable, the payment goes to the lab that performs the test.


0295U: A Closer Look

Definition:  Oncology (breast ductal carcinoma in situ [dcis]), protein expression profiling by immunohistochemistry of 7 proteins (COX2, FOXA1, HER2, Ki-67, p16, PR, SIAH2), with 4 clinicopathologic factors (size, age, margin status, palpability), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a recurrence risk score.

The test is for carcinoma in situ (DCIS), not invasive cancer.

Pricing Upward Bound

Beginning on April 1, the ADLT price is $5435.  Their Laguna Hills, CA, CLIA license indicates they're probably in a MolDx state, but MolDx has said for two years it won't handle proteomic tests, only human DNA RNA ones, which would suggest it's not handled by MolDx.  A search of the national Medicare Coverage Database for 0295U turned up no info on 0295U.  0295U was priced on the prior CLFS, up to March 20, 2023, at only $1897, giving it I believe hte largest jump (just below 3X) ever awarded via the ADLT process.

MolDx?  Dex?   Z?  Noridian?

Prelude has a Z code, but no statement about coverage, within the MolDx DEX database, suggesting the coverage isn't in the "domain" of MolDx.  This would imply that coverage is in the domain of Noridian, the regular MAC for California.  In the ADLT application process, Prelude would have had to show confirmation of payment (equals coverage) from a MAC for at least one claim.  

We didn't find an explicit coverage statement at Noridian about 0295U, but we did find a notice the code was being "developed for documentatioin" six months ago, in fall 2022.   It would not have been surprising if the code, with an established CLFS price, might have autopaid at Noridian.  I couldn't easily identify any press release or Google hit for Medicare coverage of Prelude.  


The original ADLT decision in March 2023, was covered in an earlier blog.


Wednesday, May 24, 2023

Humor: GPT4 and Tic Tac Toe

This week, OpenAI began rolling out web access and special plug-in apps to subscriptions users of GPT4.   

Apps include Expedia and a PDF uploader and reader (which native GPT4 can't do).   There are two app listings, "popular" (about 12 apps) and "all" (maybe 100 or more).    

Under "all apps" there is one for Tic Tac Toe, so I guess you can use the $10 billion dollar resources of OpenAI to play tic-tac-toe.

Tic tac toe at Wikipedia. [Warning, long.]
GPT4 analysis of Tic tac toe.