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

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.

Monday, May 22, 2023

Dumb Articles Proliferate on "Expected" Spending for Alzheimer Drugs

Hyperbolic articles continue to appear regarding the potential cost of new Alzheimer drugs.  

I wrote a blog (and submitted a JAMA comment) in January 2022 on inflated "expected costs" (quote unquote) of Aduhelm.   My blog and links, here.   '

Basically, these academic estimates took what everyone in the pharma or the business world would call an "addressable market" and then said this was "expected sales."  Two different things!!!

For example, if I have a new tennis shoe, the addressable market might be 100M people, but my expected sales might be 25,000 pairs.   

This error has happened before.  There were fears that Provenge, approved in 2010 for prostate cancer, would have sales of zillions of dollars and "bankrupt Medicare."  But my informal estimate recently was that Provenge sales never reached higher than a few-percentage-points of its addressable market.

Here we go again.  See coverage at Fierce Healthcare here.   See the underlying letter in JAMA here by Arbanas et al.  

There's nothing wrong with the JAMA article itself; it takes the total number of US Medicare patients and various other estimates to estimate a potential market.   However, like the January 2022 article, the Arbanas article again uses incorrect terms like "expected spending" which is a term that should not be used until you discount the total market by a market penetration factor (as occurred for Provenge).

An example.   Medicare Part B sales of the Cologaurd test are circa 500,000 a year (observed sales circa $250M).  But if you assumed that "expected sales" was the same thing as "total addressable market," then every Medicare patient would get Cologuard every 3 years, and Medicare sales per year would be 10M-15M units (with "expected" (sic) sales north of $5B.)  

USPSTF and Courts: Injunction "stayed" for now

 As far back as September 2022, a Texas judge cast doubt on whether Congress could use USPTF preventive care decisions as mandates for coverage.  Here.  The judge finalized his decision in March 2023, setting up a predictable chain of appelate actions.   In brief, he ruled that the volunteer USPSTF panelists are not an appropriate body for making decisions that have the effect of a federal law.

On May 15, 2023, the relevant Appeals Court temporarily blocked the Texas ruling while proceedings continue.   See NYT here.  An article at Axios provides a number of hotlinks to different rulings.

In other interesting recent news, a federal court ruled that labs seeking COVID payments under PHE COVID laws don't have a legal right of action, n cases where insurers choose not to pay them.   (Holding that Congress must explicitly create a private right of action to enforce a federal law.)  I have never seen any comment about whether there is a private right of action for healthcare providers who don't feel they are paid correctly for USPSTF ACA benefits.

Sunday, May 21, 2023

One More: GPT4 nails this week's NY Times Hard Diagnostic Case

The NYTimes for several years has run a column on puzzling diagnostics, by Lisa Sanders MD.  This week's case is a 39 year old man with abdominal pain and a strong yellow skin color.   While the general problem was easy (bilirubin disorder and gallstones), the specific genetic diagnosis took the team and consultants several weeks.

I put the first 95% of the article into GPT4, and it immediately offered the correct genetic diagnosis as choice #1.   (This was at the point in the article where the medical team was slowing down, having come up empty handed on their first ideas.)


The article is here:

GPT4 writes,

The patient's symptoms point to some sort of hemolytic anemia and hyperbilirubinemia, both of which are contributing to his jaundice. The most common genetic causes of these conditions, such as sickle cell disease, G6PD deficiency, and thalassemia, have been ruled out. The jaundice is further exacerbated by the gallstones blocking the flow of bilirubin into the gastrointestinal tract.

Given these symptoms, the physicians should consider testing for the following genetic disorders:

Hereditary Spherocytosis (HS): [CORRECT] 

This is a genetic disorder characterized by anemia, jaundice, and splenomegaly. It is caused by defects in red blood cell (RBC) membrane proteins leading to spherical-shaped red blood cells which are broken down prematurely leading to hemolysis. Spherocytosis can present with very small RBCs, known as microspherocytes. It could account for the patient's anemia, jaundice, and small blood cell size. It's usually diagnosed with a peripheral blood smear, osmotic fragility test, or EMA-binding test, and the genetic basis can be confirmed with molecular genetic testing.

Pyruvate Kinase Deficiency (PKD): This is an inherited metabolic disorder of the enzyme pyruvate kinase, which affects the survival of red blood cells. A deficiency in pyruvate kinase impairs the energy metabolism of the red blood cells, causing them to be destroyed prematurely (hemolysis). The chronic hemolysis can cause recurrent jaundice, gallstones, and splenomegaly.

Hereditary Elliptocytosis (HE): In this condition, the red blood cells are elliptical rather than round and are prone to breakdown, leading to hemolytic anemia. It's less common, but it can lead to jaundice and gallstones.

Hereditary Stomatocytosis (overhydrated or dehydrated): This group of rare disorders is characterized by the presence of stomatocytes (mouth-shaped cells) on a blood film and is associated with hemolysis. It can cause recurrent jaundice and gallstones.

In conclusion, further testing, including a peripheral blood smear and specific enzyme assays, might be warranted to pinpoint the exact genetic condition this patient is experiencing. Next-generation sequencing panels for hereditary hemolytic anemias could be considered to provide a more comprehensive analysis of potential genetic causes. It's important to identify the exact condition because the treatment and management options can differ. For example, splenectomy can be beneficial in hereditary spherocytosis but can have deleterious effects in conditions such as hereditary stomatocytosis.


By the way, this puzzle is a little less puzzling online, since the NYT puts the final diagnosis in the HTML link!

Saturday, May 20, 2023

COVID Claims under COVID Law: Labs Might Not Have "Privately Enforceable" Right to Payment

[As a non-attorney, I can't distinguish the issues, but FYI, a SCOTUS case with a large majority found, in June, that certain private rights to sue under Medicaid law, were valid - here.  The lab case in the original blog below, remains of equal interest.)



Everyone in the lab industry is aware that early Congressional acts during the COVID crisis created a requirement that insurers cover COVID testing without a copay.   Another clause in early COVID law stated that the payable rate, absent other contracting, was the lab's website public rate.  


A really interesting court case was mentioned in the May 8 issue of DARK REPORT (subscription).  A lab, GENESIS, is in dispute with private payors over its special legal right to COVID payments (federal district court, NJ).   Judge Evelyn Padin has ruled that while COVID laws created such payment rules for COVID testing, there was no "privately enforceable" right to payment included in the law.  (As such, only the feds would be able to enforce lagging payments to an unpaid lab).   


In addition, the legal case (here) quotes opinions that COVID laws only amended (by implication) ERISA law, and restrictions against ERISA lawsuits continue to apply. 


Found this interesting and was happy to find the legal decision online at  I'm not an attorney but it made me muse on whether other obligations, like private payers covering USPTF-endorsed preventive services, had or did not have a "private right to action" as perceived narrowly by Judge Padin in this developing area of law.


The case is GENESIS LABORATORY MANAGEMENT LLC, Plaintiff, v. UNITED HEALTH GROUP, INC. et al. Defendants, and has articles and additional filings and motions at Lexis (and here).


Thursday, May 18, 2023

Special Issue of Clin Chem Lab Med: Fall 2022: AI in Laboratory Medicine

A special fall 2022 issue of Clin Chem Lab Med, focused all articles on the roles of AI in laboratory medicine.


This special issue "Artificial Intelligence and Big Data in Laboratory Medicine" explores the application of AI and big data in the field. Topics covered include machine learning in diagnostics, ethical considerations, AI's role in handling COVID-19, and specific applications in predicting sample turnaround times, diagnosing diseases, and more. The issue aims to foster understanding and collaboration to effectively and ethically leverage AI and big data in laboratory medicine.


An entire issue of major journal, Clinical Chemistry and Laboratory Medicine, was recently devoted to AI and Big Data issues in lab medicine.   The volume, edited by Andrea Padoan and Mario Plebani, is titled "Artificial Intelligence and Big Data in Laboratory Medicine" and it aims to explore and present groundbreaking research, reviews, and opinion articles on the application of artificial intelligence (AI) and big data in the field of laboratory medicine.

Topics of the issue span a broad range of AI and big data applications, including machine learning in diagnostics, ethical considerations, and AI's role in handling the COVID-19 pandemic. The articles cover both theoretical aspects, such as the philosophical implications of computability theory in AI, and practical applications like the use of AI in predicting sample turnaround times, diagnosing hepatocellular carcinoma based on salivary protein glycopatterns, or even identifying patients at risk for cancer in a primary care setting.

The editorial article sets the stage for the entire issue by examining whether it is the right time for clinical laboratories to adopt AI. From there, articles delve into ethical considerations associated with AI and big data, giving the issue a holistic view on the subject.

Several articles focus on AI's role in the COVID-19 pandemic, discussing the use of machine learning models for diagnosing and prognosing COVID-19 patients, and the impact of AI in this global health crisis.

The issue also includes several specific applications of machine learning algorithms in laboratory medicine, like predicting low ferritin concentrations, surrogate searching for urine osmolality, and diagnosing diseases such as primary aldosteronism, liver cirrhosis and hepatocellular carcinoma.

The last article is a survey on the utilisation of AI and Big Data in Italian clinical laboratories, giving a geographical and cultural perspective to the issue.

Through this special issue, the editors aim to facilitate a deeper understanding of the potentials and challenges of AI and big data in laboratory medicine, fostering dialogue and collaboration among medical professionals and researchers. The goal is to help the field keep pace with technological advances and to ensure the potential benefits of AI and big data can be leveraged effectively and ethically.


Table of Contents

Volume 60 Issue 12 - Special Issue: Artificial Intelligence and Big Data in Laboratory Medicine; Issue Editors: Andrea Padoan and Mario Plebani

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)