Clinical utility of genomic sequencing

 Clinical utility of genomic sequencing: a measurement toolkit

From Genomic Medicine:

For a diagnostic test such as WGS (whole genome sequencing) to be accepted into practice, commissioned in a health system, or receive coverage and reimbursement through health insurance, evidence of clinical utility and cost-effectiveness is generally required. Unlike prospective clinical research where the ‘effectiveness’ of an intervention can be easily tied to a predefined health outcome, the concept of clinical utility in genetic medicine is rarely uniformly defined nor necessarily directly tied to a specific health outcome. As such, generating and evaluating evidence of clinical utility is complex. The challenge in defining clinical utility today is compounded by the extraordinary heterogeneity of rare diseases, as well as the polygenic nature of more common conditions for which WGS is expected to be relevant. In this paper, we aim to extend earlier conceptualizations of clinical utility as applied to the diagnostic use of WGS and suggest that this framework not only be used as a tool for evidence review

 The application of this model to WGS includes six levels of efficacy: technical efficacy, diagnostic accuracy efficacy, diagnostic thinking efficacy, therapeutic efficacy, patient outcome efficacy, and societal efficacy (Table 1, Fig. 1). The model is hierarchical; achieving a given level of efficacy is often but not always contingent upon a demonstration of efficacy at the preceding level. As described in Fig. 1, levels 1–3 are necessarily contingent but beyond level 3, a genetic test can achieve therapeutic, patient outcome, and/or societal impact in ways that are contingent upon one another or independent of one another. We retain the levels of technical and diagnostic accuracy efficacy (i.e., levels 1 and 2) as essential starting points in our guiding framework as they are fundamental precursors to achieving clinical utility. However, since these laboratory-based components of efficacy are well-debated and described in the WGS literature and in recent guidelines published by members of our group27, we focus here on four levels of the efficacy model (i.e., levels 3–6) that align most directly with a broad definition of clinical utility and extend beyond laboratory-based components of efficacy. In emphasizing these four levels of efficacy as components of clinical utility, our intent is to encourage the use of a broad set of health and non-health-related indicators of value to bolster the state of evidence in this area, rather than to convey that all aspects of clinical utility need to be achieved for WGS adoption and reimbursement.

 

 

Clinical utility of genomic sequencing

The Path to Routine Genomic Screening in Health Care

Now that whole genome sequencing is knocking at the door of the clinician, it is the time to ask for clinical utility. The understanding of how such information will change diagnostic and therapy is paramount. There is still no need for cost-effectiveness, clinical utility comes first.
And the editorial at Annals explains exactly this issue, highly recommended:

There should be little doubt that individually tailored health care management plans based on DNA analysis are coming, but the timing of their introduction into routine clinical care is contingent on further demonstrations of clinical utility and proven implementation models.

My impression: let's wait for epigenetic biomarkers, beyond whole genome sequencing that provides less than 100 actionable genes out of 20.000. Though,

 The fact that only a small percentage of people would benefit from GS today is counterbalanced by growing evidence that the benefit could be significant, and perhaps even life saving

 

Pepe Castellanos at Barnadas Gallery

To test or not to test (for coronavirus)

A Framework for Comprehensive Assessment of the Value of Diagnostic Test

The Value of Diagnostic Information A comprehensive concept of “Value” for diagnostics

A framework to understand value of lab tests is the following one:

Key principles:

• Apply broad array of patient centric value drivers from various perspectives (Comprehensiveness principle)
• Utilize appropriate range of available evidence, reflecting test type and potential risks-benefits (Evidentiary principle)
• Consider reporting direct and indirect costs incurred and avoided over timeframe appropriate for the test (Cost principle)
• Account for immediate and longer-term test impact and patient benefits in representative patient populations (Specificity principle)
• Include quantified estimates as well as qualitative analyses as appropriate (Flexibility principle)
• Incorporate multiple stakeholders’ perspectives (Engagement principle)
• Disclose why the assessment was initiated, who was involved, its purpose, and the decision-making process (Transparency principle)
• Update assessments regularly to keep up with the rapid technological and clinical changes (Relevancy principles)

 Value drivers can come from four major sources:

• Clinical impact: clinical utility and health outcomes associated with the diagnostic technology. The test needs to measure accurately and reliably the analyte/biomarker of interest (analytical validity); detect, predict the outcomes of interest in a patient population (clinical validity) and inform an appropriate clinical decision (clinical utility). Improved patient safety, tolerability, compliance and physical and psychological wellbeing shall be also taken into account.
• Non clinical patient impact breaks down to patient experience, and patient economics, such as proximity of test delivery, reduced follow-up visits, repeat procedures, improved care plan compliance and reduced burden on care givers.
• Care delivery revenue, and cost impact mostly refer to quality of care metrics and more efficient resource utilization (e.g. readmissions; follow-ups, length of stay, wait times)
• Public and population impact refer to macro implications mainly from population health, burden of disease, patient and caregiver productivity perspectives

AdvaMedDx’s Approach for Effective Value Assessment

Source: A Framework for Comprehensive Assessment of the Value of Diagnostic Tests, AdvaMed, 2017

And clinical impact depends on analytical validity, clinical validity, clinical utility, patient safety and patient response. If you have only one strategy for all the patients, like social distancing in the case of coronavirus, then the information post-test will not change the therapeutic strategy. If the test tries to prevent contagion when social distancing can't be applied (health professionals, politicians, journalists, executives, essential services), than you have to test them if there are symptoms. If the test will add information to existing comorbidities to differentiate from other symptoms, then it makes sense. Therefore, this is the current situation in my country. Test, test, test when it adds value.

Validesa i utilitat de les proves genòmiques

Genome-Based Diagnostics: Clarifying Pathways to Clinical Use: Workshop Summary

En teoria de jocs es diu que tenim un punt focal quan trobem una solució que la gent tendeix a utilitzar per coordinar-se quan falta comunicació, perquè sembla que satisfà tothom. El concepte va ser introduït per l'economista guanyador del Premi Nobel Thomas Schelling en el llibre The Strategy of Conflict (1960). El que aquest punt focal o equilibri sigui eficient o no ho sigui ja són figues d'un altre paner..
Tot d'una, quan llegia un l'informe de l'IOM sobre tests genètics, m'ha vingut a la memòria Schelling i els seus punts focals. Resulta que s'explica com davant dels biomarcadors s'ha encetat un cercle viciós (punt focal) que només es pot trencar mitjançant un canvi regulatori i d'incentius. Afegeixo un paràgraf d'interès:

The basic problem is that there has been relatively little consistency regarding which biomarkers have been introduced into clinical practice. Very few cancer biomarkers with demonstrated clinical utility have been introduced over the past 30 years. Even among those tests that have been integrated into practice, their use in certain settings has not always been supported by evidence of benefit, such as the use of prostate-specific antigen (PSA) as a screening test (Andriole et al., 2009), said Hayes. This has helped to create what Hayes has termed a “vicious cycle” in which tumor biomarkers are systematically undervalued (Figure 2-1). This undervaluation has led to limited use of these diagnostics by health care providers and poor reimbursement when a marker has been able to navigate the regulatory environment to be brought to market. Lack of use and reimbursement in turn leads to limited funding for biomarker research because the return on investment is low. The perception that markers have little utility has also led to an environment of lower academic  recognition for developing biomarker-based tests. The overall result is reduced ability and incentive to conduct properly designed clinical trials to generate high-quality evidence of clinical utility. In return, there is reduced data certainty, higher skepticism, and few recommendations for clinical use, said Hayes, which completes the cycle by contributing to the poor valuation of marker utility. Hayes focused his recommendations for breaking the “vicious cycle” of undervalued tumor biomarkers on two areas: the regulatory environment and marker reimbursement.

Actualment als USA (i aquí encara menys) no hi ha un procés de revisió de la FDA per a les proves diagnòstiques de laboratori del tipus Laboratory Developed Tests LDT on s'avaluï la validesa analítica, validesa clínica i utilitat clínica. Es regula per la llei CLIA tal com s'explica al text. La proposta és doncs que la FDA prengui part del procés de revisió i es reformuli la regulació existent. I des de la vessant dels incentius, se suggereix que s'estableixin anàlisis cost-efectivitat de les proves que permetin situar el seu preu en funció del valor que aporten.
Ens trobem doncs en un llibre clau per a un moment clau. I qui tingui ulls i vulgui que el llegeixi, són tant sols 105 pàgines fonamentals per entendre una de les qüestions determinants de la medicina del futur.
Em costa admetre que el punt focal per aquí aprop es redueixi a veure passar els dies inexorablement i la innovació tecnològica resti sense avaluar, un equilibri ineficient. En Schelling diria que cal comprometre's de forma creïble per sortir-ne, però per ara i pel que fa al regulador, no ho sé veure per enlloc.

PS. Miss-selling drugs, a The Economist.

PS. La sindicatura emet informe sobre l'Hospital Clínic. Enmig del desori observo que s'han deixat de cobrar 40 milions d'euros amb trasplantaments a forasters!

PS. A DM trobareu alguns detalls sobre el nou sistema de pagament.  Esperem més informació en el futur.

PS. Les autopistes sense cotxes ens constaran 290 milions el 2012, l'any passat van costar 80 milions.

Genome sequencing, what's it worth?

Evaluating the Outcomes Associated with Genomic Sequencing: A Roadmap for Future Research

The health economic evidence base for WES -whole exome sequencing- and WGS -whole genome sequencing- is very limited . A recent literature review identified just eight economic evaluations of either WGS or WES, six of which were cost-effectiveness analyses using diagnostic yield as the outcome measure. Only two publications presented cost-utility analyses using quality-adjusted life-years (QALYs) as the measure of health outcomes, as recommended by most health technology assessment (HTA) agencies. However, neither of these cost-utility analyses provides information on health outcomes that HTA agencies can use to inform the translation of NGS technologies into clinical practice for specific disorders.

Last May I wrote a post on this topic. Now James Buchanan and Sarah Wordsworth provide a roadmap for future research with three steps.

First, it is crucial that health economists generate evidence on the clinical utility of genomic sequencing using the methods and metrics that are recommended by HTA agencies. Here, we are primarily referring to the use of preference-based HRQoL instruments such as EQ-5D questionnaires to generate utility weights that can be used to calculate QALYs 

If there is reason to believe that patient wellbeing will change after undergoing genomic sequencing (for example, supportive qualitative evidence), but commonly used HRQoL instruments show no effect, a second step would be to explore the use of alternative health-state valuation techniques to generate utility weights within the QALY framework. The time-trade-off (TTO) technique is one such approach

A third step would be to make full use of existing evidence on the diagnostic yield of WGS and WES. Studies that link this evidence to patient survival and quality of life (for example, trials or observational studies with long-term follow-up), could inform decision making regarding the translation of these technologies into clinical practice.

Unfortunately, it is easier said than done. I'm dubious regarding the potential of QALYs on assessing value of such technology, despite I have no alternative solutions right now.

Exhibition at Saatchi gallery

NGS: from research to clinical use

 Expanding Use of Clinical Genome Sequencing and the Need for More Data on Implementation

During the past 5 years, next-generation sequencing (NGS) has transitioned from research to clinical use.At least 14 countries have created initiatives to sequence large populations (eg, All of Us, Genomics England), and it is projected that more than 60 million people worldwide will have their genome  sequenced by 2025.

If this is so,

 Understanding how NGS is being used and paid for is critical for determining its clinical and economic benefits and addressing current and future challenges to appropriate implementation.

 Without consistent information on clinical utility and how NGS tests are implemented in clinical care, it is not possible to develop an understanding of benefits and harms associated with NGS. It is not always the case that evidence of clinical utility leads to improved outcomes, and evidence about implementation is required to complete the assessment of the effects on population health. Implementation science is intended to support the integration of findings from scientific evidence to uptake in routine clinical care in the ongoing cycle of a learning health care system.

This is clearly a call for action. However, in my country the call is for both developing NGS  (nothing has started) and asessing implementation. Is there anybody in the room?

Hockney

The hole for genetic testing market entry

Technology Assessment on Genetic Testing or Molecular Pathology Testing of Cancers with Unknown Primary Site to Determine Origin
Update on Emerging Genetic Tests Currently Available for Clinical Use in Common Cancers

AHRQ has just published two reports of interest. The first is devoted  to assess the evidence on the analytical validity, clinical validity, and clinical utility of commercially available genetic tests for identifying the tissue of origin (TOO) of the cancer in patients with cancer of unknown primary (CUP) site. The second describes genetic tests that have applications in the common solid tumors (breast, lung, colorectal, pancreas, etc.) as well as tests that are used in hematologic cancers (leukemia, lymphoma) and are already available in clinical practice.While the first is an assessment, the second is informative.
There is still a third report to be released and meanwhile NRD explains its conclusions. Having selected 11 prognostic tests, only around half had evidence supporting their prognostic accuracy or clinical validity. Therefore the question is always the same: why these tests without evidence are on the market? Why have they been approved by the FDA?. There is a big regulatory hole to fill in.

Validesa i utilitat de l'òmica

Evolution of Translational Omics: Lessons Learned and the Path Forward

 L'"Òmica" és un terme que abasta múltiples disciplines moleculars, que impliquen la caracterització dels conjunts globals de molècules biològiques, com ara ADN, ARN, proteïnes, i metabòlits. Per exemple, la genòmica investiga milers de seqüències d'ADN, la  transcriptòmica investiga totes o moltes transcripcions de gens, la proteòmica investiga un gran nombre de proteïnes, i metabolòmica investiga grans conjunts de metabòlits.

Així comença el llibre de l'IOM sobre una qüestió fonamental de la medicina dels nostres dies.  I el més interessant és com explica la diferència entre l'òmica translacional i els biomarcadors. Malgrat la dificultat que presenta l'avaluació d'un biomarcador, els reptes al que s'enfronta l'òmica són molt superiors. Diu clarament a l'inici:

The complexity of omics research also makes data provenance more challenging and makes sharing of the complex data sets and computational models difficult, which limits the ability of other scientists to replicate and verify the findings and conclusions of omics research studies. Database repositories for genomic data sets are available, but data sharing is not routine, and  without access to the data sets or a precisely defined computational model, replication and  verification are more difficult than for single biomarker tests. While independent confirmation studies are expensive, the need for replication is beneficial in the omics field given the data  complexities that can lead to errors, from simple data management errors to incorrectly  designed computational models. This level of complexity does not exist for single-biomarker  test research, development, and validation.

Massa sovint es vol fer passar aquesta complexitat com inadvertida. I afegeix:

Many hope that the promise that omics science holds for medicine and public health will be realized. With the creation of high-throughput measurement technologies, it is now feasible to take a snapshot of a patient’s molecular profile at specific stages in the progression of disease pathology or at a given location in the body. However, the complexity of these technologies and of the resulting high-dimensional data introduces major challenges for the scientific community, as rigorous statistical, bioinformatics, laboratory, and clinical procedures are required to develop and validate these tests and evaluate their clinical usefulness.

Sobre el tipus de dades òmiques heu d'anar a la pàgina 40 i llegir-ho amb deteniment. Quan un acaba de comprendre el que s'explica de forma planera, aleshores s'adona que els que venen genoma i prou s'han quedat curts, la complexitat és notòria. I en especial la referent a l'epigenoma, del que ja n'he parlat repetidament en aquest blog. El capítol sobre avaluació de les proves esdevé clau. Només fa referència a validesa analítica i clínica, però és el principi sense el qual tots aquells que es plantegin fer cost-efectivitat no podran treballar. I cap al final trobo aquesta conclusió:

 A well-designed test development plan addresses a clinically meaningful question and employs rigorous test discovery, development, and validation procedures. This includes locking down all aspects of an omicsbased test prior to evaluation for clinical utility and use and avoiding overlap between discovery and validation specimens. Choosing an appropriate clinical/biological validation strategy and interacting with FDA prior to initiation of validation studies also reflect a well-designed test development plan. Making data and code available are critical aspects of test development because it enables external verification of the results and generation of additional insights that can advance science and patient care.

El rigor s'imposa i traduir la recerca en aplicacions obliga a comprendre el valor que aporten a la societat. El camí és llarg malgrat sovint apareix als diaris com que és bufar i fer ampolles.

PS. Es poden patentar les proves genòmiques? Avui un tribunal decideix, ho trobareu a WSJ.

PS. Ekaizer a 8TV, fonamental. I també a RAC1

PS. Al Diccionario RAE queda més clar encara: macarra. 1. adj. Dicho de una persona: Agresiva, achulada.

Eliseu Meifren, podeu veure'l a Sant Feliu de Guixols, paga la pena.

Cost-effectiveness of genome sequencing

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

It is quite difficult to talk about value in genetic tests without any reference to analytical validity, clinical validity and clinical utility. Once these three issues are appropriately solved, then we need to assess costs. Cost effectivenes makes sense once this three steps are covered successfully.
An analysis of cost-effectiveness of whole genome/exome sequencing it sounds too generic if there is no reference to specific baseline that allows to estimate incremental cost-effectiveness ratios.
That's the reason why a recent article trying to review existing studies fails to achieve any conclusion.

The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited. Studies that carefully evaluate the costs,
effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.

 Let's start focusing on the assessment of three key perspectives before entering into a black hole.

The hype over genetic tests

Implementation of a companion diagnostic in the clinical laboratory:The BRAF example in melanoma

Analytical validity is one of the three steps for any assessment of genetic tests, combined with clinical validity and clinical utility. Understanding how this process affects specific tests is not that easy.Fortunately you can find a detailed explanation of one of them:the BRAF genotype analysis in tumor tissue samples for identification of melanoma patients that can benefit treatment with BRAF inhibitors.
Once you begin to read the article you'll understand the complexity of being precise in a test. This is the reason why if specificity and sensibility is uncertain, different methodologies are needed (check Figure 1).
But how to do it?. How to set up external controls of quality?. All these issues are covered in this article, that explains what's going on in practical terms. I'm concerned if due to such complexity, all "genetic test talent" is not concentrated in one site of the organization-hospital, and many departments and services -oncology or cardiology- are developing their own genetic tests. Somebody should block this option before it is too late.

Clinical utility of genetic testing for breast cancer

 Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

However,

 We found strong evidence of an association with breast cancer risk (Bayesian false-discovery probability, <0.05) for protein-truncating variants in 9 genes, with a P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53).

  None of the other 25 genes in the panel had a Bayesian false-discovery probability of less than 0.10. Of note, 19 genes had an upper limit of the 95% confidence interval of the odds ratio of less than 2.0, with 2.0 representing a proposed threshold for “pathogenic, moderate risk alleles”9; we therefore conclude that these genes are not informative for the prediction of breast cancer risk. We confirmed that missense variants in BRCA1, BRCA2, and TP53 that would be classified as pathogenic according to clinical guidelines are indeed associated with clinically significant risks. We also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, are associated with moderate risk.

The summary:

 Variants in 8 genes — BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 — had a significant association with breast cancer risk.

 

Veure-les passar

El tema segueix sobre la taula. El debat sobre les proves genètiques i com regular-les preocupa a la FDA i encara que ja ha dit que cal aplicar els mateixos criteris que als subministraments mèdics (medical devices), hi ha molts dubtes sobre els detalls.

Els de Genomics Law Report expliquen el que ha passat a les compareixences recents. Si n'esteu interessats feu-hi una ullada.
Les preguntes clau:

Should the agency require proof of analytical validity, clinical validity and/or clinical utility prior to approving a particular test and, if so, what standards of proof should be required?
Should the agency regulate tests SNP-by-SNP, claim-by-claim or test-by-test, and what should be done to prepare for the inevitable arrival of tests based on whole-genome sequence data?
Should the agency oversee the labeling and advertising claims offered by companies in association with such tests?
Should the agency require companies to collect and submit data regarding the post-test benefits and harms and the actual (as compared to intended) uses of their tests?
Should the agency impose requirements on companies to prevent unauthorized testing, protect data privacy and limit companies’ ability to share genetic information without their customers’ consent?

While these questions, and countless more, will be critical to the development of sensible genetic testing regulation, one question clearly generates more and more emotional responses than any other:

Should regulators require some or all genetic tests to be routed through a clinician, or should tests be made available directly to consumers who desire them?

I mentrestant per aquí, les veiem passar...i ens costen una pasta...

PD. El gran Ferran Torrent representa una alenada d'aire fresc els diumenges, tant en directe a Rac1 com els comentaris a ARA. Cita Josep Renau: "Quan arribes a València i et menges una paella o una sípia t'oblides de la lluita de classes". I mentrestant els de FT ens recorden que "Valencia is burning"

Enough is enough

If there is a grey area in medical devices and services regulation, this is the Laboratory Developed Tests one. Up to now, FDA has refused to define the rules of the game for 11,000 diagnostic tests performed at 2,000 labs in USA. This means that no official or external reviewer has analysed the clinical validity and clinical utility as it is done in any reagent and instrument. I can't understand why we have arrived at such a situation.
Fortunately NYT reports that on July 31st, FDA announced that this will change.

The agency said on Thursday that such discretion must end because circumstances had changed. Lab-developed tests once were fairly simple, often developed by a hospital for tests on its own patients. Now the tests can be complex and are being developed by  companies and marketed widely.

Some widely used commercial tests have never had to be reviewed by the agency. These include Myriad Genetics’ breast cancer risk test, the subject of a Supreme Court patent decision last year; the Oncotype DX test from Genomic Health, which is used to determine if women with early-stage breast cancer need chemotherapy; and noninvasive prenatal tests for Down syndrome that are rapidly catching on.

In this blog I have supported several times for a clear regulation of these tests . Just the other day when looking at the statements of FDA commissioner, I was astonished:

Just as drugs need to be safe and effective for treating diseases, medical devices used to help diagnose disease and direct therapy also need to be safe and effective, Faulty test results could lead patients to seek unnecessary treatment or to delay or to forgo treatment altogether.

These statement raise more concerns about what US regulator has done after all these years. And european regulation is still worse in this sense. I have explained such disaster previously and up to now there is no news. Some times I wonder why do we pay taxes, why do we have to be part of Europe. Enough is enough.

Risks and benefits of self-testing (2)

 Direct to Consumer Testing: The Role of Laboratory Medicine

A specific issue on the topic has been released in Clinics in Laboratory Medicine. Inside the issue, you'll find this article: Direct-to-Consumer Tests on the Market Today: Identifying Valuable Tests from Those with Limited Utility 13. This is a key topic. It says:

Debate exists between the consumer and the health care provider when it comes to the value of direct-to-consumer (DTC) testing. At the heart of the issue is the observation that consumers are identifying value in DTC testing as evidenced by an expanding market, and health care providers are skeptical of their value from an analytical and clinical utility perspective. The aim of this article is to briefly review the subject of DTC testing with a specific focus on value from the perspective of the consumer and the health care provider.

 Paul Strand at KBr Barcelona

 

Where is the regulator?

Understanding the Economic Value of Molecular Diagnostic Tests: Case Studies and Lessons Learned

Maybe we have just arrived at the expected moment, when the cost of one whole genome sequencing is below $1000. (mapping up to 25.000 genes). At the same time, one test for 21 genes may cost you $4.500. This is our crazy world. In the first case you will only know your genome, in the second there will be a probability of success from a certain therapy.
There's only one question: Does anybody know any information about the reliability of such probabilities beyond the firm that is selling the test?. Where is the regulator?
After reading a recent article on the value of molecular diagnostic tests, I'm convinced that we still remain in an uncertain world in need of transparency. Given such uncertainty, better keep calm until the regulator confirms the clinical utility and cost-effectiveness of molecular diagnostic tests.

Parov Stelar Band - Jimmy's Gang (Unplugged in Moscow)

PS. You may avoid watching "The wolf of Wall Street" if you read this article.

L'assaig clínic mai vist per al cribratge del càncer

Li pregunto a Chat GPT sobre l'assaig clínic més gran en nombre de participants i em diu que és ASPREE, sobre l'aspirina i prevenció cardiovascular. I veig que Galleri, l'assaig clínic de GRAIL sobre cribratge de càncer al NHS hi ha 140.000 participants. I jo penso, això és molta gent i el Chat GPT4 no ho ha copsat. 

This is a trial in a large population in England to assess the performance and clinical utility of GRAIL’s multi-cancer early detection test when added to standard of care. Participants are randomized to either a test or control arm. The study teams remain blinded throughout the study. Participants who test positive will be referred for standard of care investigations and treatment in the National Health Service (NHS).

The study has enrolled approximately 140,000 people aged 50 to 77. Unless diagnosed with cancer, participants in both arms are asked to return for annual visits at approximately 12 and 24 months. All participants whether test positive, test negative or not tested will be followed for cancer and associated outcomes via linkage to NHS routine datasets.

Els detalls de l'assaig els trobareu aquí. I si voleu veure la validació, aquí. I mentrestant el regulador segueix pensant si autoritza la prova, resulta que ja es troba al mercat.

Health information, such as whether someone developed cancer and how it was treated, is collected from centrally held NHS records for up to 10 years after people’s first appointment. This allows the researchers to easily track people for whether they get cancer, even for people who may have moved home.

People who are diagnosed with cancer while they are taking part in the trial may not need to attend further trial appointments to give blood samples.

A quina data s'acaba l'assaig clínic no se sap del cert. Després de llegir tot això espero que se sàpiga quina és la sensibilitat i especificitat de la prova segons càncer detectat. Dic això perquè no he sabut veure com s'avaluen els falsos negatius, ni els falsos positius. I en un moment concret diuen que haurem d'esperar 10 anys. No ho sé, potser m'ha passat per alt.

Més detalls, aquí.

Mentrestant la Unió Europea ha prohibit la fusió Illumina-Grail, i ja veurem com acaba. Per ara els mesos passen i res de res...

Galleri, el test detecta (diuen) 50 tipus de càncer amb una gota de sang que cerca ADN circulant per 1.000€ (diuen, diuen).

Més d'un i més de dos volen saber si estem davant d'un nou cas Theranos, (jo vull pensar que no) i per això han començat aquest assaig clínic. A FT del dijous hi ha més detalls. I ho fan a UK perquè a Europa aquesta empresa hauria d'estar prohibida fins que no compleixi les resolucions de les autoritats.

What clinicians do and why they do it

The Nature of Clinical Medicine. The return of the clinician

Nowadays, technology pervades media and our live. This is a good moment to rethink the basics, the foundations of medicine, its values and goals. Eric Cassell contributes decisively to this aim with his new book, a must read at least for physicians and all professionals related with medicine.
Health economists should be aware of better understanding  about the goals of medicine and purposes of physicians. They reflect the true "production function".
Here is a brief summary of the book and afterwards its goals and purposes:

Clinical medicine, as a thinking discipline, is concerned not only with what clinicians do, but why. When physicians act in medicine they have some purpose or goal in mind. What they actually do and how they go about it is in the service of their purposes and their goals. Such goals cover a wide range of topics centering on patients, the doctor-patient relationship, the acts of doctoring patients, and the goals involved in being a physician among other physicians working within the institutions of medicine.

The Nature of Clinical Medicine takes its direction from a catalog of goals of medicine that range from the expected diagnosis and treatment of diseases to wider concerns for patients, for physicians, and for medicine itself. The chapters are specific in teaching the kinds of knowledge that clinicians require in order to be able to achieve these goals. The central focus of the clinician and of this book is the patient. According to Eric Cassell, everything else, including the disease, is secondary.

Summary of the Goals of Medicine

A. Patient-centered goals

1. Save life.
2. Prolong life.
3. Cure disease.
4. Prevent suffering.
5. Relieve suffering.
6. Do no harm.
7. Protect the patient from danger.
8. Do not frighten the patient.
9. Relieve the patient’s fears.
10. Make the patient better in the patient’s terms.
11. Do nothing unnecessary (or more than necessary). B. Goals related to the physician–patient relationship
12. Develop and maintain a good relationship.
13. Be trustworthy.
14. Tell the truth.
15. Be reliable.
16. Be constant.
17. Be there when needed.
18. Make a difference.

C. Goals related directly to doctoring the patient

19. Make a diagnosis (where pertinent make a tissue diagnosis).
20. Decide what the problem is.
21. Obtain the necessary information.
22. Make sense of the case (in pathophysiological, anatomical, psychological, and social terms).
23. Decide the correct treatment and its timing.

D. Goals related to being a physician among other physicians

24. Seek and maintain comprehensive knowledge.
25. Maintain the standards of medicine.
26. See that things are done right.
27. Protect the patient from bad medicine and incompetent physicians.
28. Behave in a proper, doctorly manner.
29. Look good to other physicians and the patient and family.
30. Avoid error.
31. Avoid blame.
32. Maintain relationships with peers.
33. Stay alive in the institution (hospital or medical school) and community

The relationship between purposes or goals and values (p.166). Five kind of goals:

1. Specific obligations to other people or institutions—patients, other caregivers, or the hospital
2. Responses to rights that everybody has, for example, the right to refuse treatment, or to freedom from assault or coercion.
3. Purposes based in what might be called utility. Things pursued because of the benefit to the patient, or the avoidance of injury. Also purposes directed at general benefit, like the advance of medical knowledge.
4. Purposes related to what might be called self-development values. Here, there is intrinsic value in acquiring a particular piece of knowledge or skill because it is believed to be part of the general good if even one person has special knowledge. The goal of acquiring a particular knowledge or ability lies in this arena of values.
5. Purposes related to one’s own project in life, like becoming a good clinician apart from, for example, the acquisition of a specific skill  or the general advance of medical knowledge

The urgent need to define delivery models for genetic testing

Identification of Delivery Models for the Provision of Predictive Genetic testing in Europe: Protocol for a Multicentre Qualitative study and a systematic review of the literature

The increasing role of genomics in medical decision making requires a review on how services should be organised. Unless this effort is taken promptly, it will be much more difficult to adapt the messy organization to an efficient model for the delivery of services. This issues are explained in a recent article. The ten questions:

 The transfer of genomic technologies from research to clinical application is influenced not only by several factors inherent to research goals and delivery of healthcare but also by external and commercial interests that may cause the premature introduction of genetic tests in the public or private sector (i.e., introduction of a test despite insufficient evidence regarding its analytical validity, clinical validity, and utility). Furthermore, current genetic services are delivered without a standardized set of process and outcome measures, which are essential for the evaluation of healthcare services. It is important that only genetic/genomic applications with proven efficacy and effectiveness are delivered to populations, and particularly that technologies have favorable cost-effectiveness ratios

Cost-effectiveness of genome sequencing (3)

Application of next-generation sequencing to improve cancer management: A review of the clinical effectiveness and cost-effectiveness

Once again, there is no need for cost-effectiveness if there is not a clear message on the analytical validity, clinical validity and utility of a diagnostic test.
A new article want to shed light on cancer and NGS, and says:

Our search for cost‐effectiveness studies on NGS in cancer care yielded 2037 articles. Only 6 articles included cost‐effectiveness studies of the application of NGS (targeted gene panel) in cancer

The 6 selected reports could be separated into 2 types. Three of the articles assessed the cost‐effectiveness of recommending patients receiving targeted therapy matching their genetic mutation identified via NGS; and the remaining 3 articles assessed the cost‐effectiveness of using NGS as part of the screening program to direct patients or high risk family members into prophylactic treatment

Two out of 3 articles in the “targeted therapy” group reported that NGS and targeted therapy was not cost-effective (Table 3A), using an ICER threshold of US$100 000 per Quality Adjusted Life
Year (QALY) gained. An ICER of less than US$100 000/QALYs gained is generally considered favourable for funding in the United States

Two out of the 3 articles in the “screening” group reported that the use of NGS was cost‐effective (Table 3B), that is, under US$100 000 per QALY gained.loser surveillance.

 In our evaluation of the effectiveness of NGS, we found that NGS is effective at identifying mutations in cancer patients, and we reported that 37% of the diagnosed patients proceeded to receive therapy matching their genetic profile. However, with only 6 articles available that assess the cost-effectiveness of NGS in various settings, it remains an area for future research to determine whether the technology is cost-effective in routine cancer management

Summary: the message is that there is no message with such a few observations!


Something is being missed...

Guillem Roma and Marta Roma

The value of direct-to-consumer tests

 Direct-to-Consumer Tests on the Market Today. Identifying Valuable Tests from Those with Limited Utility

For health care professionals, the analytical validity of DTC tests is a primary concern. Analytical validity of DTC genetic testing can be defined by analytical sensitivity and specificity whereby analytical sensitivity is defined as how often a test is positive when the genetic variant of interest is present in the tested sample, and the analytical specificity is defined as how often a test result is negative when the tested sample does not contain the genetic variant of interest.18 A recent study by Tandy-Connor and colleagues19 “indicated that 40% of variants in a variety of genes reported in DTC raw data were false positives” when compared with clinical confirmatory testing. This study highlights the need to scrutinize the analytical validity of DTC genetic testing and consider confirmatory testing in a clinical diagnostic genetics laboratory. 

Per the American Society of Human Genetics, “companies offering DTC genetic testing should disclose the sensitivity, specificity and predictive value of the test, and the populations for the information is known, in a readily understandable and accessible fashion.”

Unfortunately, nobody cares about it, and the regulator is still on vacation.

World Press Photo BCN