Cost-effectiveness with uncertain effectiveness

Cost-effectiveness of a gene expression score and myocardial perfusion imaging for diagnosis of coronary artery disease

Gene expression testing is quite different from genetic testing. Gene expression refers to epigenetic regulation of genes that occur without alteration of DNA. I've covered such topics several times in this blog. Today, I would like to focus on a recent published work on a new test  that assesses whether or not a patient's chest discomfort or other symptoms are due to obstructive coronary artery disease. Sounds interesting, since angiography is a costly technology.
A quick look at this recent article will raise new doubts. As you know, there is no need for cost-effectiveness analysis when effectiveness is uncertain. When talking about testing effectiveness means, sensitivity and specificity, AUC and so on. But what happens when the seller (or the model) decides about the threshold and afterwards focuses on negative predictive value of 96% and provides the desired value?. The threshold is only an option in the model. Why not change it?. There is a circular reasoning on that.
My concern is that health economics should look in detail at such issues. It is not an issue of conflicts of interest. In this case any health economist should avoid entering such territory.

When asking your physician is not enough

23andMe and the FDA

Some weeks ago I explained the FDA "closure" of DTC genetic testing business. NEJM analyses with detail the rationale behind such policy:

The goal of the FDA and 23andMe (as well as all clinical geneticists, testing laboratories, and the entire genetics industry) should be to ensure that genomic information is both accurate and clinically useful. Clinicians will be central to helping consumer–patients use genomic information to make health decisions. Any regulatory regime must recognize this reality by doing more than simply adding the tagline on most consumer ads for prescription drugs: “Ask your physician.” That is insufficient guidance unless your physician has ready access to a clinical geneticist or genetic counselor.

European regulation is 15 years old and the new directive is still being discussed. It will not be applied for at least 3 years. Meanwhile, do you know who is protecting us from inaccurate and clinically useless information?

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.

False advertising

The concern over consumer protection is growing with new health technologies. This is not new, you may think. However the lawsuit by FTC against Genelink for misleading claims is the first case in a genetics testing company. Genelink said that they analyzed your DNA and afterwards send back nutritional supplements customized to your personal genome. The regimen, the company promised, was good for diabetes, heart disease, arthritis, insomnia and other ailments.On request by FTC, they were unable to confirm such promises.
Since you may find a similar test on the corner of the street, once again my question is: where is the regulator?

PS. Some months ago, was the FDA who asked 23and me to stop selling its genetics test kit.

PS. On DTC genetic tests, a good article.

An ongoing tug-of-war

Understanding Differences Between High- And Low-Price Hospitals: Implications For Efforts To Rein In Costs

Consolidation of private healthcare providers is an increasing trend nowadays. The exact implications for competition and choice are usually unknown. It is worth having a look at other markets. This article in HA explains the impact for the US context:

Prior research shows that private hospital prices vary considerably both within and across markets, even after differences in patient populations and services provided are accounted for. The wide variations in price and the high prices at some hospitals reflect an ongoing tug-of-war between increasingly consolidated buyers (health plans) and increasingly consolidated sellers (hospitals and hospital systems).

Given the intense and growing pressure to rein in the growth in private health insurance premiums, the continuation of current trends appears to be unsustainable. It remains to be seen whether or not health plans will somehow regain the upper hand. If they do not, more radical approaches—such as state-based rate setting or restrictions on contracting arrangements between hospitals and health plans—may gain traction.

PS. HA Blog, a comment.

PS. On limiting bisphenol in food.

PS. Health expenditures NEJM Graphic 

PS.Health Policy Basics: Health Insurance Marketplaces

PS. Are Human Genes Patentable? 

PS. Regulating 23andMe to Death Won’t Stop the New Age of Genetic Testing

For another day

The Actress, the Court, and What Needs to Be Done to Guarantee the Future of Clinical Genomics

The introduction of new technologies and benefits in health care is always a perfect chaotic process. It starts with the creation of great expectations that have to be fulfilled (and publicly funded!). In some sense it could be understood as a remake of the Nintendo story of undersupply and artificial scarcity creation. Some genome based biomarkers fits partly with this paradigm.
The case of Angeline Jolie -double mastectomy after BRCA testing positive- was broadcasted worldwide in the weeks before the ruling against gene patenting. Creating uncertainty and scarcity artificially is a heavier combination. And in this situations is when common good has to be protected, and government has the key role.
Two selected messages from this week in PLOS Biology:

If clinical genomics is about to move forward at a more rapid pace due to broader public awareness and a more favorable legal climate then there is still work to be done on the ethical, regulatory, and legal fronts.

Celebrities are now drawing public attention to the utility of genetic testing. With the Supreme Court decision opening the door to more and perhaps cheaper entry into the testing market, the requisite infrastructure for managing risk and the rules for handling risk information must be strengthened. Making testing more widely available will only be morally acceptable if there are rules of the road in place.

 Meanwhile, our regulator is just waiting for another day, then it may be too late.

Music video by Nikki Yanofsky performing For Another Day. 

(C) 2010 Decca Label Group

Economics of genomics

The Economics of Genomic Medicine - Workshop Summary

Just imagine for a while that you are concerned about economic implications of genomics and you invite a distinguished professor of genetic medicine - James Evans- to the introduction of a workshop at IOM. Instead of more is better, he sends a cautious message to the audience. And beyond the potential and valuable applications for those that are already ill,  he openly critizises the current trend towards the use of genetic tests for the healthy:

Assessing the risk of common diseases through whole genome analysis of a healthy person has received the most attention, but this attention “is somewhat misplaced,” Evans said. Currently, assessment of genetic risk alleles has “rather feeble predictive power” because the increased risks tend to be small. “From a clinical standpoint I don’t know what to do with patients who are at a 1.3 relative risk for colon cancer,” said Evans. “Am I going to hurt them by doing more intensive screening, or am I going to help them?”

"I know what almost everybody in this room is going to die of,” said Evans. “We are going to die of heart disease or cancer. . . . We are all at high risk for these maladies regardless of our [genomically determined] risk. And many at decreased risk for heart disease will still die of heart disease. So we are all going to benefit from interventions that lower heart disease. We don’t really need to target people. It doesn’t do anyone much good to tweak our estimation of an individual’s relative risk for common diseases which we are all at high absolute risk of developing anyway."

 “The old adage that an elephant for a nickel is only a bargain if you have a nickel and you need an elephant applies here. I am not sure most of us need that elephant. Even if free, perceived low cost is an illusion, because the misapplication of medical tests—and make no mistake, whole genome sequencing is a medical test—is very expensive,”

A clear message for geneto-enthusiasts and marketeers. Cost-effectiveness of genetic testing starts with assessing if they are effective. If not, any economic analysis is useless . This is obvious, but we do need to repeat it, just in case.

PS. Must read, Reinhardt's blog.

PS. A report to understand the financial markets' mess and why recovery is far by now.

La capacitat predictiva de les proves genòmiques

Gene Maps Are No Cure-All

Les quatre característiques diferencials de les proves genòmiques es que són determinacions inespecífiques, d'alta validesa analítica, baixa validesa clínica i utilitat clínica problemàtica.  Això és el que ens explica un article a BMC Medical Ethics. I només a partir de la comprensió d'aquestes característiques es possible començar a parlar de les implicacions ètiques, legals i socials.
Doncs bé, avui llegia a WSJ la notícia sobre la baixa capacitat predictiva de les proves genòmiques completes (i per tant inespecífiques) a partir d'un estudi publicat a Science Translational Medicine, un contrast de la seva baixa validesa i utilitat clínica.
El resum diu:

New DNA sequencing methods will soon make it possible to identify all germline variants in any individual at a reasonable cost. However, the ability of whole-genome sequencing to predict predisposition to common diseases in the general population is unknown. To estimate this predictive capacity, we use the concept of a “genometype”. A specific genometype represents the genomes in the population conferring a specific level of genetic risk for a specified disease. Using this concept, we estimated the capacity of whole-genome sequencing to identify individuals at clinically significant risk for 24 different diseases. Our estimates were derived from the analysis of large numbers of monozygotic twin pairs; twins of a pair share the same genometype and therefore identical genetic risk factors. Our analyses indicate that: (i) for 23 of the 24 diseases, the majority of individuals will receive negative test results, (ii) these negative test results will, in general, not be very informative, as the risk of developing 19 of the 24 diseases in those who test negative will still be, at minimum, 50 - 80% of that in the general population, and (iii) on the positive side, in the best-case scenario more than 90% of tested individuals might be alerted to a clinically significant predisposition to at least one disease. These results have important implications for the valuation of genetic testing by industry, health insurance companies, public policy makers and consumers.

Està clar que només ens parla de la seqüenciació completa i la predisposició a 24 malalties. No es refereix a les proves dirigides a simptomes i malalties en concret. El tema és prou conegut, i n'he parlat en aquest blog. Encara no sé com pot ser notícia si no fos perquè això pot fer variar la valoració d'Illumina, que aquests dies vol ser comprada per 6.700 milions de dòlars i d'aquesta manera evitaria desembutxacar-se més doblers. Alguns inversors segurament pensen que aquesta tecnologia de seqüenciació completa del genoma individual l'encolomaran com predictiva malgrat no ho sigui i cal treure'n rendiment mentre el regulador segueixi de vacances. D'altres pensen que efectivament servirà per crear valor i millorar la salut.
De vegades penso que la dificultat resideix en el pànic que produeix un full en blanc a qui ha de posar-se a escriure. Aquest fet porta un dia a publicar una cosa i l'altre la contrària. Només el lector avesat en aquests afers sap comprendre quan l'estan engatussant. Ara bé, avui al WSJ han fet una cosa poc habitual que s'agraeix, mostren el finançament i conflictes d'interès dels autors de l'article a Science i diuen:

The new study was funded by the National Institutes of Health and a number of independent groups. Dr. Vogelstein and two co-authors are founders of Inostics and Personal Genome Diagnostics and own stock in the two gene-analysis companies.

Atès que la conclusió de l'article podria afectar negativament als drets residuals de propietat dels autors, ens trobem davant un cas singular de revelació de resultats negatius de recerca, fet altament inusual quan hi ha interessos pel mig.

Defenseu-nos dels geneto-entusiastes

Aquesta qüestió està agafant un camí perillós que ens porta de cap al penya-segat. Em refereixo a la medicina predictiva. El diari LV, -sempre el mateix i no troba per ara tema més suggerent- mostra cofoi que neix el primer nen sense un gen que el predisposava al càncer de mama BRCA1. No discutiré la ciència que hi ha al darrera i tampoc el negoci. Evitaré tot comentari ja fet anteriorment sobre genètica i medicina, i l'oblit de l'epigenètica i demés. Evitaré tota reflexió bioètica. Em centraré només en una reflexió tant senzilla com: els pares saben segur que si la prova dona positiva, pot ser que no tingui capacitat predictiva?.
Miro l'acreditada referència labtestonline i diu això:

The degree of risk conferred with a positive result is difficult to quantify for a specific person. Results must be interpreted in conjunction with the tested person's personal and family history. A genetic counselor/trained health care professional should explain the meaning of the results, explain treatment options for the individual that are intended to decrease risk, and testing options for other family members.
A negative result does not mean that a woman will not develop breast or ovarian cancer. It simply indicates that the person tested is not at increased risk for developing hereditary breast cancer or ovarian cancer related to the BRCA mutations for which he/she was tested. It is important to remember that 90-95% of breast cancers are not associated with a BRCA mutation. Furthermore, in the general population, the lifetime risk of developing breast cancer is approximately 12% and the lifetime risk of developing ovarian cancer is about 1.4%. The risks increase with age.
The presence of a BRCA-1 or BRCA-2 mutation means that the person tested is at an increased risk for breast and/or ovarian cancer, but it does not mean that she will ever have them. Even within a family with the same BRCA mutation, not everyone will develop cancer and those that do may develop it at different times during their life.

M'estalvio d'explicar la sensibilitat i especificitat perquè el que diu al prospecte no hi ha referència a cap estudi independent. Els criteris GRIPS sobre predicció de risc genètic tampoc no els trobareu enlloc. També m'estalvio d'explicar quin laboratori està qüestionat als tribunals per la patent sobre aquesta prova perquè ja ho vaig explicar fa dies. Tampoc vull insistir que hi ha competència ferotge en la qüestió. No vull saber el que ens ha costat als catalans. I m'estalvio d'indicar que la publicitat que els estan fent els surt gratuita, perquè és evident i és a la llum de tots nosaltres.

Voldria finalment recordar una vegada més la necessitat d'avaluar l'efectivitat de la prova i el que se'n derivi, no fos cas que s'hagi introduit a la cartera pública sense que algú se n'hagi oblidat de fer-ho. I malauradament sabem que ha estat així i s'ha pagat amb diners de tots, perquè ja s'han encarregat d'explicar-ho al diari i així l'oferta pot crear demanda. En resum, el regulador ha mirat cap a una altra banda i s'ha oblidat de defensar-nos. Una volta i una altra, i fins quan?

PD. I encara més aquí LV i aquí  EP. I aquí m'aturo.

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"

DTC

Direct-to-Consumer Genetic Testing: Summary of a Workshop
Aquestes tres sigles potser d'entrada no us diuen res, però al darrera hi ha una polèmica considerable. "Direct to Consumer" es refereix sobretot en aquest moment a les proves genètiques. Els llibres de IOM-NAP ajuden a comprendre la realitat de la medicina i un de darrer va sobre proves genètiques.
El repàs als temes clau que deixa oberts és gran. Em centro en un que està sorgint aquí aprop com un bolet: el consell genètic. I què és això?

The process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.” Counselors interpret family and medical histories; educate clients about inheritance, testing, management, prevention, resources and research; and counsel them to promote informed choices and adaptation to the risk or condition.

I sobre DTC assenyala:

Some DTC genetic testing companies offer genetic counseling—via telephone or the Internet, or sometimes in person—as part of their testing services. Some have counselors on staff, and others contract with specific counselors and refer clients to them. And at least one charges its customers for the service—$250 per hour.20 Several DTC testing companies currently offer genetic counseling services to their customers at no additional charge, so there is no cost barrier. It appears, however, that clients often are not aware that these services are available—or even what genetic counseling is—and thus do not always benefit from
them

Una mica d'ordre a les idees convé quan s'està en un moment emergent. Si qui ven la prova fa el consell genètic, ja tenim la demanda induïda. Si creem unitats de consell genètic, l'oferta crea demanda. Ara i aquí, és l'hora de la planificació, o potser hem fet tard?

MCarthysme Genètic

Surreptitious Genetic Testing: WikiLeaks Highlights Gap in Genetic Privacy Law
Les proves genètiques encobertes poden convertir-se en un nou maldecap per alguns. Si hem de fer cas al que diu Wikileaksi el Guardian, el Departament d'Estat nordamericà mitjançant les representacións diplomàtiques hauria demanat informació biomètrica detallada (ADN, empremtes dactilars, iris) de responsables de les Nacions Unides i OMS, Ban ki-Moon i Margaret Chan inclosos. Aquesta petició d'informació a diplomàtics també va arribar alamenys a 33 embaixades.
I la qüestió és què n'han de fer amb aquestes dades? Els de Genomic Law Report especulen sobre el tema i adverteixen en general dels perills de les proves genètiques encobertes. La conclusió és que més enllà d'aquest fet, cal regular millor l'obtenció de proves genètiques. Alerta!

La petja que traginem

A Survey of UK Public Interest in Internet-Based Personal Genome Testing 

The Behavioral Response to Personalized Genetic Information:Will Genetic Risk Profiles Motivate Individuals and Families to Choose More Healthful Behaviors?

L'interès per la informació genòmica creix, però ja va sent hora de preguntar-se si serveix. Dues publicacions han analitzat quina és l'actitud envers aquestes proves i si això els faria canviar el seus hàbits de salut. Al Plos One trobareu l'article. Un resum en un paràgraf:

One in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely.

I a l'Annual Review of Public Health, un altre:

To conclude, personalized genetic information has its greatest impact on behavior when disease risks are appreciable. Genetic information based on single-gene variants with low risk  probabilities has little impact—either positive or negative—on emotions, cognitions, or behavior. The difficulty of health behavior change, the rapid pace of technology in the areas of genetics (68), environmental assessment (20), and communication modalities (65) suggest the need to accelerate research in evaluating whether new understandings of genetic risk can favorably influence health behavior,

 Ja cal que augmentem l'esforç per a comprendre com l'allau de noves tecnologies tindran un impacte en la salut. L'impacte en el cost ja podem anar descomptant-lo (si és que el podem pagar algun dia).