Genetic testing: a knotty problem

Food and Drug Administration. Optimizing FDA's regulatory oversight of next generation sequencing diagnostic tests — preliminary discussion paper

Cutting the Gordian Helix — Regulating Genomic Testing in the Era of Precision Medicine

"Scientific progress alone won't guarantee that the public reaps the full benefits of precision medicine, an achievement that will also require advancing the nation's regulatory frameworks"

This strong statement reflects a wider concern on the implementation of precision medicine or stratified medicine. I have commented before on this issue, the NEJM article of this week clarifies the last attempt by FDA to shed some light and a specific approach to disentangle the current challenges. FDA has submitted a document for comments just to start a new era of regulation in health, a "collaborative framework" for creating reliable databases of genes and genetic variants underlying disease, and provide a "safe harbor" for the interpretation of genomic tests.
This is exactly the right direction. As long as, information is a public good, genetic testing -clinical validity and utility- should be provided only by the regulator.  Professionals and citizens need to trust in precision medicine and avoid snake-oil sellers.
Having said that, today I'm more concerned than yesterday on how our government is delaying to start such effort. Today is one more day lost.

Dufy at Thyssen Museum right now

PS. Somebody should think twice about the style of health policy debates in public TV.

In favour of consumer protection

Can Consumers Make Affordable Care Affordable? The Value of Choice Architecture

Healthcare.gov 3.0 — Behavioral Economics and Insurance Exchanges

Recently Google has entered in the insurance comparisons market. Right now is available for car insurance and health insurance could be the next step. This business model changes the search costs and has strong impact over current sales channels. Understanding the salient features of health coverage for any citizen, should require that government regulates the right conditions for consumer protection. If insurancee companies pay the comparison site, as google says, is there any change on how information is shown according to the amount paid?. Have a look at the Peter Ubel et al. article at NEJM or at the PLOS one, and you'll be convinced that the potential for manipulation is huge.
Therefore, if this is so, there is a role for protecting consumers against well designed biases in comparison sites.

Practice makes perfect

Comparing hospital performance within and across countries: an illustrative study of coronary artery bypass graft surgery in England and Spain

My concern over variations in clinical practice relies on a specific issue. Once you've describe it, you need to understand its implications. Thus, somebody should assess whether variations cause poor health outcomes. Before starting such a task, somebody has to measure relative performance, and this is precisely what a recent article in EJPH does on CABG surgery in England and Spain. I would like to highlight this statement:

In this article, we use patient-level data within and between two countries to assess the added value of pooling administrative data across countries and to explore hypotheses that may explain differences such as those reported in cardiac care. These may be driven by a small number of hospitals with unacceptably high mortality rates (perhaps due to coding differences or under-performance). Otherwise, country differences in outcomes may be explained by the concentration of services into specialist centres with differences in clinical facilities and staff experience, as reflected by hospital volume of surgery. These hypotheses cannot be tested adequately using within-country data or national aggregates, but lessons may potentially be learned from hospital-level comparisons across countries using comprehensive administrative data.

If we focus on performance, national aggregates confound. And this is focus of the article:

Unadjusted mortality rate following CABG surgery demonstrates a considerable difference between hospitals (particularly in Spain) and between countries (average mortality is 2.3% in England, 5.0% in Spain)

After adjusnting and pooling data from both countries, then results look different:

First, the hospitals’ performance contrasts substantially with the traditional within-country findings. Nine Spanish hospitals are identified as ‘alarms’ in the pooled assessment compared with five in the country-specific assessment. Thirteen Spanish hospitals are additionally identified as ‘alerts’ that were within the normal range when considering Spain alone. Four English hospitals are now identified as alerts and none is assigned alarm status. Second, there is a clear separation in the number of expected deaths between English and Spanish hospitals, reflecting differences in volume across countries. The median hospital surgical volume in Spain is 154 patients a year, compared with 690 in England, and the highest volume hospital in Spain treated 337 patients in 1 year, whereas the lowest volume hospital in England treated 327. Third, despite the large overall between-country difference, the vast majority of hospitals in England and around a third of those in Spain lie within or below the 95% funnel and are largely comparable in terms of their SMR.

This is an excellent explanation of "practice makes perfect" argument. And, if this were the only factor, there is a compelling reason to concentrate CABG surgery in certain hospitals and close services in others. We know that some concrete hospitals may have high adjusted mortality rates and deserve a concrete action. Urgent decision is needed, just to reduce mortality ratio by half.

PS. The whole issue on variations in EJPH represents a milestone in health services research. Congratulations to the authors and the ECHO project.

PS. GCS blog on the same topic.

PS. New book available: The Triple Aim for the future of health care by Núria Mas and Wendy Wisbaum

An illusionary free lunch

Some months ago I started a series of posts under the title "Fasten seat belts". The topic is well known, how new skyrocketing drug prices are distorting budgets and access. Yesterday we got the final resolution. Fasten you seat belt, this is the moment of truth: The government has decided that hepatitis C patients under specific conditions will get treatment. And once he has decided coverage, he concludes that he will not pay the bill. Somebody else will have to do it, autonomous communities governments. Free lunchs exists in Sepharad!
This is a complete mess and it is only the begining, new drugs are knocking at the door. For catalans, this foreign decision represents 470 m €, an additional deficit for the 2015 budget of 5.7%!!! (if all expenditure were charged in one year). Does this make any sense?. Of course Basque country is not included in such arrangements...
There is an objective need to disconnect, the time is getting closer. Things couldn't have been done worse.

Beyond the genome

FORUM Epigenomics. Roadmap for regulation. Diseases mapped

My suggestion for today. Have a look at the papers in Nature on epigenome, and at the following figure:

The Roadmap Epigenomics Project has produced reference epigenomes that provide information on key functional elements controlling gene expression in 127 human tissues and cell types, and encompassing embryonic and adult tissues, from healthy individuals and those with disease. a, Many of the adult tissues investigated were broken down by cell type or region — blood into several types of immune cell, for instance, and the brain into regions including the hippocampus and dorsolateral prefrontal cortex. Tissue samples and cells were subjected to a range of epigenomic analyses, along with genome sequencing and genome-wide association studies (GWAS). b, Embryonic stem (ES) cells, which are taken from the embryo at the 'blastocyst' stage and can give rise to almost every cell type in the body, were used to analyse, for example, the differentiation of stem cells into different neuronal lineages. The ES-cell-derived cell lines underwent the same epigenomic analyses as the tissue samples.

The key article, here.Tissues and cell types profiled:

For decades, biomedical science has focused on ways of identifying the genes that contribute to a particular trait, or phenotype. Approaches such as genome-wide association studies (GWAS) identify locations in thhuman genome at which variations in DNA sequence are linked to specific phenotypes, but if the variant is located in a region of DNA that does not encode a protein, such studies rarely provide insights into the regulatory mechanisms underlying the association. In these cases, comprehensive epigenomic analyses can provide the missing link between genomic variation and cellular phenotype.

If this is so, why are governments reluctant to introduce a ban on genetic tests with spurious associations between genome and diseases?




PS. Manel Esteller in DM.

A closely guarded secret

Stealth Research. Is Biomedical Innovation Happening Outside the Peer-Reviewed Literature?

How can we identify a snake-oil seller?. Not so easy. Have a look  at JAMA, John Ioannidis article shows his concerns about Theranos, a company that is providing lab services with a new propietary technology that has no peer-review article in any scientific publication. Nobody can check tests sensibility and specifity, no external quality controls, and so on.
If this is the path for the future of health care provision, then I am really concerned because it will be a complete disaster. No consumer protection, no regulation, uncertain science and more uncertain outcomes. After all this years, is this what citizens deserve?.
Such style of "laissez-faire, laissez-passer" medicine could represent huge profits for some and a big loss for everyone.
Otherwise some alternative should be proposed to boost publication and transparency. The author's suggestion is the following one:

To solve this conundrum, it may be necessary to find ways to realign the reward system for innovation. One possibility is to make the scientific literature more receptive to innovators. This could include models in which reports of disruptive discoveries that are in dissonance with the mainstream can still be communicated as preprints without prior peer review, perhaps in the same way as the successful example of arXiv in the physical sciences, which has now reached 1 million e-print articles. That there has been no peer review of these initial reports should be transparent to researchers and the public.

Thus, some better regulatory process is needed so that innovative ideas for financially successful applications can be scrutinized by the wider scientific community as to their validity. A company should not be forced to disclose its science secrets in detail, especially while its efforts are still exploratory rial-and error and while creating basic elements for its products and services. However, if a product or service reaches the point at which it generates substantial revenue, the science behind it should then be communicated in detail to ensure adequate review.

Opening the door to recreational genetics testing

On February 19th, the US Food and Drug Administration (FDA) authorized 23andMe to market a direct-to-consumer (DTC) carrier test for Bloom syndrome. Such test was classified as a medical device, and exempting it from premarket review. This may pave the way for DTC genetic testing in the US market.
The decision to open door for one test may represent the biggest move towards a recreational genetic testing market. You know that from this blog I have backed a ban on developing such markets and the need for an effective regulatory review different from the flawed medical device system.
The european regulator is still on holiday, I said that some months ago and it is still "out".

PS. Variations in health care in GCS Blog.