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.

Lakoff brilliant analysis

Handbook of Neurosociology

Today I would like to quote a clever analysis of US health reform. Just as an alert for any other country that wants to start a similar process.

Solving a Social Science Puzzle

In 2009, when President Barack Obama chose the policy provisions for his health care plan, polls showed that most provisions (e.g., no preconditions, choice of plans) were supported by 60–80% of Americans. Yet, when the whole plan was polled, fewer than 50% supported it. Why? Why the disparity between the parts and the whole, when the whole literally equals the sum of the parts?
The answer is straightforward from the perspective of real reason. When President Obama came out with the provisions of his health care plan in early 2009, the conservatives decided to attack it not on policy grounds but on moral grounds. They chose two areas of morality: Freedom (“government takeover”) and Life (“death panels”). And they repeated over and over that “Obamacare" (naming matters) was a government takeover that was a threat to individual freedom, with death panels that were a threat to life itself.
Note that the policy provisions were about the everyday details of dealing with one’s HMO. They were in the Practical Health Care Details frame. The conservative attack was in the Morality frame, activating freedom and life. The conservatives understood that all politics is moral, that political lead- ers all say they are doing what is right, not what is wrong.
The policy details and the moral attack were in different frames, located in different parts of the brain. From the perspective of real reason, the whole health care act was, for those with a conservative worldview, not equal to the sum of its policy parts. Conservatives and independents (actually biconceptuals, who are progressive in some respects and conservative in others) had their conservative moral worldview activated by the conservative moral attack. This separated the moral whole from the practical parts.
For progressives, their morality and the practical details fit together; for conservatives and biconceptuals (aka “independents”), they were different subject matters.
Such an explanation is natural when you think in terms of the brain and frame-circuitry. It is not possible when you think in terms of the logic of Enlightenment reason, where the whole is necessarily (logically) the sum of the policy parts

PS. You may find former posts about George Lakoff's work on cognitive science, here and there.
PS. This is the coda of the first chapter of the book. The whole chapter is a must read for those interested in "brain circuitry", language, metaphors and politics.

Thresholds' controversies

Guidance on priority setting in health care (GPS-Health): the inclusion of equity criteria not captured by cost-effectiveness analysis

The threshold for cost-effectiveness is under controversy again. This is not new. FT explains a new York University paper that has created great concern. Is it NICE cost-effectiveness way of implementation really "cost-effective"?. From their point of view, thresholds are higher than they should be to guarantee access.
Thresholds are only one side of the coin. The other one is the introduction of equity criteria in cost-effectiveness analysis. Three years ago, I explained this topic in a post commenting on Tony Culyer''s article. He says that there are two "dragons" in dealing with cost-effective analysis: equity and our ignorance about how to introduce it. I then quoted this statement:

‘Arguably the biggest threat to our public health care system is not our ability to pay for the increasing cost of care, but rather a loss of public confidence.’’

An older post on Eddy's work explains similar concerns over thresholds and equity. We have to convene that there is not only one method to do it. However, some well known academics have published an interesting proposal: criteria for access to be considered jointly with cost-effectiveness.

The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others).

Basically, these criteria are well known. The difficulty of its measurement has yet to be overcome.

PS. My former post on the same topic and authors in York. 

Medicine as a data science

THE PATIENT WILL SEE YOU NOW
The Future of Medicine Is in Your Hands

Maybe the title is the most confounding factor of the new great book written by Eric Topol.  Once you have finished reading it, you'll be convinced that he set the expectations to high, ordinary people should develop certain skills beyond their capabilities to apply such concept. I would say that a greater part of the medicine is in your hands, not medicine at all. The rationale behind the book is that medicine digitization allows patients to know more about their disease and how to "manage" it in certain cases. The most important thesis is that future medicine has to be considered a data science. And this is exactly the impact of the digitization of diagnostic and treatment: pervasive application of Bayes theorem in clinical practice, using big data and analytics.(Remember my archimedes posts, surprisingly Topol forgot it).
The book includes many topics that those that follow this blog it would sound familiar, i.e. ch. 4 about Angelina Jolie and BRCA genetic tests, a must read. And chapter 5 is a journey on the new omics of the medicine, a topic that I have also covered in the blog.
Nowadays, Eric Topol is the writer that is able to capture what's going on in medicine and its impact on society. That's why this book is a key reference of our time and I strongly recommend it.

PS. If you don't believe me, check Forbes, NYT, WP, WSJ.
PS. The book is also an invitation to change the current academic programmes for life sciences universities. Better now than later.

Less volume, more value

From 2009 to 2013, the number of primary care visits has fallen by 12.5%, from 51.1 million to 44.7 million, 6.4 million visits less. This is a lot!.
Sometime ago I posted on the same topic. The number of professionals has shrunk slightly, 2.5%. The result is that there is more time for the same patients because the population is closely the same. Therefore, we have to confirm that the impact of electronic prescription and other organizational strategies have a larger effect than anybody could guess, compared to the copayment mantra. However, a deeper analysis of the causal factors and its relationship with health outcomes is needed. We know that there is less volume and we have some clues about more value, though not enough for a sound conclusion.

Health policy extremism and radicalisation

Going to Extremes: How Like Minds Unite and Divide

After reading this accurate article by Guillem López-Casasnovas, I thought that it was worth to quote Sunstein book. His key messages are:

• When groups polarize and separate from mainstream society – either psychologically or physically – they can become extremist.
• People change their attitudes when they want a group to accept them.
• People will abdicate moral decisions to a recognized authority.
• Collective behavior, or “groupthink,” provides a means of identifying decision-making processes that lead to extremism and mistakes.
• Information moves and amplifies among groups via “social cascades.”
• Investment clubs making decisions by unanimous votes produce the worst investment returns.
• Group deliberation produces sounder decisions than individuals acting alone.
• Techniques to blunt extremism include traditionalism, consequentialism, and checks and balances.
• Informational cascades can affect markets and mass behavior.
• In a democracy, information, criticism and skepticism combine to improve an institution’s performance.

Take care, we are right now on a social and informational cascade. Have you noticed?

A bit worse before it gets better

Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease

A new mental frame was created some weeks ago when President Obama gave a speach on the creation of the initiative on Precision Medicine. To be honest, the term was in the title of a 2011 report by IOM.
In my opinion, it is a bundle: stratified medicine+big data+regulatory science+... This is the bundle of the new buzzword, and unless new details arise, nothing specially new.
Now the New Yorker speaks abouts the problems of precision medicine, and focuses on the risks. The final paragraph illustrates the issue:

For Solomon, genetics is simply a new tool with a learning curve, the same as any other. “When the electrocardiogram was first developed, about a hundred years ago, most physicians thought it was voodoo,” Solomon said. “Now, if you don’t understand it, then you shouldn’t be practicing medicine.” But Mary Norton sees that analogy as too simplistic. The pace of genetics research, the variability of test methods and results, and the aura of infallibility with which the tests are marketed, she told me, make this advance a more complicated one than the EKG. Norton believes that, as genetics becomes increasingly integrated into medical care, “over time everyone will come to have a better understanding of genetics.” But, as the demand for DNA testing increases, she says, “it will probably be a bit worse before it gets better.”

Could we avoid the initial bit worse of  "imprecision of stratified medicine"? . I'm full convinced that appropriate regulatory efforts could mitigate such impact. Unfortunately, governments are on vacation.

Dancing to public accountants' tune

I would have never imagined that the health policy could have been distorted and dictated to by public accountants. Yes, you have heard correctly. European Union and its statistical arm, Eurostat, has decided what is a public firm. And the decision is so anomalous that it deserves a short comment.
We all know and agree that public accountants need to define with accuracy the size of government deficit. They consider what is public administration according to several criteria (p.25), this is their responsibility. However, the collateral damage of doing it in a weird manner, puts a severe strain on the health system as we know it today.
Management autonomy has been introduced in the last decades within the publicly financed system under a myriad of different organizations. Today, the application of ESA 2010 -the accounting rules in place since last September 1st- represents that all of them have to follow the same path and autonomy will be jeopardized. We will be dancing to public acountants' tune.
Management autonomy helps to boost efficiency, even in public systems where incentives are low-powered. Hence, when somebody complains in the near future about inefficiency, we'll have to remember that european public accountants and its politicians have contributed to worsen health systems. Thank you so much, accountants.

PS. Please save this post for the future. It will have strong implications.

PS. This is the end.