The FDA's new 'ban' on antibiotic use in animals needs more teeth

The CDC estimates that 2 million people in the US every year contract antibiotic resistant infections, and 23,000 die as a result.  Antibiotic resistant bacteria -- another on the list of looming crises we're smart enough to do something about but are doing far too little far too slowly.  So it would be good if, as reported by New York Times, the US Food and Drug Administration had announced what will be a major policy to slow down the routine overuse of antibiotics in the food supply.  But it seems unlikely.

For decades, healthy cows, pigs and chickens have been given antibiotics to maintain their health and to boost their growth, and more recently, so have farmed fish, but this is a major cause of the waning effectiveness of antibiotics. There seem to be multiple pathways leading from antibiotic use in animals to antibiotic resistance in humans.*  

Chicken house; Wikimedia Commons

 Low dose, prolonged use of antibiotics in animals creates ideal conditions for the selection and growth of antibiotic resistance.  How they spread from animals to humans is difficult to document and probably there are numerous pathways, but it does seem sometimes be possible by consumption of food carrying resistant bacteria, and indeed farm workers often harbor antibiotic resistant strains of gut bacteria that indicate they originated in animals on the farm, but so can people who eat meat or fish contaminated with resistant bacteria.  There is evidence of horizontal transfer of resistance genes, too, from bacteria most often found in animals to those that prefer human hosts.

The 'ban'
Now the FDA says it is effectively banning the use in food animals of those antibiotics that are medically important in human health, and that are used solely to enhance animal growth. A second piece of the new regulations is that a licensed veterinarian will be required to oversee antibiotic use if the grower wants to deliver these drugs to prevent illness.  The changes will become effective over the next three years.

How will it work?  The FDA is requesting that drug makers change antibiotic labels to exclude their use in animal growth promotion.  Whether they do this or not is entirely voluntary.  Given the huge vested interest drug manufacturers have in selling antibiotics to food producers -- 70-80% of antibiotics in the US are used in the food supply** -- and that farmers have in promoting fast growth in their animals, whether this will actually work is an open question, and there are many doubters. Though, the two pharmaceuticals that make the majority of antibiotics have said they will comply.

Comply or not, there are loopholes.  A food producer can claim that the same daily use of low doses of antibiotics now meant to enhance growth is required to prevent illness, which would mean it's allowed.  Thus, it's possible that nothing will change.  Many critics would much prefer that antibiotics be allowed only to treat infection, and would like to see the FDA ban the preventive use of antibiotics. 

Why we need a policy that works
It is important that we have a policy that works.  Maryn McKenna describes the dire consequences of losing antibiotics in her sobering, excellent recent piece for Wired, ("When We Lose Antibiotics, Here's Everything Else We'll Lose Too").  Not only will we lose the obvious, the ability to treat infection, but also, as she writes, we'll lose the ability to treat cancer when it requires suppressing the immune response, to do organ transplants, kidney dialysis because it relies on an implanted portal into the blood stream, many kinds of surgery, Caesarian sections will be risky, and much more.  As she points out, in the pre-antibiotic era, "one out of every nine skin infections killed" -- life will be a lot more dangerous again. 

And, clearly, the way animals are raised for food on industrial farms will also have to change.  But there are many arguments in favor of this already, even apart from the antibiotic resistance issue.  Animals raised in the kinds of crowded conditions pig or cattle or chickens are too often raised in increases their risk of illness.  And, these animals are often raised on feed that that also makes them more susceptible; smaller farms, and more humane conditions would greatly reduce the need for antibiotics.  And, as McKenna also points out, many crops depend on antibiotics as well.  When fruit or vegetable diseases now controlled with antibiotics can no longer be, that will be another major problem.

So, the FDA may be taking a desirable first step, but the stakes in public health terms are very high.  If the critics turn out to be right about the loopholes, there's a lot to lose. 

-----

*Smith, DL et al., Animal antibiotic use has an early but important impact on the emergence of antibiotic resistance in human commensal bacteria, PNAS, 2001. 

Marshall, BM; Levy, SB., Food Animals and Antimicrobials: Impacts on Human Health, Clinical Microbiology Reviews, 2011. 

**Mellon M, Benbrook C, Benbrook K L. Hogging It: Estimates of Antimicrobial Abuse in Livestock. Cambridge, MA: Union of Concerned Scientists; 2001. 

National Research Council, Committee on Drug Use in Food Animals. The Use of Drugs in Food Animals: Benefits and Risks. Washington, DC: Natl. Acad. Press; 1999.

Viagrette: Half a screw per month. . . . or are you being screwed?

Finally, after literally decades of Viagra envy, and by popular demand, no doubt fueled by the manufacturer, Sprout Pharmaceuticals, it looks like the Women's Viagra (chemical is fibanserin) will soon be available at a drugstore (or online scammer) near you.   Here's one version of the story, from the BBC.  You should apparently overlook that it only gives an average half turn of the screw per month and has negative side effects that might be dangerous.  It looks as though the biggest danger, that Sprout won't garner its financial bonanza, has fortunately be averted by our dispassionate FDA. We suggest that Sprout call it Viagrette, and their slogan should be "The best is yet to come!".

In the pink.  From the BBC story

One doesn't want to minimize the issue of female loss of fun, sexual desire or responsiveness. But the facts that it hardly works and has potentially serious negative downsides even in the limited trials that have been done, clearly were undermined by both political and economic pressures.  This may be a feminist issue, of Viagra Dreams, and if its promise is not a fantasy at least one women's coalition group, Even the Score, that feels that women's sexual dysfunction issues have been given short shrift by the FDA, has been pressing for its approval. But that doesn't make this the right test case, the proper thing to approve to address prior discrimination.  Instead, there is more than a little taint of this mainly being about opportunistic social politics, and one can't be blamed for thinking is suggests the FDA, rather than a watch-dog in the public interest, is the lap-dog of the corporate world.


If there could be a genuine, properly targeted female equivalent to Viagra, that would be a good thing.  Nobody but some very dated, prudish, or sexist religious groups would object.  Research on developing such an agent that actually worked and was safe could be useful, even if it would be a huge profit maker for the company that develops it. One might argue that research devoted to the pharmaceutical bottom line, and thus skewed toward frivolous drugs (such as the drug the FDA just approved to treat double chins), is research misplaced, given the real life-devastating diseases that people face.  But these are businesses, after all, and their business is making money.

Half a thrill is....ill
We don't want to denigrate anything that can make life more meaningful or pleasurable for anyone, and coupling can certainly be among the most important aspects of a satisfying life.  It's fine for women as well as men to be Sprouting with desire.  Risk-benefit calculations are typically very difficult and inaccurate, but it's also true that half of 'thrill' is 'ill', and in this case the side effects could be serious, and the benefit itself is subjective--self-reporting of amelioration of excitile, rather than objectively erectile, dysfunction as far as we understand.  But selling this pill on the promise that it can in fact improve a woman's libido seems to be highly irresponsible, because countless women will invest countless dollars, often swayed by what clearly will be a tsunami of enticement advertising, for hardly any, if any, benefit.  And this for risks that are probably being underestimated, since among the usual temptation to interpret trial results through rose-colored glasses, once a drug is on the market, being taken by many more people than it was tested on, the list of side effects inevitably grows, not shrinks.  Because of the likelihood of its plans for heavily self-serving promotion, Sprout Pharmaceuticals, ever-so-public spirited, said they wouldn't advertise it for...a whole year!  Is this being too cynical?

It is possible, if going pink doesn't work or if its negative side effects are better documented, that word of mouth will overpower slick advertising, and the wonder drug will wilt into failure.  But given how our culture works, it seems far more likely that the natural as well as engineered demand, with the many groups who stand to gain, including Sprout but also various types of therapists who can now diagnose some new 'conditions', for which there is a 'treatment', will bloat this new semi-drug into another commercial Viagra. And if it's considered medicine it will be built into health-care costs. Or, should we ask if for half a screw a month, Sprout is screwing a gullible public? Is this too cynical?

Pharma has been dreaming for many years not of the proverbial sugar-plums dancing over their heads, but of new blockbuster drugs, ever since statins and Viagra and other lifetime meds were marketed (and as patents expire).  They're determined BiDil and By Golly to play whatever shenanigans will prevent the juicy bits from slipping through their fingers.  The two most obvious apples of their desires, since Viagra's miracles were discovered (inadvertently, as we recall), have been a female Viagra and a treatment for male pattern baldness. The latter still evades success, but you can be sure that pockets will be picked by 'the little pink pill'. Lifetime meds are what make sense, that is, are good for business. Will the costs then further burden any semblance of a national health-care program this country might have?  Is this being too cynical?

Satisfying whose desires?
Anyway, for a while at least, it's gonna be cash-in time.  This has currently been intended as a premenopausal remedy,  but it doesn't take much imagination to wonder whether various reasons will be found to extend the usage to older women, too.  Why not?  One can anticipate be that vested interests will make enough effort that at least some later-age effect will be found, or even that prescriptions in practice will be made to last a lifetime. Is this too cynical?

We can have a bit of fun imagining the senior romps that will be enabled (something one might see on the TV series Derek).  If that is what happens it may give retirement centers a bit of a burden, as they'll probably have to have late-hour EMTs on hand for those who experience side effects, direct or indirect, of this new medication.

Is this being too cynical?  Time will tell.

Real Truth in Labeling for the new statin replacement

The FDA is about to or just has approve a new cholesterol-fighting drug to supplement or replace statins.  But is it taking all the 'side effects' into account?  Should it?  The new substances (several pharmaceutical outfits apparently have them near to market) inhibit a different genetic pathway from what statins do and can be used to treat high cholesterol in those who can't handle statins, or for whom statins aren't lowering their LDL cholesterol, and may also actually be much more effective even for the current millions who take statins.

These drugs inhibit the action of a gene called PCSK9 and interfere with the liver's detection and response to LDL levels in the body; see the NYT story here from last week for more details about the drugs.  The excited news reports, at least, describe what are truly remarkable reductions in LDL levels without untoward side effects. If these facts stand up to larger or longer term trials and experience, it will be a major pharmaceutical success....in more ways than one.

One immediate issue is the 'usage creep' that almost inevitably seems to follow the appearance of a new drug, and in this case one with fewer side effects and higher efficacy with regard to lowering the most dangerous type of circulating cholesterol (the 'bad', or LDL form). Recommended approval is for use in three groups of patients: those whose high LDL cholesterol can't be lowered sufficiently with statins, those at particularly high risk because of previous heart attack or diabetes and high LDL, and those with high levels of LDL who can't tolerate statins.

But if these agents are as effective as reports suggest, and with less or even no serious side effects, then even if they are initially approved or recommended for just these specific groups, usage will surely expand as the definition of who is 'at risk' expands. Perhaps people whose cholesterol is responding to statins but who don't like the side effects, or someone whose close relative has had heart disease but whose current LDL levels are not high will ask for this treatment as a preventive, or doctors will think 'off label' usage is absolutely proper, assuming no serious side effects. Hell, if the makers are extremely lucky, maybe it will turn out it even treats erectile dysfunction or male-pattern baldness! And then, what about extending to, say, younger ages or even simply to everyone, like putting vitamins in milk or iodine in salt?  This is what we mean by usage creep.

One might reasonably say that this is just what should be done.  Precedent might suggest that eventually we'll find that the agents are less effective than current tests suggest or have some serious long-term but as yet undiscovered downsides.  However, things that can't be known until the drug is used by millions of people for numbers of years.  Making decisions about usage is harder than one might think.

One reason for concern about usage creep is already being mentioned in the blaring news stories about the apparently genuinely major advantages of these compounds.  That is, the obvious issue of the financial mega-bonanza to be reaped by the pharmaceutical firms.  These drugs are going to be very expensive.  The money to be made is certain to encourage usage creep.  Could we expect otherwise?

But worse than just profiteering is that, even with Obamacare available so that presumably even the poor could have access to these beneficial drugs, putting the whole population, so to speak, on these pills for their whole lives, could bankrupt the health-care funding system that is already a heavy burden on society.  It's being suggested that these new pharmaceuticals could simply by themselves eat up any reasonable premium level for health care plans.

But there is another issue, and that relates to truth in advertising and the issue of side effects--and here we don't refer to incomplete data that may be leading to premature approval or anything like that.  Instead, it's more of a philosophical issue:  What does a list of side effects mean, in this case, and what would the whole truth actually be? What should the manufacturer or the FDA tell you so you would be truly better informed when you take the new drugs for the rest of your life, as so many are likely to do, across the developed world?

From the Sanofi website; Sanofi is one of the makers of these statin replacements

What the FDA and medical community doesn't list on the label
The FDA requires that known side effects of drugs be clearly stated on packaging or labeling material, and surely physicians will know about them.  Isn't that right?  It should be, but there is a sleeping tiger here, that apparently nobody has thought about or, if they have, that they've buried so deep you never will realize it.  In fact, there will be huge unstated negative side effects of these new drugs.  Indeed, shouldn't a proper labeling for these new medications include something like the following?:

"WARNING: Use of this product will greatly increase your risk of Alzheimer's Disease and other dementias, arthritis and other muscle and joint diseases, some forms of cancer, diminished vision and hearing, other degenerative disorders, and accidental death."

Of course such truth in labeling won't happen, and the reasons are subtle and if taken seriously would lead us, as a society, to think more deeply about the role of medicine in health, and of the meaning of health, in a real world in which life is finite.  There is no one who can provide 'the' answers to the problems that are raised, and indeed each person would, in principle, provide his/her own answers.

But at least, there should be a societal discussion.  The reason has to do with the concept of 'causation' and the demographic realities in a world of competing causes.  If these drugs lower LDL cholesterol anywhere nearly as much as they seem on present evidence to do, and if the association between LDL cholesterol and heart disease is as linear as is hoped, then that by itself will eliminate or greatly forestall the occurrence of fatal heart disease in those who take them.  But then what?

If people live much longer as a result, they will inevitably get the sorts of diseases that could be included in an empirically correct labeling!  If you don't get heart disease, it is simply obvious that you will get something else, and it is likely to be slower and more progressive than the quick end to life that heart attacks can be.  Note that our warning list did not include some causes, like kidney failure, diabetes, and the like that could be stalled or avoided by lowering LDL cholesterol--so we are being quite conservative here.

The problem is that of what are known as competing causes, and we've written about it before.  It is inevitable that you will die of something.  If not heart disease, something else.  One might say, well, OK, but at least I'll have more years of life before that something-else gets me. This is likely to be true to some extent, but there are two cautions.

First, people with heart disease often have other health issues because by and large heart diseases gets people at older age, and they are more likely to have less healthy lifestyles.  That includes more risky conditions than high cholesterol.  So, these other causes may be lurking just around the corner, so the removal of heart disease may mean that the gain in years might not be very much!

Secondly, other disorders that those saved from heart attacks will eventually get, if they don't have them already, are ones with gradual onset: you become more and more affected over time.  Mental deficiencies, joint and mobility problems, vision and hearing, are clear examples.  And the nature of accelerating risk is that if you slow it down you defer the onset of serious-level symptoms but you also stretch out the decay process at the end: you have more years with more and more serious symptoms before your body finally conks out.

What is 'cause'?
Are we just playing word games here?  Is it accurate to suggest that the new drugs will 'cause' dementia?  Surely the chemical doesn't mess with neurons!  Let's assume that's true and that no such direct molecular effect is ever found. Then the effect of the medication is related to the occurrence of these other traits, but not in a directly causal way.

This raises questions about causation.  It is more than simply saying that correlation is not the same as causation, because while the active mechanisms responsible for, say, Alzheimer's or joint disease, are not affected by the LDL-reducing drugs, they open the way for the former to act because the person lives longer.  Correlations such as the brand of car you drive being associated with some forms of disease arise because both may be the result of income levels and associated dietary habits. The dietary habits, not the type of car, are causes of interest.

But in the case of competing causes of disease, reduction of one is a sort of mechanistic effect, not just a spurious cause.  If a mechanism is changed in a way that allows a different mechanism to proceed for longer times, this is part of the overall mechanism of the related traits.  The chronic late-onset diseases most of us in the rich world die of now are directly the result of so successfully controlling infectious diseases, our previous killers. One definition of cause is that if you remove it, the effect changes, in this case the protective effect, relative to cancer, of dying of a heart attack.

And what if widespread use of these new drugs puts serious pressure on the health care system, so that some treatments will have to be deferred or denied to more people than presently?  Is that so unlikely?  And is that then not a cause of deteriorating health?

And what if it worked miracles and the relative fraction of our population (and the world's population) of wearing-out old people substantially increased?  That puts all sorts of pressures and pinches on everyone else, indeed, even on the normal living needs of the increased elderly segment.

Causation is not so simple and straightforward a notion.

So, what is 'health care'?
The new LDL reducers raise many deep, and deeply important questions.  The point here is to be realistic about disease in our society and have an open consideration of how to deal with the kinds of game-changing environmental or behavioral aspects of our society, and their long shadow of implications.

In a very serious sense, even if indirectly, the new LDL-lowering agents might have disastrous effects for countless numbers of people.  It's a discussion we should be having.  The news media should be leading the way, to force that on the scientists and health system.

Indeed, these issues should force us to consider what, exactly, we even mean by 'medical care' and 'health care'.  How do they relate to each other, and to the idea of 'public health'?

We think these are real, complex, disturbing, serious truths that have no one answer, and that affect individuals as well as society.  This is not a matter of complaining about science, policy or even drug company profits.  It is about profound issues in human life, that should be discussed openly and fully, because they affect everyone's future.

Personalized medicine and Fragile X: complexity, disease and economics

Fragile X is a genetic disorder that typically causes distinct facial features as well as moderate to severe mental impairment and social withdrawal, and as such it is considered to be the most common single-gene cause of autism.  The disorder was determined some time ago to be  "caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain" (Lutz et al., 1998, cited in OMIM).  That this repeat expansion is causal, for whatever reason, it well established by a strong association between the genetic variant and the trait. As with nearly all genetic disorders, even when 'the' cause has been identified as a variant or variants in a single gene, the manifestation of this disorder is a spectrum of severity.

There is currently no drug treatment for the "core symptoms" of fragile X, though several drugs that treat various behavioral symptoms are available.  A recent story in the New York Times describes the experiences of several families with a drug that was developed to reduce social withdrawal in children with fragile X or autism, manufactured by Seaside Therapeutics, but was still undergoing clinical trial.  Why autism should have any physiological connection with fragile X is not known, but there is an overlap of symptoms.  The drug, arbaclofen, or STX209, affects neurotransmitter signaling and hence, brain function and its behavioral implications.

A Phase 2 clinical trial was carried out over three years ago, and the results announced in 2011.  Seaside said

...clinically meaningful improvements on global and specific neurobehavioral outcomes were observed in the general study population. The improvements were statistically significant in pediatric patients with more severe impairments in sociability -- a core symptom of fragile X syndrome.

Following the trial, Seaside Therapeutics continued to supply the drug to some children for whom the drug was considered to be beneficial.  According to the NYT, the drug made an enormous difference in the lives of a number of children.  Some were able to speak for the first time, others halted aggressive behaviors, and so forth.  This seemed at least statistically, as well as subjectively, to be a cause-effect relationship.  There were parents, of children with autism as well as fragile X, who considered arbaclofen a miracle drug.

In 2012 Seaside initiated a Phase 3 trial, to further test the drug.  In announcing this trial, the president of Seaside said,

“In our Phase 2 study, we were very excited to observe clinically meaningful improvements in social impairment in patients receiving STX209—marking the first time a drug candidate has positively impacted a core symptom of fragile X syndrome. The Phase 3 study is the most comprehensive study ever undertaken in patients with fragile X syndrome and represents the first time that a drug candidate will be evaluated for a core symptom of fragile X syndrome as the primary endpoint.”

But, production is now being halted because the drug has not proven to be a successful enough treatment for social withdrawal in children with autism in the Phase 3 study.  This seems to be a bureaucratic and financial issue rather than a scientific one.  According to a Seaside vice president, quoted on the "Age of Autism" website,

The FDA requires companies to pick one, and only one, assessment as the “primary endpoint” of the study. In their eyes, the result on that one pre-selected endpoint makes or breaks the study. In our recent autism study, STX209 did not show an advantage over placebo (see above) on the primary endpoint of social withdrawal, so the FDA and some news reporters regard it as a negative study. In fact, STX209 did show advantages over placebo on a number of other assessments. Some of these secondary endpoints are just as meaningful as the social withdrawal assessment, or even more so, but in the FDA’s eyes, they don’t make the study a positive study, because they were not pre-selected as the “primary endpoint.”

The pharmaceutical giant, Roche, had been backing development of the drug, but they've recently pulled their support as they cut back on research and development in general, and it seems that Seaside cannot afford to continue manufacturing the drug alone.

Seaside released this statement:

"The study termination is due to resource limitations at seaside, and is not due to any safety issue associated with STX209. We know that this termination will be disruptive and disappointing for many. We are planning to complete phase 3 and the results of this study should be available late summer. If the results are positive, seaside will discuss with FDA the required next steps for approval of STX209. 

"This means the drug could potentially become available in the future but there is still nothing guaranteed."

Parents who saw tremendous improvement in their children on this medication are devastated.

Well, we started this post after reading the piece in the New York Times, thinking that we knew where we were going with it -- like most other genetic disorders, fragile X is a complex disorder, and only a subset of children in the studies would respond favorably to the drug because of the heterogeneity of the phenotype and variation in genetic background, and so of course it's understandable that it's difficult to ascertain the drug's efficacy.  By implication, genetic background determines whether a child responds poorly or well to STX209, and which children respond well and which respond poorly hasn't been determined.

While that may well be true, that's not the real story here.  Instead it's economics.  And that's heartbreaking.  So here is a case when 'personalized genomic medicine' might be a correct way to identify cause or predict effect, and here, where the association actually works (regardless of why), we have other issues interfering with effective care.  Life is complex, but our culture often advances things that don't do good, and impedes ones that actually do.

Fear for sale? Are DTC genetic testing companies selling anything else?

Direct-to-Consumer Genetic Testing
Two opinion pieces appear in this week's Nature (here and here) on the problems facing the direct-to-consumer genetic testing industry.  These are companies, such as 23andMe, deCodeMe, or DNA Direct, that sell estimates of the likelihood of a consumer having a genetic disease or trait.  Obviously, what is on offer, and what people mainly want to know about, is what to be afraid they might get.  Fear for sale is not too far off the mark for this industry.

The industry has been growing fast, as more and more genes 'for' traits and diseases are published, but legal and scientific questions about what these companies have to offer abound.  

The burgeoning, but virtually unregulated, direct-to-consumer (DTC) genetic-testing industry faces some serious changes in the United States. In a series of hearings last month, the US Food and Drug Administration (FDA) hinted that it will impose new regulations on companies selling such tests. The agency has also sent letters to test makers, as well as to one maker of the gene chips on which many such tests rely, saying that the firms are not in compliance with its rules.

In addition, the Government Accountability Office (GAO) last month unveiled the findings of its year-long investigation into the scientific validity, safety and utility of the gene tests used by the industry. The report called some of the tests misleading, pointing out inconsistencies in the results they provided, as well as some companies' shady marketing practices.

Not all companies have been found to have shady marketing practices, or to intentionally mislead, but many of the other issues pertain to all of these companies because they pertain to both the science and the product they sell.  Indeed, it can be argued that the probabilistic nature of these tests means that they all mislead, even if unintentionally, especially as so few people have a good sense of what probability means.

Regulation

Genetic-testing services are proliferating fast. In 1993, tests were available for about 100 diseases. By 2009, the number was almost 1,900. Some forms of testing are major advances in the diagnosis of certain conditions, such as Rett syndrome and types of brittle bone disease. The clinical utility of others — such as the high-throughput genotyping that is widely offered by companies that sell tests directly to consumers — is debatable.

The problems with these companies are multiple, some having to do with the marketing of tests, and some with the quality of the testing and the test results themselves.

According to the FDA, these companies are performing medical tests and marketing medical devices without a license, and this needs to be corrected.  There's no doubt that's how many people view these tests, and how they interpret the results.  As such, the FDA believes it should regulate these companies as it regulates any company selling medical devices or medical tests.  The FDA has recently brought this to the attention of many of these companies -- here is the letter sent to 23andMe on this subject in June, e.g..   

But, many observers believe that the way the testing is done also needs to be regulated to standardize DNA sequencing results, for example, and otherwise assure that results are valid.  So, that's also something that's under consideration.  According to the Nature piece, less than 1% of DTC genetic testing is regulated in the UK, and the proportion is low in the US as well.

Science 
While regulatory and legal issues are real and must be thrashed out, a deeper and thornier issue has to do with the science -- the actual causal connections (if and where they exist) between DNA sequence differences and a particular disease or other trait, and the assumption that we have accurate knowledge of those connections, which is usually far from the case.

If you send your DNA to 3 of these companies, you'll get not only risk estimates for 3 different sets of diseases and traits, but estimates you're given for the same diseases can differ.  Yet isn't there just one truth out there?  The  problem arises because the study results these companies are basing their estimates on can vary considerably, depending on who's included in the study, how the trait is defined and so forth, and which results the company chooses to use to calculate their own estimates will determine the estimated risks they send to you.  Further, there are often in fact no correct answers when it comes to complex diseases -- your risk of type 2 diabetes, or heart disease or stroke is genetic and environmental, and your particular genetic component is unique to you, and exposure patterns are always changing, which all means it can't be necessarily be accurately predicted from a pool of other people's genes.

Different genes and different alleles contribute to risk in different populations, and in every individual.  And, risk of complex diseases is due to the contribution of more genes than have yet been identified, or even that will ever be identified for you.  Even if all the genes that contribute to risk of type 2 diabetes could be identified for your neighbor, or even your parents!, the list won't be the same for you.

And this is before we even begin to consider the environmental contribution to your risk of disease, and this can be very elusive.  One example is risk of breast cancer in women with BRCA1 or 2 mutations -- mutations which confer some of the highest risk of cancer known.  Risk is very different depending on whether a woman was born before 1940 or after, because of changes in exposure to environmental risk factors.  And, we can't predict future environmental risk factors, so it's impossible to know what gene by environment risk will be going forward, which is what these companies in effect are doing.  Yet recent history very, very clearly shows that secular trends in risk, which must be due to lifestyle exposure differences, frequently make huge differences in risk.

The solution?
Most results of DTC genotype testing amount in some way to fear for sale.  That may not be the companies' intent, but it's not unfair to describe them in this way, because it's increasingly unlikely, as more data accumulate, that anyone will be given a no-worry clean bill of genetic health.  Everyone is at risk for something!  Especially if the criteria for expressing risk are not particularly major or definitive.

And, as we've said, the risks they are selling are mainly pretty elusive.  But when it comes to real and substantial risk, we've already got a system, called genetic counseling, for estimating risk for hundreds of known single gene disorders.  These are genes for which risk and predictability are extremely high, and that are primarily pediatric disorders like Tay Sachs or cystic fibrosis, though Huntington's, which strikes in adulthood, is another example.  Prediction of these disorders has long been done by genetic counselors, who are trained to predict risk (which, with these disorders, is fairly simple to do, as they generally follow Mendelian rules of inheritance) and to inform and counsel people about their risk.  They work in closely integrated ways with clinics, physicians, and medical schools.  Counselors are professionals who are tested, regulated, and must keep up their license with regular education.  So, where risk is actually definable, we've got no need for DTC testing. 

If genetics was still in the business of finding genes that follow Mendelian rules, they'd just be added to the list of traits that genetic counselors understand and counsel about.  But, largely driven by the profit motive it must be said, the genes these days being identified 'for' complex diseases by and large have individually small effects, effect estimates vary considerably by study, and they are simply not now, or probably never will be useful for accurately predicting your risk of complex disease.

So, how the DTC genetic testing industry does its testing is one question, and the FDA is trying to decide how to regulate this.  Whether the industry has anything of real value to sell you is another question entirely.  That's the rub.

Faith in science? Industrialized agriculture and antibiotic resistance

Someone asked me the other day on Twitter whether I thought that the words "science" and "belief" were compatible.  I said yes, though I know that a lot of scientists think (...believe...) that faith has nothing to do with science.  Science is facts, faith is religion, based on sacred texts and the like, which are basically hearsay without empirically acceptable evidence.  But, the history of science indicates that this distinction is far from being so simple -- there was a time when people believed that the moon was made of cheese, diseases were caused by bad air, Newton was right about physics, the continents didn't move.  And these beliefs were based on empirical evidence, observation -- dare I say 'facts'? -- not mere guesswork.

In that light, two recent pieces about the role of agriculture in the rise of antibiotic resistance are interesting.  The New York Times described a new study in the Journal of Occupational and Environmental Medicine ("Persistence of livestock-associated antibiotic-resistant Staphylococcus aureus among industrial hog operation workers in North Carolina over 14 days," Nadimpalli et al.)
that reports that workers at industrial hog farms can carry antibiotic-resistant bacteria, Staphylococcus aureus, in their nostrils for up to four days.

Twenty-two workers provided 327 samples. S. aureus carriage end points did not change with time away from work (mean 49 h; range greater than 0-96 h). Ten workers were persistent and six were intermittent carriers of livestock-associated S. aureus. Six workers were persistent and three intermittent carriers of livestock-associated multidrug-resistant S. aureus. One worker persistently carried livestock-associated methicillin-resistant S. aureus. Six workers were non-carriers of livestock-associated S. aureus. Eighty-two per cent of livestock-associated S. aureus demonstrated resistance to tetracycline. A majority of livestock-associated S. aureus isolates (n=169) were CC398 (68%) while 31% were CC9. No CC398 and one CC9 isolate was detected among scn-positive isolates.

As the NYT piece notes, eight-six percent of this sample of hog farm workers carried bacteria for at least 24 hours, compared with about one-third of the non-farm worker population.

This is a problem because the resistant variety of S. aureus, MRSA, has made its way into hospitals and is responsible for thousands of deaths.  Further, many people believe that industrial farming is the cause of much of the antibiotic resistance that is now becoming such a problem, because animals are fed antibiotics to speed their growth, and many of those antibiotics are used to treat human diseases.  Indeed, the majority of the antibiotics used in the industrialized world are given to animals.  When bacteria on the farm become resistant to antibiotics, as this study shows, they don't necessarily stay on the farm.  How they spread has been difficult to document, but might include consumption of contaminated meat, and Nadimpalli et al. report another pathway.

Hog farm; Wikipedia

Responding to the increase in antibiotic resistance that many believe industrial farming to be responsible for, the US Food and Drug Administration this year put a voluntary ban on the use of antibiotics for growth promotion. Critics saw this as a weak response to a very large problem, but pharmaceutical companies and some farmers say it will do what it is meant to do; reduce the use of antibiotics for non-medical purposes, and thus reduce the possible evolution of resistant bacteria that are harmful to humans. Of course one always has to ask the political question of who wields the power and influence over any sort of decision that may affect a particular industry.

But much of this is controversial. Is agricultural use of antibiotics in fact to blame for the problem, or is it overuse of antibiotics by the medical system?  Indeed, there's less of a problem in, say, Scandinavian countries where for decades physicians have prescribed antibiotics at a much lower rate than they have done in the US. Do resistant bacteria really spread in considerable numbers from farm to city?  This may be less controversial with the publication of the Nadimpalli et al. paper, but critics will say that the sample size was small and anyway, documenting a mechanism doesn't mean this is what has happened.

We all tend to pick and choose facts to support our convictions.  Indeed, if you look at how scientists, in any field, cling to their explanations, 'convictions' is perhaps a muted term for what is being clung to.  How we think about these questions may well reflect what we believe more generally about the food system, how or even whether animals should be farmed for meat, whether we patronize farmers'  markets rather than industrially produced food, and so forth rather than what we, or anyone, actually know about the causes of antibiotic resistance.  That is, our personal sociopolitical positions seem clearly be correlated with, if not strongly influencing, our scientific position.

Yesterday, an opinion piece by Iowa veterinarian and pig farmer Howard Hill appeared in our local paper, and in papers around the country.  Hill believes that farmers are being unfairly blamed for antibiotic resistance in humans.

...the claim that "70 to 80 percent of all antibiotics sold in the United States each year are used in livestock" is a straw man. More than a third of those drugs aren't used in human medicine, another third are not considered highly important to human medicine, and most of them aren't used for growth promotion. Critics also ignore the fact that there are a lot more cows, pigs and chickens than people. In 2011, for example, 30 million pounds of antibiotics were sold for use in more than 3 billion livestock and poultry, compared with 7 million pounds for 311 million people, meaning each person used nearly five times more antibiotics than were used in each food animal.

Is he making selective use of the data?  Yes, but isn't everyone who talks about this issue?  And does that make our assertions wrong?  Doesn't prior belief influence our understanding of what the data show?

While Rome burns
President Obama yesterday issued an executive order aimed at combating antibiotic resistance.  The order accepts that industrial agriculture may have a role in increasing resistance, but it adds little to the FDA order of several months ago:

The Food and Drug Administration (FDA) in HHS, in coordination with the Department of Agriculture (USDA), shall continue taking steps to eliminate the use of medically important classes of antibiotics for growth promotion purposes in food-producing animals.

Not many teeth here.  Years ago Europe took much the same approach, requiring that the use of antibiotics for growth promotion be reduced, but a lot of reclassification of antibiotic use for medical purposes followed, as many expected in the US following the FDA announcement last December, which we blogged about here,  and again with this Executive Order.

Again in Scandinavia, the use of antibiotics for growth promotion has been banned, beginning in Sweden in 1986, but farmers have not suffered.  According to a piece in the BCMJ in 2011:

In 1986, Sweden became the first country to regulate the withdrawal of antibiotics used in food animal production. By 2009, Swedish sales of antibiotics for use in agriculture were reduced from an average of 45 tons of active substance to 15 tons. Sweden was followed by Denmark, the United Kingdom, and the Netherlands. 

Danish swine and poultry production continued to flourish with gradual reductions of antibiotic use beginning in 1992 and continuing to 2008 (latest data). During this time, Danish farmers increased swine production by 47% while reducing antimicrobial use by 51%. As well, poultry production increased slightly while reducing antimicrobial use by 90%. Denmark remains one of the largest pork ex­porters in the world.

So, whether or not growth promoting antibiotic use in animals is a major cause of resistance is not really an issue, and we needn't even continue to have the discussion.  If there is any chance it is, why not ban it entirely?  Experience in Scandinavia suggests there won't be dire economic consequences -- unless you're a pharmaceutical company making antibiotics for animals.

Faith in science
We have often written here about the economic interests that drive the course of Big Science.  Can we have faith in science if there is considerable faith in science?  People are, after all, only human, and people of all faiths, including science, defend their faiths.  Further, it's often impossible to disentangle belief from vested interest.   If you've got a hammer, or a hammer to sell, everything looks like a nail.