Tuesday, May 31, 2011

Treating lab tests or people? Chasing our good HDL cholesterol

Adults with high blood cholesterol levels have been shown to suffer increased chances of having a heart attack or stroke. Various advisory committees have recommended that patients should make efforts to reduce their blood cholesterol levels.
However, there are two types of cholesterol, low density and high density, with the former getting nicknamed ‘bad’ cholesterol (or LDL-C)  and the latter ‘good’ cholesterol (or HDL-C) the L standing for ‘lipid’.

Long term observational studies show that people with high levels of bad cholesterol have an increased risk of acute cardiovascular events (MACE) such as heart attacks, strokes and death. Peopole with high levels of good cholesterol have decreased rates of MACE.

Thus it is logical to assume that treatments to decrease bad cholesterol or increase good cholesterol,  would lower risks of MACE.

To determine if this works in practice, not just in theory, there have been randomized trials of one class of cholesterol lowering agents (the statins, brands such as Lipitor) showing that taking a statin lowers the LDL-C and, and,  here is the critical part, also lowers the rates of MACE including heart attacks, strokes and death.

It is logical to assume that these good patient outcomes (not just lowering the bad cholesterol but also improving survival and reducing rates of heart attack and stroke) would also ensue if we were able to increase the amount of ‘good’ cholesterol.

Indeed government regulatory agencies, informed by experts, decided that while a clinical trial to prove that raising good cholesterol would entail health benefits, the costs and delays in doing such a trial were thought unnecessary and fenofibrate was approved for treatment of adults that had low levels of good cholesterol (HDL-C).

On the 19th of May the US FDA Advisory Committee on fenobibrate/fenofibric acid [link] (Trilipix, Abbott Laboratories) received preliminary results of the the ACCORD trial and were asked to consider this evidence. Fenofibrate had been approved for the treatment of high triglycerides in 1993. The company sought approval for the treatment of low levels of good cholesterol.

The trial aimed to show that when Trilipix was administered with a statin (such as Lipitor, (simvastatin) to adult patients with mixed atherogenic dyslipidemia (Fredickson Type IIb) not only would their bad cholesterol (LDL-C) fall, as it does with statins, the good cholesterol (HDL-C) would rise AND, importantly, they would suffer fewer heart attacks and strokes.

The results of a planned interval analysis reveal that after a total of 2,765 patients with diabetes type II were randomized to simvastatin alone or simvastatin plus Trilipix major acute cardiovascular events (MACE) were not decreased in the group taking Trilipix: The addition of Trilipix did not change rates of MACE: 11.3% of patients in the simvastatin  and 10.8% in the simvastatin plus fenofibrate group, a trivial and both clinically and statistically insignificant result. There was no benefit.

Furthermore there was evidence of harm in the group taking Trilipix and a suggestion that MACE events were slightly greater women randomly assigned to the Trilipex plus statin group as compared to men.  Side effects were also found in patients taking Trilipex: These included increased elevations in serum creatinine (kidney function worse) and aminotransferases (liver effects). Two patients taking Trilipex developed a venous thromboembolic event (phlebitis) vs. none in the statin only group. There were no reports of massive muscle disease (rhabdomyolysis, thought to be associated with niacin/Triplix like drugs) and no reports of severe renal or liver failure. One patient taking Trilipex developed pancreatitis. These adverse events did not occur frequently and the findings may be due to chance.

The results have not been formally published. It is undoubtedly too early to change course and completely avoid Trilipex in combination with statins. Indeed the FDA panel assembled to study the results recommended, (on vote of 9 vs. 6) no change to current FDA approvals and that the drug maker must conduct another clinical trial.

Clinicians and patients however should take note. While therapy must always be individualized and guidelines (even from the FDA) are just guidelines it might be wise to avoid aggressively targeting therapy to increase HDL levels. The outcome events simply don’t support such an approach and there is a potential for harm.

All drugs have multiple effects when ingested or injected. It is unclear why statins reduce MACE event rates. The LDL-C is certainly a good marker to guide therapy but statins have multiple effects and the benefits probably derive from some non-cholesterol lowering effects of the drug.

Chasing laboratory test results without clinical trial results showing life-altering benefits will always be a judgement of faith or hope.

There is a good clip of Dr. Steven Nissen of the Cleveland Clinic discussing this issue on NPR news.


Sunday, December 6, 2009

Peeling the onion of financial conflicts of interest - Publishing research

Financial conflicts of interest in research bias towards results, conclusions and recommendations that favour the interests of the sources of the money.  Even though those receiving the money or financial support for their projects 

{Photo Credit - Darwin Bell}
always claim theywere not biased, abundant hard evidence shows just the contrary.

Knowing this, health sciences journals have played a leading role in helping to reveal the conflicts: Initially by providing general guidance for authors about disclosure and then, when that didn’t work, by asking explicit questions about financial relationships with individuals or institutions that might benefit or lose or otherwise be affected by the research, review or opinions expressed.  Editors hoped (without any evidence and indeed with little probability) that published revelations would help readers detect biases or at least increase levels of skepticism.

There have been, however multiple loopholes in the process of revealing and reporting conflict of interest the least of which was addressed by a recent proclamation of the prestigious International Committee of Medical Journal Editors (ICMJE).<1> 

Many authors claimed not to know that their relationship with such and such an institution, company, product or patent etc., was a financial one and therefore did not disclose it. Or they believed they needed to reveal the relationship only if they thought it influenced their research. The most recent ICMJE remedy is a set of definitions of what constitutes a financial conflict of interest along with a prototype for reporting such conflicts.

This timid step is not entirely unhelpful. We should see more honest reporting of the type that Author X owns shares in company Y making product Z that is mentioned in their research, review or commentary.  Medical journals, scarred by multiple humiliations of failure to detect and report authors with financial conflicts of interest to their readers ought to have an easier time of it. Their journals will be less likely to hear, after publication, that a particular author failed to understand that he or she had an unreported conflict of interest.

But will this help the readers, patients or other researchers? Knowing that authors of published research have conflicted financial relationships does not mean that the research is flawed. So how should we, the readers,  interpret such statements as;  author X’s study was funded by company Y or that author X, writing a commentary in a journal, receives speaker fees from company Y?  Given that research, reviews and commentary articles by authors with financial conflicts are more likely to be biased does not explain how these conflicts get translated into results, opinions and conclusions and from there to influencing the reader, often a prescribing physician.

For research articles, which form the basis of knew knowledge, this is especially important. Readers and journal editors need to know more about financial relationships between researchers and their sponsors: Not just that they exist.

We know many of the mechanisms embedded in financial conflicts of interest that result in biased studies and biased study reporting in journals.  The recent revelations made public in the class action law suit pitting Pfizer Inc., the maker of Neurontin (gabapentin), against patients who received the drug show that financial conflicts influence and are directly related to  biases in study design, analysis, interpretation, write-up and publication of research. (an in depth review of some of this is here) A summary article of part of the problem was recently published. (article here)<2> 

The law suit and discovery documents associated with it reveal the many ways that researchers lose control of their studies by relinquishing study design, execution, data collection and analysis, interpretation and even writing up of the study and subsequent publication to company sponsors of the research.

We and others have found that in random samples of researchers these sources of real bias are highly prevalent. For example in our study (in press)  only 11% of over 700 Canadian investigators of randomized trials registered in the clinical trials data base had control over 11 key aspects of their research: study design, data collection, analysis, writing up their papers, deciding when and were to publish and so on. (abstract here - then dig into program abstracts) <3> Most had very little control over multiple aspects of the research.

It is important, that ICMJE and journal editors further peel the onion of financial conflict of interest. In situations where there are declared conflicts of interest authors need to report and journals publish details of the research sponsors' roles in the research and in the write up of the manuscript and decision to publish. Editors need to know who had ultimate responsibility for study design, data collection, analysis, write-up and decision to publish.

Some will argue that supplying such detail is unnecessary, time consuming and bureaucratic. These same individuals will also argue that although they may have competing financial interests, these are not conflicts and their presence did not (and does not) influence their integrity as researchers; contrary, however, to a widening body of research that proves the opposite.

Certainly supplying more detail on the relationships between researchers and sponsors will require additional effort and a bit of time. The process can be simplified. In our work, led by Dr. Paula Rochon at the University of Toronto, we have designed an easily-used electronic reporting template that takes about 10 minutes to complete. The ICMJE should consider adopting this template. For randomized controlled trials, trial registries should insist that these key aspects of human research be revealed when studies are first registered. The financial conflicts could be published along with the other aspects of trial design and recruitment.  Research ethics boards should not approve research on human subjects that is shackled by sponsor control over critical aspects of the research. REBs should have ready access to detailed information on conflict of interest and its effects on research they are evaluating. 

The Canadian Institutes of Heath Research (CIHR) is expected to  adopted a checklist based on the one we developed for use in their grant proposal evaluations.  We urge ICMJE and clinical trials registries to push harder at conflict of interest and adopt a similar template as well.  Fuller disclosure can only be helpful.

1.Drazen JL et al.  Uniform format for disclosure of competing interests in ICMJE journals. N Engl J Med 2009;361:1896-7 (full text here)

2. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label ues. N Engl J Med 2009;361(20):1963=71 (free abstract here)

3. Investigator Experiences With Financial Conflicts of Interest in Clinical Trials. Paula A. Rochon, Melanie Sekeres, John Hoey, Joel Lexchin, Lorraine E. Ferris, David Moher, Wei Wu, Sunila R. Kalkar, Marleen Van Laethem, Andrea Gruneir, Jennifer Gold, M. James Maskalyk, David L. Streiner, An-Wen Chan. Peer Review Congress, Vancouver, 2009 (full abstract here - pdf of conference abstracts)

Tuesday, December 1, 2009

The sacred and overly screened female breast - new recommendations rightly recommend discontinuing screening mammograms in younger women.

The United States Preventive Task Force recently released its latest guidance on screening healthy women for breast cancer. To general astonishment the Task Force recommended that mass screening for breast cancer in healthy women between the ages of 40 ad 40 be stopped, along with efforts to teach women to regularly palpate their own breasts, searching for lumps and bumps.

Image Ductal Carcinoma in Situ From - Breast Cancer.org

The Task Force, an unbiased group of experts in cancer screening, epidemiology and disease modeling of effectiveness determined that the potential benefits were slim and greatly outweighed by the very real harms.Public and political reaction to the announcement was immediate, appropriately embedded in current socio-political narrative of women’s health and widely dismissive of science and evidence: Responses were irrational and often personal - claiming that the members of the Task Force were ‘Bush appointees’.  

I have sympathy for a cult that celebrates an organ which is both a procreative and nourishing. I too would wish it no harm: The point of the Task Force recommendation, however, is that screening for small cancers in the breasts of women between the ages of 40 and 49 years is harmful. How can this be so?

Harms and benefits need to be considered together. It is a rare human environments that sees benefits without risks or harms. For breast cancer, the benefits are often tritely and misleading summed as ‘curing’ cancer. Breast cancer advocates regularly proclaim that breast cancer can be cured, beaten, vanquished, extinguished, destroyed, survived. There are testimonials. But what exactly is a cure?

Common sense has it that ‘cure’ means the particular disease has been eliminated and will never, ever, ‘come back’. We don’t know that for sure about breast cancer, or indeed about almost all cancers. We do know that some women with breast cancer live a long time with the disease and it does not seem to bother them very much. Others suffer greatly and live only a short time. These women can have what appear to be similar types of breast cancer when they are first diagnosed.

Scientists and rationalists, therefore, don’t use the word ‘cure’: They use ‘survival’ and survival rates. What is measured is survival after diagnosis for say 5 or 10 years. Thus we can measure the effects of different treatments including screening with mammography for breast cancer in metrics of 5 or 10 year survival rates. It appears true that the 10 year survival rates for women aged 50 to 69 who are screened by mammography for breast cancer are slightly more likely to still be alive and less likely to die of breast cancer in the 10 years after screening than women who are not screened. This is not cure necessarily (and usually isn’t), but it is an improved chance of survival.

These ‘odds’ are often expressed as the number of women who would need to have a mammogram and the associated treatments if the mammogram was positive in order that one woman’s life would be extended. For women aged 40 to 49 this number is 1,904. This means that 1,904 women would have to be screened in order for 1 woman to benefit from the screening. Looked at this way we can say that 1,903 women would have had an unnecessary mammogram.

How can a mammogram be harmful? There are several harms that are relatively trivial and can be ignored - the hassle of getting the mammogram, the discomfort of the procedure, possible anxiety while waiting for the result. But there are others that are more serious.

First, there are the false-positive mammograms. The mammogram shows a potential lesion and there is then a biopsy or lumpectomy that turns out to be negative for cancer. Both procedures are more than trivial and the latter may deform the breast.

Secondly, and most importantly, by far the most common type of cancer detected is called a ductal carcinoma in situ (DCIS). The cancer is classified by looking at it under a microscope. Almost all cancers detected by mammograms are of the DCIS type. We don’t in fact know much about this type of ‘cancer’. But it is clear that many of these cancers spontaneously revert to normal with no treatment.

Unfortunately we don’t know how to separate those that require treatment fro those that don’t. So the standard practice is to treat them all as malignant (even though we know that most are not). The harms associated with treating a benign tumour are unnecessary surgery (which is often deforming) and the associated chemotherapy and radiotherapy. There is also real anxiety that persists for years and decades of follow-up visits to check for spread of the tumour. Cancer is not a trivial diagnosis.

Difficult decisions are always difficult.

The Task Force could have sidestepped this decision by simply presenting the information - the data - and leaving it to the woman to assess risk. But it didn’t. The Task Force, recognizing that such a decision is all but impossible on individual grounds, made a clear recommendation - for the average woman aged 40 to 49, the odds of improved survival from breast cancer that come from mammography are so small and the odds of having to go through unnecessary surgery and radio/chemotherapy so large that most women in this age group should not have mammograms.

The implications of this recommendation are multiple. First the recommendation ought to mean that as a society we cease to promote mammography screening for women aged 40 to 49. Promotion means organizing screening programs and advertising and promoting them. The evidence indicates that such promotion puts 1903 women at risk of harm in order to possibly prolong the 5 or 10 year survival of 1 woman.

To my mind the Task Force has it right. For the average woman aged 40 to 49, mammography is harmful and should be avoided. Individual women and their physicians might decide otherwise, based on other factors such as family history: But as a public mammogram screening program promising that benefits outweigh harms is a misleading and itself harmful.


The Natural History of Invasive Breast Cancers Detected by Screening Mammography
Arch Intern Med. 2008;168(21):2311-2316. get article

Tuesday, October 20, 2009

Swine flu in the nursing home...Should patients with chronic dementia get aggressive care?

This situation will surely arise during the current influenza season.

In the Nursing Home where I work about 20% of the residents have a long standing dementia. Most are unable to recognize me although I will see each of them about every 4 weeks for one reason or another. Many have family members they do not recognize (although the bedside walls are often covered with family photographs). Most are incontinent and wear rubber panties or diapers. Almost all are getting several medications for Alzheimer’s Disease, depression, and/or behavioural problems such as continuous crying. A few have decreased food intake and are losing weight, but most eat a little. About half are bedridden. Their average age is well over 80 years.

All will be offered and probably get seasonal and pandemic 2009 A(H1N1) vaccines. All have received pneumococcal vaccine. Although this should prevent influenza infections, it may not - the very old respond poorly to vaccination and their natural host defenses are compromised by age and perhaps use.

Influenza used to be called (by those who are not yet old) ‘the old man’s friend’ because it provided relief from chronic discomfort by a quick death. But my patients, almost all, are not chronically uncomfortable. They smile, they may, if incoherently, speak. They eat, some can walk a little with assistance, they generally sleep fairly well, most with a chronic sedative of some sort administered more out of habit than necessity I expect.

Most have next-of-kin who visit regularly and have power of attorney. So it will not be for me to decide to transfer a resident with a severe respiratory infection to an intensive care bed somewhere. But I will be asked by next-of-kin for advice.

There are ponderable ethical issues; should age or dementia be disqualifiers for scarce medical care; are the demented ineligible for medical care in some circumstances; others perhaps. I don’t know the answers here.

But what are the medical issues? A recently published study of 323 nursing home residents with advanced dementia in the U.S. demonstrated that over a period of 18 months, 55% had died and that during their last 3 months of life41% underwent at least one burdensome intervention (hospitalization, emergency room visit, parental therapy or tube feeding). <1>
Certainly a viral or bacterial pneumonia would be one further cause of dying. I expect that few of these patients would survive even if admitted to an intensive care unit. But then, dyspnoea (shortness of breath) is a distressing symptom and patients deserve relief whatever their mental status or functional state. In my nursing home we have no oxygen available: such patients will have to be transferred to hospital emergency rooms for simple symptom relief even though there is a very high probability of death.

There is no algorithm for this ethical and clinical care dilemmas. Case by case, with the goal being to bring comfort to the patient.

1. Mitchell SL et al. The clinical course of advanced dementia. N Engl J Med 2009;361:1529-38

Wednesday, July 8, 2009

Pop’s up again...

I’ve had a year. Well almost a year since the last post.

Here goes again.

A brief explanation involves describing a move to this Island off the coast of Maine and New Brunswick http://www.flickr.com/photos/bubbalouie
~ about 2,000 permanent residents along the 15 or so miles of coastline on the East side of the island (there is no road on the West side), living in 3 or 4 villages (numbers depending on definitions) situated each in a cove that once sheltered fishing boats alas now almost gone (except for lobster and whales-watching tourists), a thriving high school (surprising in a way), a small hospital and nursing home (where I do a little internal medicine - aka geriatrics) and a fabulous bakery (that operates in the tourist season), a tourist season that thrives because of the beauty of the place and ancient migratory bird routes that touch down along the its coasts and archipelago.

In the interim - it’s almost as if I returned from space - we have Obama and hope, Michael Jackson and death, the US moving distinctly to public health care, the Canadian Medical Association moving in the opposite (and self-interested) direction, a continuous stream (perhaps now a river) of revelations of pharmaceutical company driven manipulations of drug trials (doing, analyzing and interpreting and reporting all designed to promote drug benefits and minimize drug harms), and perhaps not much else worth noting.

I did speak at the annual COPE meeting in London earlier this year. COPE (Committee on Publication Ethics) is the brilliant idea started about a decade ago by the Richard’s Smith (BMJ) and Horton (Lancet). The editors were dealing with issues of misconduct - author, publisher, sponsor and had: A) no place to discuss these problems - were they problems? Yes - an B) no UK national organization to deal with them - What does an editor do when he/she discovers an author has fabricated scientific data? For example.

COPE has carried on and is now an international organization with a growing audience and membership. Liz Wager is the current President. Worth checking out if you are a journal editor. http://publicationethics.org/

Equator-Network www.equator-network.org is also working in the same area, but is focused on improving the reporting of research studies. Most published studies - and I mean most - probably well over 50% - are incomplete when published. Incomplete means missing key information that permits the discerning reader (and we should all be discerning or better discerning and extremely skeptical) to determine if the design, methods, results and interpretations are valid. Part of my COPE talk www.slideshare.net/hoeyj/editorial-integrity-conflict-of-interest showed how Pfizer published manipulated research on its drug gabapentin (Neurontin) that eventually found its way into national US guidelines for treatment of patients. Work done by Kay Dickerson for the plaintiffs - full report worth reading is at http://dida.library.ucsf.edu/tid/oxx18r10

And to wrap up for today’s post a few observations on medical practice in 2009 vs. medical practice in 1993. Yes 1993, the last year that I saw patients. I went back into practice for a couple of reasons not worth discussing here, but the really striking differences between practice in ’93 and practice in ’09 are:

A) Lots of new drugs - and so many are but minor atom changes on the underlying chemical (i.e. within a class they’re all pretty much the same).
B) But most of them - pretty much all so far that I’ve encountered - are largely ineffective or so mildly effective that patient’s don’t get any better
C) A few new laboratory tests - especially imaging - that produce such exquisite diagnostic information that physicians find test ordering irresistible because of curiosity and, and fear of malpractice suits for ‘missing’ something, usually untreatable.
D) Except in the nursing home where because of age or dementia, patients seem to be diagnostically neglected.
E) Information availability. It is so much fun to be able to look things up - books, recently published papers, systematic reviews, and so on - sitting here in my study. I think I’ll be a better physician, even after the decade long layoff.

More on practice later.

Thursday, September 18, 2008

Censoring Science and scientists - The Insite Example

Censoring Science and scientists - The Insite Example
(Insite, Canada's only facility for supervised injections of illicit drugs)

Censored is a powerful and friendless word with few public advocates. When Galileo, perhaps the most famous censored scientist, published his proof that the universe is heliocentric not geocentric (that the earth was not the centre of the universe but rather revolved around the sun) the idea was unacceptable to the religious beliefs of the Catholic church of late Renaissance Italy. The proof was banned, books were burned and Galileo himself sentenced to house arrest.

Today, there are few similar examples. Yet in the privacy of our lives, offices, businesses and yes even governments ideas and evidence are suppressed, often to the point of unspeakablity. Just try to get scientists working in industry or government to comment on their work: One is quickly referred to communications departments. This censorship, which is ongoing and comprehensive, has given us ‘whistle-blowers’ and freedom of information legislation.

Similar recent examples, albeit without the arrests, of modern censorship by government are easily found. Here is an example of the text of a presentation on the health effects of global warming by Dr. Julie Gerberding, head of the prestigious Centers for Disease Control and Prevention (CDC) in the US. The censored portions of her text (over half the text was censored) were made by President Bush’s office. The censorship was not made known to Gerberding’s audience and only later came to light when revealed by an investigative committee of the US Senate.

Dr. Julie Gerbending - October 23, 2007 - Testimony before the Senate Committee on Environment and Public Works (censored version)

“The health of all individuals is influenced by the health of people, animals, and
the environment around us. Many trends within this larger, interdependent
ecologic system influence public health on a global scale, including climate
change. The public health response to such trends requires a holistic
understanding of disease and the various external factors influencing public
health. It is within this larger context where the greatest challenges and
opportunities for protecting and promoting public health occur.  
Scientific evidence supports the view that the earth’s climate is changing. A broad array of organizations (federal, state, local, multilateral, faith-based, private and nongovernmental) is working to address climate change. Despite this extensive activity, the public health effects of climate change remain largely unadressed. CDC considers climate change a serious public health concern. ...”

Health and health care are quintessentially political. Nowhere is this perhaps more clear than when dealing populations already marginalized by poverty, skin pigment, body weight, gender ... addiction. Scientific findings and proposals confront popular ideologies embodied in our elected governments. We have the government we deserve.

Yet governments today can’t ignore science any more than they can ignore economics, accounting, finance. Modern governments are expected to act wisely to improve the lives of the electorate and to invest (our) money in public projects that work and to evaluate their effectiveness. We expect governments to make policy decisions not on the basis of ideology, but by using tools of science, particularly those drawn from fields of evaluative sciences, like epidemiology, economics, finance and others.

Faced with science that it can’t censor publicly, governments turn to other techniques - distortion, suppression, delay, denigration come to mind; these are less visible than the red pen, but all are attempts to create a culture that denigrates science as elitist, impractical and amoral (the last of wich is of course what science is supposed to be.

How is Science marginalized?

I have considerable sympathy for politicians: they often find themselves near the centre of ideologic discussions which by definition, are controversial and by the nature of politics, are public. Although expected to act rationally, politicians are in politics because of their ideologies and highly motivated to champion causes favoured by at least some of the public who voted for them or are likely to do so in the (near) future. They are also decent human beings trying to do the right thing in the face of considerable uncertainty: As are the government employees who do the background work needed to develop policy and recommend changes to policy.

So, in the face of uncertainty, called upon to make wise decisions using the best scientific evidence, yet finding that evidence contrary to current ideology, governments try to marginalize the science; both the science that is out there - published - and the science that the government itself commissions or otherwise controls. Harassment of scientists by denying, or threatening to deny, funding for research, or by denying access to data needed for their research, are common recourses of governments. In this case the Federal government cut all funding for research on Insite, precluding scientific evaluation of the facility. This makes it virtually certain that there will be no further comprehensive evaluations of Insite.

Disparagement of science and scientists is another tactic used by governments (and others) when faced with uncomfortable scientific evidence. In a classic instance of shooting the messenger, Health Minister Clement in testimony before the a recent session of the Standing Committee on Health (May 29, 2008) had this take:

“On the question of science, let me assure you I've read many of the studies that have been published on Insite. These studies have the weight of publication as well as some articulate proponents who insist that their positions are the correct ones. Many of the studies are by the same authors who, quite frankly, plough their ground with regularity and righteousness. Indeed, while in our free society scientists are at liberty to become advocates for their position, I've noticed that the line between scientific views and advocacy is sometimes hard to find as the issue on Insite is developed.”

These comments deprecate all of science (among other aspersions that published studies somehow have an unfair advantage over unpublished ones!) and are on the edge of libel in their characterization of the scientists evaluating Insite and, more broadly, Science itself.

Another tactic is to completely sidestep the evidence by creating pseudo-scientific alternatives. Usually this involves forming an Expert Advisory Committee chosen by the government. In the case of Insite, Minister Clement created an Expert Advisory Committee made up of a mix of individuals with some expertise in the general area of crime and drugs, but little in the area of evaluative epidemiology or in public health research or in the management of patients with severe drug addictions. The rationale for the choices is not given. The resulting report (available here) is a summary of commissioned work and the expert committee’s interpretations. The individuals selected to serve on the committee have worked in areas related to the problems of law enforcement and drug addiction, and I’ve no doubt of their good intentions; --, but the whole exercise avoids the critical scrutiny that publication offers and occasionally demands as a condition of publication, including peer review.

When governments want expert scientific opinion it is always unclear to me why they don’t use existing agencies with real expertise in research - in this case the Canadian Institutes for Health Research. Such an agency, at a clear and visible arms-length from government, could easily set up an advisory committee, commission further studies and ensure that the commissioned research meets acceptable national and international standards. And ensure that it is peer reviewed and published.

Governments may form advisory committees and then censor their reports. In the case of Insite, Minister Clement relied at least in part on the Ministerial Advisory Council on the Federal Initiative to Address HIV/AIDS in Canada. Formed in 1998, the Council issues reports (and I am informed has visited Insite) but these reports, and the work of the committee, are published at the discretion of the Minster of Health: The mandate (dated November 2007) includes this stunning paragraph:

“These [reports, policy papers, meeting minutes] are considered as confidential advice to the Minister and their release and dissemination are therefore subject to the Minister’s review and approval.”

In fact the last published annual report is for the year 2004-5. (I am told that the missing reports are currently being ‘translated’ and will be published shortly.) Will they be censored? Will they be complete? Will the Minister alter the record? Will we know? I do not doubt the good will, sincerity and expertise of the members of the Advisory Council, but I do question their independence and wonder at their willingness to accept such a constraint to their work, one that might and likely would limit and should certainly be perceived as limiting their areas of inquiry to those likely to be acceptable to the Minister, and raises some serious questions about the political naivete of scientists who sit on such committees.

Making science not policy the target

Is it really possible to scientifically evaluate a program like Insite? Science never reveals a truth, but rather works to remove uncertainty: politics claims to reveal truths and definitely creates uncertainty. Science rarely provides a yes/no answer: Is needle exchange effective? Do injection centres improve addicts’ health? The health of communities in which they live? These public health problems are too complex, the time frame for most evaluations too short and scientific strategies too limited (we can’t do randomized clinical trials for example). While it is certainly worthwhile to criticize the research (and the criticisms so far are school-book elementary) the criticism has not been accompanied by realistic proposals for alternative research designs.

One needn’t be an epidemiologist or an economist to realize that trying to keep track of the disparate and authority-suspicious population of patients using Insite is going to be a lot harder than, say, keeping track of a cohort of university professors or politicians. Governments and other ideologic critics often expect too much from science and then are critical and disparaging of the reports they receive. Isufficient scientific evidence is equated with showing no evidence of program effectiveness, a profoundly illogical conclusion.

Gathering evidence and then setting up special committees to examine and summarize it is not wrong - if done at arms’ length from government. The problem is misusing science: censoring, underfunding, disparaging the (limited) evidence science produces, in claiming, falsely, that no evidence equals no effect, and in camouflaging ideological policy as rational, science-based public management.

Cutting funding, non-publication of reports and deliberations of expert panels, denigration of science and scientists, bypassing the rigours of publication and independent peer review with confidential and in-house documents, and placing the blame for policy inadequacy on the scientists, are all forms of censorship. Politics is hard, the decisions are tough, the ideologies vocal and voting, but still, the right thing to do is to share and make pubic the policy dilemma and all of the extant evidence, however fragmentary and fragile.

thanks to Udo Schuklenk and Rosemary Jolly for helpful comments on this piece. 

Wednesday, July 30, 2008

Screening for hypercholesterolemia - new guideline recommends screening of all children and drug therapy for those older than seven. Wise?

Pediatricians and family physicians alarmed by the growing prevalence of obesity in children in their waiting rooms and increasingly frustrated by their lack of success in encouraging parents to try to get their child(ren) to lose weight and exercise more may welcome the recommendations of the Committee on Nutrition of the American Academy of Pediatrics.<1> The recommendations reverse previous guideline recommendation for obese children and now recommend cholesterol screening and treatment. Now they can do something. But should they follow the guidelines?

The new guidelines recommend screening for hypercholesterolemia in all children beginning at 2 years of age and (presumably)repeated annually. The screening is two-pronged beginning with an individual assessment of risk based on family history and the child’s current obesity and presence of other risk factors for cardiovascular disease (CVD). Then, those 8 years of age or over are treated with diet plus pharmacotherapy depending on the levels of hyperlipidemia.

Alas there are no clinical trials of drugs for hyperlipidemia in children and hence no evidence that drug therapy will reduce the child’s risk of cardiovascular disease later in life. Nor are there even medium term studies of risk of taking these drugs in children. There is some evidence that children with a homozygous defect in their metabolism of cholesterol (familial hypercholesterolemia) do respond to drugs commonly used to treat hypercholesterolemia in adults and that this may result in some improvement in the health of their arteries by slowing the normal growth of lipid and plaque changes that occur in these high risk children. Although in the short course of these studies the usual side-effects seen with these drugs in adults were also seen in children it will take much longer term studies to assess risk in growing children.

What’s wrong with the recommendation that children be screened for hyperlipidemia?

Screening is the deliberate selection of “healthy individuals for the purpose of separating them into groups with high and low probabilities of a given disorder”<2>, in this case all children over the age of two. The purpose is to identify those at risk and to treat them at an earlier point in time to prevent later disease. In screening there is “the implicit promise that those who volunteer to be screened will benefit.” <2>

This is a bold promise in any screening question but it is an audacious promise to children with hypercholesterolemia. There is but fragmentary and tangential evidence of benefit. Granted the evidence needed to make the promise will be difficult to attain, requiring large clinical trials lasting for decades and demanding that children and their parents administer daily doses of cholesterol lowering drugs (or placebos).

There is even no evidence (and probably no expectation) that even a fraction of children and their parents will take cholesterol lowering drugs for even a few months for a few years. We can expect considerable non-compliance, especially as children leave the parental grasp.

The Academy guidelines do not consider the costs of their recommendations - costs to individuals and to society. There are approximately 72 million children (under the age of 18) in the U.S of whom 10.6 million have no health insurance and would likely have no way to pay for screening and the decades of cholesterol lowering drugs. Health insurance companies in the US and technology assessment agencies in Canada and other countries should proceed cautiously when assessing this new offering by the American Academy of Pediatrics. Money might be more wisely spent elsewhere.

The screening for hypercholesterolemia recommendations of American Academy of Pediatrics meet few of the criteria for an acceptable screening intervention. <2,4> . Failure to meet the promise of an efficacious treatment, failure to assess harm, failure to assess and evaluate cost and opportunity cost ought to render this set of recommendations inoperable.

The algorithm, however, might be useful to pediatricians and family physicians faced with individual obese children with multiple risk factors for cardiovascular disease. They may opt to evaluate the lipid status of these patients and to consider lipid lowering agents after assessing the receptivity of parents and children to life-long therapy and the probabilities of reasonable compliance. But this is not screening, it is clinical practice, or as Sackett and Holland have it, “case finding”.

1. Daniels SR, Greer FR, and the Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008;122:198-208
2. Sackett DL, Holland WW. Controversy in the detection of disease. Lancet 1975
3. Census Brief. Children without health insurance. CENBR/98-1 March 1998
4. UK National Screening Committee. Criteria for appraising the viability, effectiveness and appropriateness of a screening program.