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

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.

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.  

Censored
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. 

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”.

References:
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.

Type 2 Diabetes - Time to relax: Two clinical trials show no benefit and some risk of tight control of blood sugar

What your doctor is reading or should be

Two clinical trials published earlier this month show that aggressive control of blood sugar not only failed to yield benefits, it made things worse - higher death rates and more myocardial infarctions and strokes in the group with tight control of their blood sugars, compared with the control group managed conventionally.

The ‘ADVANCE’ trial, sponsored by a pharmaceutical company using their drug gliclazide (a sulfonylurea) as the main agent to reduce blood sugar and the ‘ACCORD’, trial, funded almost entirely by the US NIH (National Institutes of Health) using several drugs evaluated the effects of tight control of blood sugar of the risks of developing complications of diabetes. The ACCORD study was terminated before the planned end date because a scheduled interim analysis showed a statistically significant higher death rate among patients in the tight control group. Tight control was a target of maintaining glycalated hemoglobin, Hbg A1C, - a measure of control of blood sugar levels now used by most physicians and patients to evaluate diabetes management - below 6 %.

The objective of both studies was to see if tight control, defined as getting the patient’s glycalated hemoglobin from an average of about 8% before the study to below 6% in patients randomized to tight control and to between 7 and 8% in the usual care group. These targets were fairly well achieved in both studies. Patients in the tight control groups were more likely to be prescribed oral agents and were more likely to be taking insulin (77% in the tight control group vs. 55% - ACCORD study).

The results were spectacular and unexpected - in both studies. The ACCORD study was stopped prematurely because of an excess of deaths in the tight control group (5%) compared to the standard therapy group (4%). This 22% increase in death rates per year (1.41 vs. 1.14 deaths per year) was statistically significant (95% CI 1.01 to 1.46) and forced the premature stop.

The ADVANCE study chose to define its primary outcome for the randomized trial as a combination of microvascular and macro-vascular complications. The rationale for choosing this mixed outcome is not explained. Using the combined outcome, the ADVANCE study showed that patients who were on tight control were more likely to avoid development of macroalbuminuria (an indicator or microvascular disease of the kidneys) 2.9% in the tight control group vs 4.1% in the usual care group, hazard ratio 0.70, 95% CI 0.57 to 0.85). There was no effect on development of clinically important microvascualar renal disease such as a need for dialysis/transplant or death from renal causes. Serum creatinine - a measure of renal deterioration that indicates patients might one day need dialysis or transplant doubled in 1.2% of tightly controlled patients vs 1.1% of usual care patients, a statistically insignificant difference.

In short, after an average of 5 years of tight control in the ADVANCE study, the only difference between the two study groups was in the proportion of patients who developed very early indications (macroalbuminuria) or microvascular disease. The study did not show an excess of deaths from macro-vascular causes (stroke and heart attacks).

While the authors of the industry funded ADVANCE study tout the result as showing “a one-fifth reduction in microvascular complications” the authors of the ACCORD study concluded that there is a previously “unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes mellitus.”

Here is a summary of the key outcomes in both trials:


Both studies, as expected showed that patients on tight control had more insulin reactions although the differences in frequency of severe events (in the ACCORD therapy defined as those that required medical attention) is remarkable. In the ADVANCE study severe hypoglycemia was defined as “transient dysfunction of the central nervous system” to the extent that they “required help from another person”.

Differences in softer (and perhaps harder) clinical outcomes may be due in part to the geographic locations of study participants and differences in the usual patterns of practice of clinical medicine. In the ADVANCE study it appears that patients were drawn from Australia, New Zealand, the UK, several European countries and China (perhaps including members eligible for care in a military hospital) as well as from Montreal and New York. The ACCORD study drew patients from across the US and Canada.

Interpretation

The results of both studies give pause and the results from the ACCORD study demand action on the part of clinicians treating patients with type 2 diabetes mellitus. In the face of an substantial increase in the risk of death from all causes, clinicians must be much less aggressive in encouraging patients to get better control of their blood sugars. This appears to be dangerous in patients with type 2 diabetes mellitus. In the ACCORD study only 50% of patients achieved glycalated hemoglobin Hbg A1C levels of 6.5% or less. Even this modest achievement in blood sugar control resulted in harm.

There is no good explanation for the results (why would more aggressive control of blood sugar in patients with type 2 diabetes lead to heart attacks, stroke and death). But there need not be an explanation in order for clinicians and their patients to change direction on the management of type 2 diabetes mellitus. More is not only not better, it is worse - in terms of life expectancy and the frequency of severe hypoglycemic episodes.

The negligible benefit on microvascular disease noted in the ADVANCE study is perhaps not a surprise as there is some evidence that tight control does result in slower progression of damage to very small blood vessels. Nonetheless it is worth noting that this did not manifest itself in a lesser frequency of development of retinopathy, nor of severe renal failure requiring treatment, nor in the worsening of renal function as measured by serum creatinine. These benefits can be considered minimal and come at a cost of higher death rates overall.

Implications

For patients and families

Patients with type 2 diabetes can’t escape being told daily on television and in magazine and Web advertisements that controlling blood sugar is essential to their health and longevity. Devices to measure blood glucose (after every meal and before and after every physical activity) abound, along with advertisements from multiple drug companies anxious about their market and share values.

Blood sugar, however, does not appear to be a central or perhaps even a peripheral cause of the complications of diabetes. Blood sugar more and more looks like an innocent bystander or itself the product (not the cause) of some other disorder of blood vessels. This is a bit like the old saw that a carpenter with only one tool - a hammer - sees the solution to every building problem as requiring a nail. We can measure blood sugar. So we develop ways to smash it down to the ‘normal’ range, with glucose meters, oral hypoglycemic agents and insulin.

Certainly blood sugar can be problematic, especially when it is very high and other metabolic changes occur - but these are rare in type 2 diabetes. When first diagnosed with diabetes, most patients have no symptoms. The diagnosis is an unwelcome surprise. Patients then learn they are at risk of developing ‘complications’ of diabetes such as renal failure, leg ulcers, blindness, heart attacks, congestive heart failure and stroke.

Commentators on these 2 studies agree that patients (and their physicians) should back away from the target of achieving ‘normal’ levels of glycalated hemoglobin (6%). They agree that it is more important to emphasize efforts to achieve normal body weight, to follow a Mediterranean diet, to take medication for hypercholesterolemia, and treated for hypertension if present. All interventions reduce the chances of heart attack, stroke and death.

But these 2 studies force a larger consideration - the wisdom of screening asymptomatic individuals for abnormal blood sugars. By doing so we label individuals as being at risk of later serious and life threatening complications for which there is no effective therapy. The ‘do no harm’ principle of medicine is violated. Sure, we can make weak arguments that perhaps their long term risks of microvascualar complications could be reduced by close attention to blood sugar, but even this is modest at best and comes with additional risks that are much more serious.

A diagnosis of type 2 diabetes mellitus is not a gift, it is a burden that patients will have to carry for the rest of their lives. A burden of increased frequency of visits to physicians, of glucose measuring devices, or pharmaceuticals with side effects of hypoglycemia and perhaps other risks and an instantaneous trip from the land of the healthy to the land of the sick, with no return ticket.

For society

The FDA and similar agencies in other countries must revise approvals for the advertisement to physicians and directly to patients of information about diabetes and its treatment. In future advertisements need to include a warning that tight control of blood sugar increases the likelihood of death.

Current guidelines (US American Diabetes Association) suggest “the A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” This recommendation requires revision as do the screening and case-finding recommendations for the detection of asymptomatic type 2 diabetes mellitus.


References
Advance Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72

Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2009;358:2545-59

 The irritating imprecision of medicine - will network analysis help?

A friend of mine thought about buying a car the other day and went to the dealer to inspect new models. He’s interested in reliability of the car as he travels a long distance usually on back roads visiting customers and trying to make sales.

“The best model” the dealer said, “is this one. It rarely breaks down, in fact over 10 years only 16% have to be replaced or have major repairs.”

“That’s one in six” my friend said. The dealer replied that he could buy (expensive) insurance to cover the period not under warranty. “Best we can do” he said.

Each time I use the Framingham calculator I’m reminded of the similar imprecision of modern medicine.

As I fiddle with it today, entering a total cholesterol near the top of the range, a ‘good’ cholesterol in the middle of the range and a normal blood pressure yields a hypothetical me with a 16% chance of a heart attack over the next 10 years. While this is prognostically 4 times higher than if my total cholesterol were the lowest on the scale and my good cholesterol highest, it still means that even with these excessive cholesterol levels my chances of having a heart attack is still far below even 50/50. Most men my age with bad cholesterol values don’t have a heart attack or die. Indeed if there were 6 men similar to me only one of us would have a heart attack in the following 10 years.

Why do some get heart attacks and others don’t? This is the irritating imprecision of medicine. While all cholesterols (good and bad) are the same, each of the 6 men have different ‘other factors’ that play into a complex yet unknown equation that somehow leads one of us to suffer the bad outcome.

When I see a patient with a bad condition I always remember my first patient with cancer of the lung. Mr. Walker was 59, and other than pain in his shins (an infrequent but known secondary effect in a small number of patients with lung cancer) he was well. Yet there was no hope. Removal of the lung would not save Mr. Walker - we had good epidemiological studies showing dismal prognosis and as most older patients could not survive with a single lung, high operative mortality rates. I presented his case to our professor, a man older than the patient. To my recommendation that Mr. Walker be sent home without having his lung removed, my professor replied that a few of his lung cancer patients who had surgery survived for very long periods, so why deny this one the chance. The professor recommended that I see if my patient could walk up a flight of stairs without stopping. If he passed this ‘stress test’ he could survive with one lung, said the professor. He was old enough to have seen enough lung cancer to know that not all were alike.

Wouldn’t it be fine if our physician knew which of the 6 of us was going to suffer the bad outcome? Not everyone who smokes a pack a day for 40 years will get lung cancer. In fact, most won’t. We all know committed smokers who believe that inhaled smoke gives the lung tissues a protective coating. Perhaps they are right.

Of 100 men with prostate cancer limited to the prostate 75 will not have any evidence of metastases 10 years later. (For those having a prostatectomy only slightly more, 85, do not develop metastases over 10 years. Although the disease phenotypes are the same - cell type adenocarcinoma, anatomic location within the prostate at the time of diagnosis - only about 25% of men go on to develop metastases.   While this might look like the play of chance, science insists there must be a reason. Greater diagnostic precision will reduce prognostic imprecision and lead some men to avoid debilitating and unnecessary prostatectomy.

Physicians make diagnoses on the basis of anatomical location of symptoms, physical signs (anatomical and physiological - e.g. blood pressure) and laboratory tests that measure specific body systems for homeostasis such as oxygen transport, blood sugars, blood, immune response, the presence of pathogenic organisms and toxins, and so on.

A series of papers over the past decade have demonstrated that we need to rethink our reductionist conceptions of diseases as being a set of distinct entities, like congestive heart failure, or sickle cell disease or AIDS and begin to understand that these illnesses are each complex involving multiple genetic, environmental and social factors. As we begin to understand these factors and their relationships, our conceptions of disease will change, diagnostic and prognostic labels and estimates will be altered, and new systems of understanding human physiology and pathobiology will enter the language of diagnosis and the practice of medicine. These discoveries have arisen in the emerging field of network analysis.

The genetic component can be thought of as a limited but as yet incompletely identified set of genes that control human development and cellular function throughout life. Some genes are known to be involved in specific areas of human development and pathophysiological response because mutations in these genes result in specific diseases, such as sickle cell anemia, familial cardiomyopathy, pulmonary arterial hypertension, diabetes, various cancers and so on. Some of these are monogenetic in that a single mutation is common to all who have the defect. In others seemingly identical diseases can result from mutations in more than one gene or can arrive from different mutations in the same gene - for example the clinical disease -  familial pulmonary arterial hypertension -  can arise from over 50 different mutations.

It seems helpful to conceptualize two categories of genes, those that have a specific role with a particular type of cell and those that are more generic. The specific-role or primary genes become apparent when mutations arise. Sickle cell anemia derives from a mutation in a single gene that results in the substitution of valine for glutamic acid at a specific position in the molecule that makes up the beta-chain of hemoglobin. Under hypoxic (or other) conditions this results in the formation of hemoglobin polymers which cause the erythrocyte to assume a sickle shape. Genes involved in various malignancies probably function in a similar but more complex way.

The other category of disease modifying genes have broader effects that serve to modify threats to cells from the specific disease-related genes and from environmental threats such as temperature, radiation, hydration and tonicity, oxygen, micro and macro nutrients, infective agents and toxins. The ability of an individual to accommodate these genetic and environmental threats is also part of the genomic makeup of that individual. The resultant pathology depends on the interaction of the gene with the environment.

Conceptually, it might look like this:


From the same paper here is the disease network for sickle cell anemia, a disease that can present with many pathophenotypes:

The figure is copied from the article by Loscalzo, Kohane and Barabasi <1>
The primary genetic abnormality, hemoglobin S (red) can be affected by other genetic abnormalities, if they are present (grey). The various clinical presentations of sickle cell anemia (in blue) are thus the result of a network of cellular and sub-cellular events, aided and modified by environmental agents (green) and the genomic elements that control the bodies generic reactions (yellow).

On a general level none of this is new or surprising. We know that our genetic complement and our lifetime interaction with environmental factors are somehow responsible for our particular pathophenotype experience - the disease we have. What is perhaps new is the notion that although the phenotypes may look identical, they are not: What is different about them is how they are produced - their underlying networks of causation and damage control. Understanding these networks will add precision to diagnosis and will be helpful in developing pharmacologic interventions that disrupt or disconnect the disease causing elements of the network.

While the primary nodes of causality - primary and secondary genomes and environmental factors (physical and social) are limited, the secondary networks of each primary node are more complex and the number of possible interactions between them large. Thus a single anatomic or cellular or molecular pathophenotype might have been the product of a very large number of possible interactions involving the primary nodes of causation.

Even in this simple schematic model, there are an exponential set of of possible interactions each of which might produce a different presentation of the ‘same’ anatomic or functional disease or pathophenotype. Thus some adenocarcinomas of the breast are affected by primary genomes such as the BRACA genes, secondary genomes such as estrogen receptors, and are likely further modulated by environmental causes, and perhaps environmental factors that play a role in prognosis and the role of the secondary genome in control of proliferation, immune response, apoptosis/necrosis and so on.

Although logically unassailable the new model of disease would be mathematically unusable due to the exponential number of possible combinations of nodes and sub-nodes (if all possible connections are considered to be random events).

Fortunately they are not. The pathways are part of non-random networks between primary and secondary nodes of influence, themselves interconnected. Network analysis is changing the way we look at biological, social, economic, electronic and other networks.

Practical applications are in the future, perhaps decades from now. But we should pause when considering a diagnosis to hand on to a patient, for each diagnosis comes with a prognosis and a set of care burdens and, unfortunately, with considerable imprecision about likely outcomes. Recent publications on aggressive control of blood sugars are only the latest to confirm how little we know about the natural history of the diseases we diagnose. (see next post

References

1. Loscalzo J, Kohane I, Barabasi A. Human disease classification in the post-genomic era: A complex systems approach to human pathobiology.

Type 1 Diabetes - Ongoing clinical trials of immune suppressant therapy

What your doctor is reading or should be.
April 16, 2008

(photo courtesy of nicointhebus (Nicolas Monnot)

The recent onset of diabetes in the child of friends of ours led me to the registry of clinical trials. There are 68 studies in the registry recruiting children for studies on type 1 diabetes in children. Our friends, whose son is 8, had already contacted an investigator for one of the trials who encouraged their participation.

This trial and several others take advantage of new understandings of the proximate causes of Type 1 diabetes now believed to be related to autoimmunity, or said another way, due to the body somehow reacting against itself, or parts of itself, in this case the beta cells in the pancreas that make insulin. The result is a gradual decrease in beta cells and usually the gradual onset of diabetes, high blood sugars and later the vascular and other complications that may arise.

The idea behind many of the trials of aggressive intervention in new onset Type 1 diabetes is to try to slow the gradual destruction of beta cells by interfering with the autoimmune system that is producing antibodies that stimulate T-Lymphocytes that are causing the damage. One way to do this is to block the antibody receptor site on the T-Lymphocyte.

One of the trials (registry number NCT00129259) involves the molecule hOKT3gammal (Ala-Ala), which is administered intravenously over a 14 day period. This regimen is repeated a year later. The aim is to determine if patients receiving the molecular antibody (drug) will retain more of their ability to produce insulin. In a previous study of a very small number of patients, this seemed to be the case with about 70% of patients with new onset Type 1 diabetes receiving the drug maintaining or increasing their insulin production compared to about only 20% of control patients, who received usual care for their diabetes.<1> For information on this trial see www.clinicaltrials.gov


Interpretation

While this is an exciting area of new research, the results so far are but preliminary. All the trials do not rule out the possibility of the results being due to chance (as the number of patients in the trials is small) or bias (most studies are open label - meaning that the investigators and the patient’s physicians know whether their patient is in the treatment or control group).

Also, the immune system is complex, important for a very large number of body functions and protections and incompletely understood. Alterations in T-cells, a key component of our immune systems, may generate adverse events during the trials (so far no serious events have been detected) or later. Early trials involving small numbers of patients are unlikely to detect infrequent yet serious adverse events.

Implications

For the patient and family

Type 1 diabetes always comes as an unexpected and unpleasant surprise. The possibility of a treatment that could reverse or slow the onset of insulin-dependent diabetes, or reduce the need for insulin and perhaps even delay or deny the onset of known adult complications of diabetes, generates hope. It is unlikely, however,  that the drugs being studied will be released for clinical use for at least several years.

Participation in a trial may provide parents with a way to express their non-competing feelings of hope and anxiety by ‘doing something’. Unfortunately, outside the US there are few trials to available.

To find a trial in your area, use the search function at the registry (www.clinicltrials.gov) and enter the search terms: type 1 diabetes, open studies, interventional studies, child and country. The trials are described and contact information is provided (usually a telephone number and address).

For Society

While type 1 diabetes is not common, it is a serious illness and deserves our attention, research and treatment resources. Finding a way to prevent the illness or severely limit its effects would provide relief to many families, especially those who harbour the genetic signatures that in some way enable the disease to take hold.

Reference

Herold KC, Gitelman SE, Masharani U. et al. A single course of anti-CD3 monocoloanal antibody hOKT3 1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005;54:1763-9