Happy New Years

You know you are getting old when your kids have more plans on New Years Even than you do.

We've traditionally stayed home, but we've already gone to a "Noon Years Eve" celebration at the zoo and will also go to an early kid's celebration at the Phipps Conservatory tonight. Whew.

Adrianne is sick so we may put off our fancy dinner (steaks, blue cheese salad, etc.) and these wines until tomorrow.

Codewords

There has been a brouhaha lately about "ghostwriting." Basicially, a pharma company writes an article and then pays a researcher to publish it under his or her name. Not very ethical, eh?

I recently came across this, in an editorial extolling a medicine made by Schering-Plough based on a study funded by Schering-Plough:

Editorial assistance was provided by Thomson Gardiner-Caldwell London, supported by the Schering-Plough Research Institute, Kenilworth, NJ.

I think I know what that means. Needless to say, the "author" has "consultant arrangements" and "is on the speakers bureau" of Schering-Plough as well.

This kind of thing is embarrasing and from a respected journal to boot.

More ugly pictures

For those of you who liked the pictures of my feet post Arkansas

Given it was 50F yesterday when we arrived back in Pittsburgh and still in the mid-40s this am, and that almost all the snow had melted, I figured it would be no problem to do a nice trail run this morning. Wrong.

The ice we got several weeks ago had not completely melted, which I discovered pretty quicly as I slipped and slided a bit before actually falling. I didn't realize how bad it was until I finished my run (I did get off the trail and finish up on some well-salted sidewalk). Yuck.

It looks a lot better now that I've gotten it cleaned up.

Long-acting beta agonists

Are long-acting beta agonists (LABAs) safe. I've argued in the past that they are, but now a perspective piece in the NEJM argues that they are not. (Inexplicably, it is not available as free fulltext. If you are going to publish editorials on controversial, life-threatening topics, I think you should make them available to people).

Fernando Martinez, a respected asthma researcher and participant in the FDA panel discussion about LABAs presents some new data and argues they should be used only as a last resort.

First he reviews two earlier studies which appeared to show an increased rate of death in patients using salmeterol. The increase was not statistically significant in the first study, and the second, the infamous SMART (Salmeterol Multicenter Asthma Research Trial) has never been published. It did, however, show, an increase rate of death by a factor of 4 in patients using salmeterol (p value 0.02). Unfortunately, neither trial required concomitant use (or even recorded use) of inhaled corticosteroids (ICS) which are the current first-line in treating persistent asthma. GlaxoSmithKline and many asthma specialists have argued that this likely resulted from patients using salmeterol without ICS, leading to treatment of bronchospasm but nut underlying inflammation. Unfortunately (contrary to my previous post) the SMART data don't allow this hypothesis to be tested.

He goes on to data presented to the FDA by Novartis, who manufactures another long-acting beta agonsit, formoterol (sold as Foradil in the US). Again the data shows an increase risk of serious events (presumably fatal or near-fatal asthma exacerbations) with use of formoterol, although this is comprable to that seen with regular use of albuterol. No statistical information is given, but the increase seems to be independent of ICS use.

Martinez does present some data contrary to his hypothesis that LABA increase severe asthma exacerbations. First, he notes a case-control study from the UK which showed there was no increased use of LABAs in patients with fatal vs. non-fatal asthma. Second he notes that overall death rates for asthma have if anything decreased with the introduction of LABAs. He notes some problems with the case-control study (older patients, some with COPD) and theorizes that the decrease in deaths from asthma may have been in spite of not because of LABAs, perhaps because of increased use of ICS.

He goes on to suggest starting with ICS alone, adding leukotriene antagonists like Singulair or even theophylline (which is almost never used anymore) and reserving LABA for those still requiring albuterol (a short acting beta-agonist) twice or more daily. He thinks the manufacturers of LABAs should fund additional studies to confirm or refute the hypothesis that use of LABAs in addition to ICS increases severe asthma exacerbations

Do I agree? I'd say for the most part no. Martinez cherry-picks by including only 3 of the many studies that have been done with the ICS/LABA combo. For example, this Cochrane review looks at 85 studies of ICS/LABA in persistent asthma and doesn't note an increased risk of severe exacerbations; this one examines nearly 6,000 patients randomized to leukotriene antagonists or LABA in addition to ICS and specifically finds no increased adverse events. Finally, another Cochrane review of LABA vs. theophylline finds that LABA have less adverse effects (admittedly this is out of date as patients weren't necessarily on ICS).

Secondly, I find it hard to imagine that a medicine that helps so much with asthma control could lead to increased mortality. I can't tell you how many patient tell me that Advair (fluticasone/salmeterol, an ICS/LABA combo) has changed their life. They've gone from constant asthma symptoms and restrictions on what they can do to exercising and doing whatever activities they want. This is borne out by trials as well.

Of course, other medicines such as anti-arhythmics for heart disease improved secondary end-points while increasing the risk of death, which is also counterintuitive. Maybe regular LABA could mask worsening asthma preventing optimal treatment. Against this would be the fact that studies of ICS suggest that most of the benefit is obtained at low doses, such as those in the lowest strength of Advair (100/50)

I do agree with Martinez that GSK should fund a study of Advair (fluticasone/salmeterol) versus fluticasone alone to answer this question once and for all.

UPDATE: original data from the pharma companies submitted to the FDA here.

Too funny

Psychotherapy, always trying to establish itself as "scientific," doesn't seem to be making much progress. At a recent conference:

In the opening convocation, Dr. Hunter "Patch" Adams - the charismatic therapist played on screen by Robin Williams - displayed on a giant projection screen photos from around the world of burned children, starving children, diseased children, some lying in their own filth.

He called for a "last stand of loving care" to prevail over the misery in the world, its wars and "our fascistic government." Overcome by his own message, Dr. Adams eventually fell to the floor of the stage in tears.

Many in the audience of thousands were deeply moved; many others were bewildered.

Evolution vs. intelligent design

An excellent editorial by James Q. Wilson, explaining why evolution is science and intelligent design isn't, and why only the former should be taught in public schools:

What schools should do is teach evolution emphasizing both its successes and its still unexplained limitations. Evolution, like almost every scientific theory, has some problems. But they are not the kinds of problems that can be solved by assuming that an intelligent designer (whom ID advocates will tell you privately is God) created life. There is not a shred of evidence to support this theory, one that has been around since the critics of Darwin began writing in the 19th century.

Vocabulary

Not to be snooty, but it is unusual that I come across a word or usage which I have never encountered before except while reading. One's spoken vocabulary is generally much smaller than the number of word's one knows the meaning of. I frequently encounter words whose meaning I cannot remember, some of which (sanguine, phlegmatic, saturnine) I have looked up a million times but can't keep straight, although even those are mostly while reading.

So I was a bit surprised to encounter 2 words in the course of my activities in 2 days that didn't elicit even a glimmer of recognition. See if you know them

1. Mangle (not the verb but as a noun)

2. Chabad (this I saw on a sign while running, which is an even more unusual source than usual)

Drink up!

Apparently light drinking is not enough to protect your heart, at least according to this editorial in the Lancet (no free text). There are no randomized controlled trials of alcohol consumption so only observational studies exist, and these do show evidence of a cardiovascular protective effect even with light consumption (1-3 drinks per week) versus non-drinkers.

Of course, these kind of observational studies only show correlation not causation, and inferring causation can lead one astray (I've posted a lot more about this here). For example, epidemiologic studies of hormone replacement therapy showed a protective effect against heart disease and breast cancer, whereas later, randomized ones showed HRT actually increased the risk of these diseases. Why? The most likely culprit seems to be the "healthy user effect." Women who worked out, ate well, etc. were also likely to take HRT. These so called "confounding" factors more than made up for the deleterious effects of HRT.

Could a similar situaton exist for alcohol consumption and heart disease. Maybe. One study of light to moderate vs. non-drinkers showed that for the majority of risk factors, non-drinkers were at less risk.

However, the arguments for a protective effect of heavy alcohol consumption are more compelling. Heavy drinkers are in general much less healthy than light or non-drinkers as most alcoholics smoke, don't exercise regularly or keep their high-blood pressure well controlled, etc. Despite the fact that these confounders work against them, they still are protected against coronary artery disease:

Although less palatable, there is more compelling evidence for a coronary-protective effect of moderate to heavy drinking than for light to moderate drinking. In heavy drinkers, confounding will obscure rather than exaggerate any coronary protection because of their heart-unhealthy behaviours. The observations of relatively “clean” coronary arteries in autopsy studies of alcoholics are also consistent with a coronary-protective effect of heavy drinking.

So bottoms up!

Happy Festivus!

or whatever holiday you celebrate.

Dangers related to the 12 days of Christmas, especially to our Candian neighbors, are reviewed at Gruntdoc (not safe for work)

In our household, Colin got a Gamecube and several games of which the Simpsons Hit and Run is his favorite, while Isabel got a doll from American Girl (where else) and Adrianne got the 3rd and 4th years of Red Dwarf on DVD. Among other gifts, I recieved a pair of Montrail Hardrocks, which it sounds like I'll need at Laurel Highlands, since someone on the Ultra list recently noted that compared to Laurel Highlands, Western States is like running on a freeway

Korean stem cell finale

It looks like the end of the line for Dr. Hwang and his stem cells.

In memorium:

I see the summer children in their mothers
Split up the brawned womb's weathers,
Divide the night and day with fairy thumbs;
There in the deep with quartered shades
Of sun and moon they paint their dams
As sunlight paints the shelling of their heads.

As I read the article, the investigating panel has not ruled out that Hwang did create 2 stem cell lines, albeit using far more eggs than reported.

Why he would cheat to report 11 lines when even 2 lines would have been an enormous achievement? My answer is that they didn't even suceed with the first 2 lines. And probably past papers from the group are fraud too.

By the way, I can only imagine the panel was able to come to a conclusion so quickly because other researchers admitted outright fraud.

A Christmas Carol

Different versions of "A Christmas Carol". This is a year old, but still hilarious.

Biology types will like the Richard Dawkins version:

Ghosts don't exist. Scrooge does whatever he wants. Tiny Tim dies. Later, Scrooge dies. No one cares. The Christmas Carol meme lives on indefinitely.

Happy Festivus to all

Evolution at work

Contra Richard Dawkins, evolution need not always be depressing:

Reindeer have a body clock that does not rely on a 24-hour day/night light cycle, according to Norwegian researchers. It may explain how they stay awake to carry out their Christmas duties. Instead, the herbivores’ stomachs seem to keep their body clocks ticking along. . . .

“Our data showed that reindeer have not evolved strong biological clocks – they have very weak circadian machinery – probably since there is no selective advantage for it: most of the time there is no difference between night and day,”

accoriding to lead researcher Karl-Arne Stokkan

A fascinating insight

Why is so much published research later contradicted (e.g. value of hormone replacement therapy and vitamin E)? One reason maybe that "high profile" research is statistically more likely to be a fluke. This article in JAMA in July showed that 16% of highly cited research studies were later contradicted and others were either never replicated or showed a magnitude of effect that was not replicated.

Now the letters in response to the article are out, and one goes a long way to explaining the paradox. It points out that research studies are analagous to diagnostic tests and p-values can be roughly translated into the false positive rate. But of course the false positive rate itself doesn't tell us much about how to interpret a positive test, what we really want to now are it's positive predictve value, which depends on the prior probability of the disease.

For non-medicos I apoligize if you can't follow, but I am not the one to explain medical statistics, but basically this means that EKG changes in a 70 year old diabetic smoker with known high cholesterol are a lot more likely to accurately diagnose a myocardial infarction than similar changes in an 18 year old triathlete.

Now in what situation is a test with a low false positive rate (i.e. a high specificity) likely to lead a clinician astray? When the a priori chance of the patient having the disease is very low.

Hear is where the clever insight comes in. By its very nature, highly publicized research has a low a priori chance of being correct. That a new antibiotic is effective for cellulitis is no big deal, that a bacteria causes ulcers is (though this was true, of course). So, studies that are truly novel are also more likely to be wrong, regardless of p value. Pretty cool.

Of course one problem with this Bayesian reasoning is that it is hard enough in clincial care (how exactly do I know if a patient has a 40 or 70% a priori chance of having asthma?) but completely impossible in research. As Colin West, the letter's author puts it

As noted by Davidoff,one solution to this quandary is to better understand Bayesian approaches to study analysis and interpretation. Until such approaches are rendered comprehensible to the average researcher, however, we should at least understand the limitations of the P value

The author of the original study even has a paper arguing that the majority of published research is wrong (Ioannidis JPA. Why most published research findings are false. PloS Med. 2005;2:e124.) but I can't get it to load on the PLOS website

Intelligent design goes down

"The overwhelming evidence at trial established that intelligent design is a religious view, a mere re-labelling of creationism, and not a scientific theory."

according to Judge John Jones in a decision that can be only described as a complete and total victory for those of us who want science taught in schools to reflect, you know, actual science.

Grand rounds

is here. Nice picture

Science and scientific misconduct

I have been irritated at the journal Science for some time, mostly because they make it so hard to access material on-line. For example, the retraction of the Hwang stem-cell paper is apparently not available to non-subscribers.

I am also perrenially irritated at the reluctance of the scientific enterprise to weed out fraud and sloppy practices. As someone with experience (4 years getting a Ph.D. and 2 years doing research as a fellow) I can tell you there is a lot out there that no one can replicate, it is just lower profile than stem cells. And here I am NOT talking about labs I worked in but papers you'd cite just to have someone tell you that despite there being no correction and no contrary data in the literature the results were widely known to be wrong. Of course some of this was not fraud or dishonesty at all but due to sloppiness or bad interpretatin of date, etc., that is honest error. Still, I found the world of molecular biology to be far less rigorous and much poorer at error correction that it should be.

These two sources of irritation have now intersected in the stem cell mess:

At another press briefing this afternoon in Washington, D.C., Science editor Donald Kennedy said that in their phone call, Hwang and Schatten told editors that the data in three areas--cell surface marking, DNA fingerprinting, and teratoma formation--"could not be trusted." But even though the paper contains errors that were known at the time of submission, Kennedy said there is not at present evidence to conclude scientific misconduct.

If knowingly submistting fake data isn't scientific misconduct what exactly is?

UPDATE: well, the retraction, such that is is, along with the original paper is here, so Science is innocent of the charge above. But the correction issued in November regarding faulty data in one table is only available to subscribers. You'd think Science would see the benefit in getting all the data out in the public domain to encourage discussion, etc. but I guess not

UPUPDATE: more about Science in the eye of the storm here

Korean stem cells ad naseum

Dr. Hwang Woo-suk, who has been under sustained fire for apparently faking his results, is not giving up:

Admitting that his team made "human errors," cloning researcher Woo Suk Hwang has asked Science to retract his celebrated paper reporting the creation of patient specific embryonic stem (ES) cells. But in another twist in an increasingly complicated story, the researcher today rebuffed the claims of a colleague who said yesterday that Hwang had admitted falsifying data. At a packed press conference 16 December at Seoul National University, a defiant Hwang said that he and his colleagues did succeed in creating such cells, and he intends to replicate his results.

It turns out "at least" 6 of the cell lines no longer exist, having been killed off after developing contamination with fungi. While this seems like an awfully convenient excues, it is difficult to prevent contamination of mammalian cells in culture with faster growing fungi and bacteria, so this is not an unreasonable explanation. Hwang claims they are working to unthaw frozen sameples of the other 5 lines to demonstrate they are legitimate. No mention is made of sending samples to outside labs, which would be the gold standard as confirmatory data coming from Hwang's own lab would be suspect.

I would say there is a <5% chance this work is legit. I suspect there will be problems with the other cell lines and/or Hwang's group will claim the lines are as advertised but refuse to release them to outsiders to verify their results. I say this based partially on the fact that the 6 (or more) lines that are no more had apparently been lost by the time of submission. Given that no one had ever made even a single line from a specified donor, reporting they had 5 good lines would not have been any less impressive than reporting 11. Time will tell.

Socialized medicine and free speech

A Norwegian doctor is the subject of an ethics complaint for publically objecting to rationing of medical care. The doctor, Sverre Kjeldsen, disagreed witht the government dictating that cheap diuretics had to be used as the first line agents in patients with hypertension.

The news report that provoked the case was a front page news story in a Norwegian national newspaper, Dagbladet, published on 11 February 2004. In the report Sverre Kjeldsen, professor of cardiology at the University of Oslo, was quoted as saying that “the authorities urge us to kill the patients with pure rat poison,” in an article that suggested that high doses of cheap thiazides worked in a similar way to rat poison.

The news story came after a change in drug regulations made by the Norwegian parliament in 2004, making low dosage thiazides the treatment of first choice for the management of hypertension. Doctors have to prescribe them unless they can give an explicit medical reason for making another choice

The journalist got the story badly wrong as thiazides do not work like rat poison; instead, a common medication to prevent clots (aka "thin the blood") called warfarin (or coumadin) is also used as a rat poison (more here).

I don't have an informed opinion on what medicine should be used first for hypertension, but I find it troubling that critics of government dictated health care decisions face "ethics" charges for speaking out.

South Korean stem cell "breakthrough"

The wheels are coming off:

A growing number of scientists say independent testing is needed to resolve charges that South Korean researchers fabricated experimental findings in two landmark papers on stem cells derived from cloned human embryos.

A group of eight leading researchers, led by Ian Wilmut, the Scottish biologist who cloned Dolly the sheep eight years ago, is urging Woo-Suk Hwang and his cloning team to submit samples of the embryonic stem cell lines and of the cell donors for genetic analysis.

I've posted previously about the issues involved, but at this point I'd have no faith in this report, and very little in previous work from the group.

If you were accused of a crime and were innocent wouldn't you be eager to give DNA that could clear you? If the work is good, why would Hwang et al. not agree to independent verification?

UPDATE: The wheels are all the way off:

A doctor who provided human eggs for research by cloning pioneer Hwang Woo-suk said in a broadcast Thursday that the South Korean scientist agreed to withdraw a key research paper because most of the stem cells produced for the article were faked.

Roh Sung-il, chairman of the board at Mizmedi Hospital, told KBS television that Hwang had agreed to ask the journal Science to withdraw the paper, published in June to international acclaim. Roh was one of the co-authors of the article that detailed how individual stem cell colonies were created for 11 patients through cloning.

Remeber, you heard it here first!

Seriuosly, I always wonder why people fake these kind of high profile breakthroughs. You know others will try to replicate it and fail. Better to fake data in some obscure area that no one will ever care about or try to replicate. Of course even better to just do the actual work to start.

Health insurance as cake

Two excellent articles from Arnold Kling on what should be done about the cost of health insurance, which, as he points out, really means the cost of health care:

The cost of health insurance has been rising, leading to well-publicized problems in the employer-provided health insurance system and increasing numbers of uninsured. But blaming insurance companies for that is like saying that the calories in a double-fudge chocolate cake are all in the icing.

The cake of health care expenses consists of health care services -- doctor visits, surgeries, and all the rest. The icing consists of health insurance -- administrative costs, profits and all that. In dollar terms, the icing represents less than ten percent of the iced cake.

Many proposals to reform health care finance mistake the icing for the whole cake.

Of course many what many advocates of "reform" really want is wholesale rationing of care. But they don't think it's fair that some would pay for care outside the system, so they need to go to single payer to disallow that.

Kling makes eminently sensible proposals for catastrophic coverage (covering care >10,000K per year per person), pointing out that current policies are akin to car insurance that pays for gasoline and oil changes.

I agree, but also think that at some point we must recognize that a system in which everyone is entitled to the care the richest/most desiring of care are willing to pay for is unsustainable. I'll try to post more on this later.

Kling proposes truly catastrophic coverage be mandatory and that other health care be paid for directly by consumers. This would certainly lead to an end to the current view that health care is a "free good." Right now, none of my patients has any idea how much a visit to me costs, how much skin testing is, etc. Why? Because they aren't paying.

I was a bit disappointed that Kling didn't address health care savings accounts (HSAs) which allow workers to accumulate health care dollars pre-tax and carry them over year to year (unlike the ridiculous current flexible spending accounts where you forfeit your money if you don't spend it, encouraging unnecessary expenditures) coupled with high deductible catastrophic coverage.

Are twins stupid?

A study from the BMJ says maybe:

At age 7, the mean IQ score of twins was 5.3 points lower (95% confidence interval 1.5 to 9.1) and at age 9, 6.0 points lower (1.7 to 10.2) than that of singletons in the same family

Of course twins tend to be born earlier and smaller than single births, which could account for some of the discrepancy. Indeed, correcting for these factors narrowed the gap to 2.5-4 IQ points with confidence intervals that overlapped zero and hence could have been due to chance. Of course, this only explains the difference, doesn't eliminate it.

Even 6 IQ points is not a huge number for an individual, and these are averages. Nonetheless, I'd think this study merits some consideration when we think about the effect of fertility treatments which have led to an increase in twins, triples etc.

People unclear on the concept

The mayor of this Brazilian farm town has proposed a solution: outlaw death. Mayor Roberto Pereira da Silva's proposal to the Town Council asks residents to "take good care of your health in order not to die" and warns that "infractors will be held responsible for their acts."

To be fair it sounds like the mayor knows this is preposterous and the the whole thing is intended to protest a federal ban on building a new cemetery

Genes, chemicals, and cancer

Two articles in the NYTimes today about cancer and what causes it, one focusing on environmental exposure to chemicals and the other on a new initiative to comprehensively examine the genes involved in various cancers.

In contrast to much of the hysteria out there about environmental exposures, the first article points out how little evidence there is linking environmental exposures to cancer:

Rates of cancer have been steadily dropping for 50 years, if tobacco-related cancers are taken out of the equation, said Prof. Richard Peto, an epidemiologist and a biostatistician at Oxford University.

What appear as increases in cancers of the breast and prostate, Dr. Peto added, are in fact artifacts of increased screening. When healthy people are screened, the tests find not only cancers that would be deadly if untreated, but also a certain percentage of tumors that would never cause problems if let alone.

His analysis of cancer statistics leads Dr. Peto to this firm conclusion: "Pollution is not a major determinant of U.S. cancer rates."

The article goes on to, in a nice way, expose the lack of sophistication of many "believers" in the exposure-cancer risk. Not being scientists, they don't have any evidence, but rely instead on emotion:

Barbara Brenner, executive director of the Breast Cancer Action Coalition, an advocacy group in San Francisco, said that at the very least people should look for the least toxic alternative to chemicals in common use that may cause cancer.

Having had breast cancer twice, Ms. Brenner is impassioned by the cause. "I have a firsthand experience, and I would do anything - anything - to keep someone else from having that experience," she said.

Of course, how do you know what the least toxic alternative is?

None of this is to say that the environment plays no role in cancer, it certainly can (think second hand tobacco smoke), but that the role is likely small. The article describes some ongoing research into unravelling the connection.

The second article details a new initiative to find genetic mutations in specific cancers. The search has been spurred on by the success of imatinib (Gleevac) which inhibits a specific altered protein in certain leukemias and GI tumors. It has been a stunning success, the exemplar of the utility of targeted molecular therapies for cancer.

The new initiative is huge, a 3 year pilot study budgeted for $100million to focus on 2 or 3 types of cancer (you can bet breast will be one). The full study would run 9 years and cost more than a billion dollars.

This seems like a lot of money, given how many other smaller research projects you could fund.

Korean stem cells

More problems for Dr. Hwang Woo-suk and his claims of having created multiple human stem cell lines, including from individuals with a variety of diseases:

University of Pittsburgh researcher Gerald Schatten has demanded that the journal Science remove him as the senior author of a report it published in June to international acclaim that detailed how individual stem cell colonies were created for 11 patients through cloning.

"My careful re-evaluations of published figures and tables, along with new problematic information, now casts substantial doubts about the paper's accuracy," Schatten wrote in a letter to Science released late Tuesday by the university. "Over the weekend, I received allegations from someone involved with the experiments that certain elements of the report may be fabricated."

It is never a good sign when your collaborators start acting like rats abandoning a sinking ship. At this point I'd have no faith in anything Hwang has published, it's probably all faked.

You'd think Schatten would have "carefully" evaluated the figures and tables before he agreed to be senior author. But by bailing now, he'll probably save his own career given there is no evidence (and no reason to believe) he knew about the fabrication. Given that if it were accurate, being senior author on the paper might merit the Nobel prize, you can be sure Schatten wouldn't be bailing if he wasn't sure the data were faked and/or wrong.

To review, in an apparent landmark paper in Science this June Hwang (and Schatten) claimed to have created embryonic stem cell lines from 11 patients with a variety of diseases. Then he "resigned" based on reports that, contrary to his claims, several subordinates had served as egg donors and other donors had been paid. At the time, I suspected something else was afoot (it is always about you isn't it? - ed).

Now, it is clear that some of the photos published as part of the Science paper were copies of one another, even though they were represented as being from separate patients. Hwang pleaded a clerical error, but now apparently a member of Hwang's group have alleged fraud in generating the figures; that is, the photos were intentionally misrepresented, not duplicated due to a simple error.

In general, scientists are very cautious, particularly with this kind of grountd-breaking research. I can't imagine that photos were inadvertently duplicated and no one in Hwang's group noticed. It just doesn't add up.

Sick, but funny

The new Scott Peterson book for kids

(Hat tip Ace of Spades)

Grand Rounds 2:12

is here.

Snowy Pittsburgh

Sorry for the relatively light posting the last few days, but I've been busy!

We are getting our first story floors redone starting Thursday, which meant we spent much of the weekend moving furniture, boxes, etc. up or downstairs. Lots of carrying as well as general picking up.



Add to that a bunch of snow this weekend (as any who watched the Bears-Steelers game today will be able to attest too) which I spent time shoveling, a holiday party Friday night, Colin's basketball game yesterday and 2 research projects, one of which I'm starting the IRB (institutional review board) process with and the other in the midst of data collection and I haven't had time for much else, including blogging. Well, maybe for a snowball fight or two!

These pictures are views from the back of our house down into Oakland, which is the Pittsburgh neighborhood all the universities (University of Pittsburgh and Carnegie-Mellon) and hospitals are located.

The large tower is called the Cathedral of Learning and is the iconic image of Pitt, as the University of Pittsburgh is commonly known. It is the second tallest academic building in the world, after a tower at Moscow State University.

We are getting great sunrises this time of year (we face roughly south) and I'll try to post some photos of those as well

Abortion and crime

I have not (yet) read Freakonomics, but I like the concept of using economics (and science in general) to address practical issues.

But it appears that Steven Levitt may have screwed up when he concluded that legalizing abortion substantially reduced the crime rate. Apparently, he and co-author John Donahue committed an “inadvertent but serious computer programming error” which meant they never actually did one of the controls they claimed.

Other researchers have had trouble substantiating a link between the legalization of abortion in 1973 and the subsequent drop in crime as children born subseqently (or not) came of age.

The article is short (and like most things in the Economist) well-written and interesting; it has the clever title "Oops-onomics" to boot. Unlike most Economist articles, however, it is available online.

I should note I don't find this particular issue particularly compelling. My views on abortion, that it is not the government's business, would be the same even if legalizing abortion increased crime.

Rationing of health care in Britain

A decision by NHS trusts in Suffolk to deny replacement joints to obese patients has led to concerns that other financially stretched NHS trusts could take similar steps to ration treatment.
From this weeks BMJ:

As part of a series of new "thresholds" to treatment, three primary care trusts in east Suffolk—Ipswich, Suffolk Coastal, and Central Suffolk—have announced that patients will no longer be considered for hip or knee joint replacements if they have a body mass index (BMI) >30. . . .

Dr Keeble said that serious financial pressures were behind the decision: "We cannot pretend that this work wasn’t stimulated by the pressing financial problems of the NHS in east Suffolk."

UPDATE: Aggravated Doc Surg has further thoughts here

Uh oh

Computerized physician order entry (CPOE) is looked on as a panacea which will decrease medical error, improve efficiemcy, and improve patient safety. Only it looks like it has some major, unintended consequences, like increasing death according to an article titled "Unexpected Increased Mortality After Implementation of a Commercially Sold Computerized Physician Order Entry System: in this months Pediatrics.

The authors, from my institution, studied the outcomes of kids who were transported to Children's Hospital of Pittsburgh (CHP) for care. Transport is used to move patients who need more specialized care than the referring institution can provide. In Western Pennsylvania, CHP is the primary site for tertiary (i.e. highly specialized) pediatric care, so many smaller hospitals will transport kids. Reasons can range from need for ICU level care (most outside hospitals don't have pediatric ICUs) to requirment for specialist input. Kids who are transported range from not that sick to in extremis, with the overall level of illness being less than you might expect. To be fair, community hospitals have a real range of expertise, so some just aren't comfortable with really sick kids. In addition, it is generally better to transport before someone is in extremis.

Anyway, the findings were suprising and alarming:

Among 1942 children who were referred and admitted for specialized care during the study period, 75 died, accounting for an overall mortality rate of 3.86%. Univariate analysis revealed that mortality rate significantly increased from 2.80% (39 of 1394) before CPOE implementation to 6.57% (36 of 548) after CPOE implementation. Multivariate analysis revealed that CPOE remained independently associated with increased odds of mortality (odds ratio: 3.28; 95% confidence interval: 1.94–5.55) after adjustment for other mortality covariables.

Put in plain English, kids transported after implementation of CPOE had a more than 3 fold increased risk of death. Ouch

The authors go on to speculate on what went wrong. They conclude that doctors and nurses spent more time sitting at the computer and less taking care of patients:

The usual "chain of events" that occurred when a patient was admitted through our transport system was altered after CPOE implementation. Before implementation of CPOE, after radio contact with the transport team, the ICU fellow was allowed to order critical medications/drips, which then were prepared by the bedside ICU nurse in anticipation of patient arrival. When needed, the ICU fellow could also make arrangements for the patient to receive an emergent diagnostic imaging study before coming into the ICU. A full set of admission orders could be written and ready before patient arrival. After CPOE implementation, order entry was not allowed until after the patient had physically arrived to the hospital and been fully registered into the system, leading to potential delays in new therapies and diagnostic testing . . . .

This initial time burden seemed to change the organization of bedside care. Before CPOE implementation, physicians and nurses converged at the patient's bedside to stabilize the patient. After CPOE implementation, while 1 physician continued to direct medical management, a second physician was often needed solely to enter orders into the computer during the first 15 minutes to 1 hour if a patient arrived in extremis. Downstream from order entry, bedside nurses were no longer allowed to grab critical medications from a satellite medication dispenser located in the ICU because as part of CPOE implementation, all medications, including vasoactive agents and antibiotics, became centrally located within the pharmacy department. The priority to fill a medication order was assigned by the pharmacy department's algorithm. Furthermore, because pharmacy could not process medication orders until they had been activated, ICU nurses also spent significant amounts of time at a separate computer terminal and away from the bedside. When the pharmacist accessed the patient CPOE to process an order, the physician and the nurse were "locked out," further delaying additional order entry.

Before CPOE implementation, the physician expressed an intended order either through direct oral communication or by writing it at the patient's bedside (often reinforced with direct oral communication), with the latter giving the nurse a visual cue that a new order had been placed. The nurse had the opportunity to provide immediate feedback, which sometimes resulted in a necessary revision of that order. In addition, these face-to-face interactions often fostered discussions that were relevant to patient care and management. After CPOE implementation, because order entry and activation occurred through a computer interface, often separated by several bed spaces or separate ICU pods, the opportunities for such face-to-face physician–nurse communication were diminished.

They go on to note that they've made some changes (orders can be entered before patient arrives), but many problems still remain. A second physician still needs to sit and enter orders and there remains an unacceptable lag in getting medications started.

In the past I've defended CPOE, but it is hard to do so after this study. Of course, many of the problems can be potentially overcome (e.g. by preentered "sets" of orders that often go together) and the centralization of pharmacy is really a separate issue, but I still find this article very troubling.

A walk on the wild side

is the title of an interesting article in last week's BMJ about emerging zoonotic diseases. Zoonotic diseases (aka zoonoses) are diseases spread from animals to humans. Malaria would be a classic zoonoses, while some diseases that are now endemic in humans, like measles, probably evolved from zoonotic diseases.

According to the article 75% of emerging infectious diseases are zoonotic, including avian flu, Lyme disease, West Nile and Ebola viruses and some I hadn't ever heard of, like Nipah virus. This is spread to humans by some combination of pigs, dogs and bats (like in the picture). It killed 106 people in Malaysia, but never spread from human to human. A similar virus has emerged in Bangladesh, this one apparently capable of human to human spread.

Why now? One answer is that we are increasingly encroaching into wild lands. I am skeptical about this as humans have always been encroaching on something. I think these kind of disease outbreaks have always occurred, we just notice them more now. Even 100 years ago if 100 people died of an unknown disease, no one really took notice. Now the CDC sends in its hot-shot epidemiologists and we find out what is causing it. More worringly, the rise in air travel has made it a lot more likely that a small outbreak will spread (like SARS) rather than just burn itself out.

Grand Rounds 2:11

here at The examining room of Dr. Charles

In the US on the other hand. . .

UK patients want fast access to good care

Headline from the BMJ 11/19

Quote of the week

In regards to the ridiculous "War on Christmas" meme:

"At our home, we celebrate Christmas as the birth of Christ, but I'm not offended by Happy Holidays" said Christy Taylor, of Clarington, Ohio. "I'm not looking for a validation of my beliefs from Sears."

As a practicing Catholic, that gets it exactly right.

Runner-up: "When you get old, if you can't find a job do you have to go to grad school?" my 5 year old daughter, Isabel.

Not this year

I wasn't selected in the Western States lottery.

I'm planning on doing this race, the 70.5 mile Laurel Highlands Ultra instead. And maybe a return trip to Arkansas to try to improve on my effort there.

I'm also now a "two-time loser" and have qualified for the 2007 race (the qualifying period began 10/1/05), so if I want to do the race in 2007, I'm in.

Face transplantation

This ha been all over the news, but I don't know much enough about it to have much to say.

Barbados Butterfly, in contrast, does know enough, and has lots of useful links, including ones about the ethics.

Adrenal insufficiency

As shown in the figure on the right, the adrenal gland produces cortisol in response to ACTH (Adrenocorticotropin hormone) produced by the pituitary.

Cortisol is the bodies very own corticosteroid, doing things like supporting blood pressure and suppressing inflammation. Prednisone and dexamethasone are other corticosteroids given pharmacologically. If you don't make your own cortisol, you die unless you get replacement therapy. Tuberculosis is the most common cause of adrenal insufficiency (i.e. cortisol deficiency) worldwide, but autoimmune attack on the adrenal gland is the most common cause in the US. In these cases adrenal insufficiency usually develops slowly, giving the body a chance to adapt. In overwhelming infection, for example, the adrenal can be deprived of blood supply, infarct and cortisol production can be lost suddenly, leading to death unless someone recognizes what is going on and gives replacment therapy.

More rarely, the pituitary or hypothalamus can fail, leading to no ACTH and no cortisol, even though the adrenal is working normally. These are termend secondary (pituitary) and tertiary (hypothalamus) adrenal insufficiency. To distinguish between primary and higher order adrenal insufficiency, endocrinologists do something called an ACTH stimulation test where they inject ACTH and look for a rise in cortisol (endocrinologists love doing tests to either stimulate or suppress secretion of hormones). There are both regular and low-dose ACTH stim tests, but until now, I didn't know why. According to an article in the JAMA (no free text):

The choice of the 250-µg dose is based solely on the fact that ACTH comes in 250-µg vials. However, with this dose, ACTH reaches plasma levels that are approximately 1000 times the values observed in maximally stressed healthy individuals, thereby potentially causing a falsely normal cortisol response by an adrenal gland that is in fact partially impaired

Glad to see they were thinking when they came up with the original test! Hence the development of "low-dose" ACTH stim testss which use just 1ug, a more physiologic dose.

As an allergist, my biggest concern is secondary adrenal insufficiency caused by prolonged use of steroid medications like prednisone. Sometimes even high doses of inhaled steroids can lead to adrenal suppression (patients are on so much steroid medicine the adrenal stops making your own).

Note the steroids discussed here are distinct from the steroids used by most pro athletes.

This "patient page," which accompanies the JAMA article gives more info on adrenal insufficiency

Natural selection at work

This is funny.

I doubt, however, that creationists will refuse Tamiflu if the avian flu does come

Market based health care reform

is the proposal of this article (which only those who subscribe or have institutional access can actually read). It is compelling about how the government makes things worse:

Unfortunately, a handful of U.S. public policies prevent markets for health services from accomplishing this objective. In two areas—tax policy and health insurance regulation—government policy has actively hindered the operation of markets. In three other areas—the provision of health care information, the enforcement of antitrust laws, and medical malpractice rules—government policy has failed to adequately promote the proper functioning of markets. In doing so, it has contributed to the spread of wasteful (inefficient) medical practice, rising health care costs, and rising rates of uninsurance. Although makingmarkets work is not a silver bullet, it is a necessary first step.

They point out that making employer sponsored health insurance but not other forms of spending on health tax-deductible has led to an overreliance on insurance as opposed to out of pocket spending. Solution: make out of pocket spending and individually purchased insurance tax-deductible as well, and give tax credits for the poor to buy insurance. Health savings accounts would also be expanded.

They go on to talk about how over-regulation has made the insurance market non-competitive. For example:

One particular form of state insurance regulation—benefit mandates—has expanded dramatically over the past forty years. In 1965 there were fewer than a dozen such mandates throughout the fifty states and the District of Columbia; by 2003 the number had risen to more than 1,800. Benefit mandates now require coverage of off-label drug use (thirty-seven states), acupuncture (eleven states), and chiropractic (forty-seven states). According to the Congressional Budget Office (CBO), states’ benefit mandates have raised the cost of a typical insurance plan 5–15 percent. According to one study, about one-quarter of those who lack coverage are uninsured because of the cost of state mandates alone.

So insurers in 47 states are forbidden from offering policies that exclude chiropractic. I wish I had the choice to save money by forgoing this form of health care. They propose a federal (versus the current state) market for insurance to make things simpler and cut back on this kind of wasteful regulation (although I'm skeptical that Congress would do any better).

If you can get access, read the article. Whatever one thinks about universal health care, I think proposals for a single payer are not realistic in the current political environment, so this kind of incremental reform is what we need.

You heard it here first

Researchers with South Korea's cloning pioneer Hwang Woo-Suk rejected reports suggesting that some of his landmark research may have been faked. A South Korean TV station confirmed it was working on a report that would challenge whether Hwang's work was genuine.

Here is a quote from my post last Friday:

I have no inside information, but I suspect there are some other problems with the work of this team. Their results have been controversial and hard to replicate, now the group's leader is stepping down over what might be considered signficiant but not overwhelming ethical issues. . . .

I would not be surprised to learn soon that there are significant questons about the accuracy of the South Koreans data.

Of course today's news report also quotes Science editor-in-chief "Donna Kennedy" when the well known editor-in-chief is actually Donald Kennedy

Outsourcing science

An interesting post from The Daily Transcript suggesting we are making it too hard for scientists to immigrate and as a result an increasing amount of science will be done elsewhere.

While I agree that we need to make it easier for scientists to come here, I see the fact that more choose to return to their home country rather than stay in the US as a good thing in that it indicates the scientific enterprise is expanding.

Science is not a zer0-sum activity, especially from the perspecitve of socities. The invention of the transistor in California benefited the whole world, not just the US. Biotech and engineering research in, say, India, will benefit people all over the world as well.

In the past, research has been dominated by the US, Western Europe and to a lesser extent Australia and Japan. This is changing, but the rise of top notch research elsewhere will only be a good thing.

I do agree that slipping US commitment to research is a bad thing.