Distinguishing statistical significance from clinical significance

In the past post I was talking about the difference between statistical and clinical significance and how many reported studies have apparently mixed up the two. Now here's a nice case where people seem to be aware of the difference. The article is also interesting in its own right. It deals with AstraZeneca's cholesterol lowering statin drug Crestor being approved by the FDA as a preventive measure for heart attacks and stroke. If this works out Crestor could be a real cash cow for the company since its patent does not expire till 2016 (unlike Lipitor which is going to hit Pfizer hard next year).

The problem seems to be that prescription of the drug would be based on high levels not of cholesterol but of a protein named C-Reactive Protein whose high levels are supposed to constitute an inflammatory marker for high cholesterol. The CRP-inflammation-cholesterol connection is widely believed to hold but there is no consensus in the medical community about the exact causative link (many factors can lead to high CRP levels).

The more important recent issue seems to be a study published in The Lancet which indicates a 9% increased risk of Type 2 diabetes associated with Crestor. As usual the question is whether these risks outweigh the benefits. The Crestor trial was typical of heart disease trials and involved a large population of 18,000 subjects. As the article notes, statistical significance in the reduction of heart attacks in this population does not necessarily translate to clinical significance:

Critics said the claim of cutting heart disease risk in half — repeated in news reports nationwide — may have misled some doctors and consumers because the patients were so healthy that they had little risk to begin with.

The rate of heart attacks, for example, was 0.37 percent, or 68 patients out of 8,901 who took a sugar pill. Among the Crestor patients it was 0.17 percent, or 31 patients. That 55 percent relative difference between the two groups translates to only 0.2 percentage points in absolute terms — or 2 people out of 1,000.

Stated another way, 500 people would need to be treated with Crestor for a year to avoid one usually survivable heart attack. Stroke numbers were similar.

“That’s statistically significant but not clinically significant,” said Dr. Steven W. Seiden, a cardiologist in Rockville Centre, N.Y., who is one of many practicing cardiologists closely following the issue. At $3.50 a pill, the cost of prescribing Crestor to 500 people for a year would be $638,000 to prevent one heart attack.

Is it worth it? AstraZeneca and the F.D.A. have concluded it is.

Others disagree.

“The benefit is vanishingly small,” Dr. Seiden said. “It just turns a lot of healthy people into patients and commits them to a lifetime of medication.”

To some this may seem indeed like a drug of the affluent. Only time will tell.

The age of radical intolerance; the firing of David Frum

Of all the articles I read about the health care bill, the best came from David Frum, not a liberal but a conservative who was a speechwriter for Bush. The article so persuasively scolds the Republicans and documents what they did wrong that it's worth copying it out in its entirety (italics mine).

Conservatives and Republicans today suffered their most crushing legislative defeat since the 1960s.

It’s hard to exaggerate the magnitude of the disaster. Conservatives may cheer themselves that they’ll compensate for today’s expected vote with a big win in the November 2010 elections. But:

(1) It’s a good bet that conservatives are over-optimistic about November – by then the economy will have improved and the immediate goodies in the healthcare bill will be reaching key voting blocs.

(2) So what? Legislative majorities come and go. This healthcare bill is forever. A win in November is very poor compensation for this debacle now.

So far, I think a lot of conservatives will agree with me. Now comes the hard lesson:

A huge part of the blame for today’s disaster attaches to conservatives and Republicans ourselves.

At the beginning of this process we made a strategic decision: unlike, say, Democrats in 2001 when President Bush proposed his first tax cut, we would make no deal with the administration. No negotiations, no compromise, nothing. We were going for all the marbles. This would be Obama’s Waterloo – just as healthcare was Clinton’s in 1994.

Only, the hardliners overlooked a few key facts: Obama was elected with 53% of the vote, not Clinton’s 42%. The liberal block within the Democratic congressional caucus is bigger and stronger than it was in 1993-94. And of course the Democrats also remember their history, and also remember the consequences of their 1994 failure.

This time, when we went for all the marbles, we ended with none.

Could a deal have been reached? Who knows? But we do know that the gap between this plan and traditional Republican ideas is not very big. The Obama plan has a broad family resemblance to Mitt Romney’s Massachusetts plan. It builds on ideas developed at the Heritage Foundation in the early 1990s that formed the basis for Republican counter-proposals to Clintoncare in 1993-1994.

Barack Obama badly wanted Republican votes for his plan. Could we have leveraged his desire to align the plan more closely with conservative views? To finance it without redistributive taxes on productive enterprise – without weighing so heavily on small business – without expanding Medicaid? Too late now. They are all the law.

No illusions please: This bill will not be repealed. Even if Republicans scored a 1994 style landslide in November, how many votes could we muster to re-open the “doughnut hole” and charge seniors more for prescription drugs? How many votes to re-allow insurers to rescind policies when they discover a pre-existing condition? How many votes to banish 25 year olds from their parents’ insurance coverage? And even if the votes were there – would President Obama sign such a repeal?

We followed the most radical voices in the party and the movement, and they led us to abject and irreversible defeat.

There were leaders who knew better, who would have liked to deal. But they were trapped. Conservative talkers on Fox and talk radio had whipped the Republican voting base into such a frenzy that deal-making was rendered impossible. How do you negotiate with somebody who wants to murder your grandmother? Or – more exactly – with somebody whom your voters have been persuaded to believe wants to murder their grandmother?

I’ve been on a soapbox for months now about the harm that our overheated talk is doing to us. Yes it mobilizes supporters – but by mobilizing them with hysterical accusations and pseudo-information, overheated talk has made it impossible for representatives to represent and elected leaders to lead. The real leaders are on TV and radio, and they have very different imperatives from people in government. Talk radio thrives on confrontation and recrimination. When Rush Limbaugh said that he wanted President Obama to fail, he was intelligently explaining his own interests. What he omitted to say – but what is equally true – is that he also wants Republicans to fail. If Republicans succeed – if they govern successfully in office and negotiate attractive compromises out of office – Rush’s listeners get less angry. And if they are less angry, they listen to the radio less, and hear fewer ads for Sleepnumber beds.

So today’s defeat for free-market economics and Republican values is a huge win for the conservative entertainment industry. Their listeners and viewers will now be even more enraged, even more frustrated, even more disappointed in everybody except the responsibility-free talkers on television and radio. For them, it’s mission accomplished. For the cause they purport to represent, it’s Waterloo all right: ours.

Follow David Frum on Twitter: @davidfrum

Due to the high volume of traffic this piece is receiving, comments have been suspended. We will restore comments once traffic returns to normal levels.

Note the last statement.

Yesterday, David Frum was fired from the American Enterprise Institute where he worked for writing this article.

There is no better instance than this of the intolerance, bigotry and utter inability to compromise that have become the defining features of the Republican party. As CNN analyst Jeff Toobin put it, "one of the biggest changes in the politics of this country in the last thirty years has been the disappearance of the moderate Republican".

Even if they had any good points against the Democrats and the health care bill (and it would not have been difficult for them to keep pressing the economic shortcomings) those points have been completely drowned out by the vile playground behavior displayed by Republican activists over the last year, some of which was actively supported by the Reps and most of which was tacitly endorsed through silence. As Frum noted on CNN, there were actually some real chances for the Republicans to adopt a reasoned approach with which they could have gotten in some concessions into the bill. But as it turned out, they were only interested in fear-mongering, hate speech, doomsday predictions and pessimism; the "party of no" indeed. All they have done is to oppose, threaten and warn about dire consequences without providing constructive and balanced criticism aimed at compromise. In the process they have threatened their own existence; as many conservatives themselves have noted, support for the Republicans is going to be severely crippled once the "death panels" and the government takeover fail to materialize.

With such behavior, the Democrats did not have a single obligation to compromise. In fact they must have been smiling in glee all the time; the Republicans with their vile behavior gave them the perfect excuse not to negotiate, and they were handed a conscience-free health care bill by their opponents on a golden plate. One only wishes Obama had done this earlier.

We can only believe, and indeed hope, that this trend will continue in the absence of evidence that the Reps have any intention at all of being more civilized.

Middle Ages March

As far as possible I try to avoid writing about the teaching of evolution and opposition to climate change in this country because of their overly politicized nature, but this piece in the NYT is one that no one can wisely ignore. It details a growing movement to conflate rejection of evolution with rejection of climate change that many people, and sadly especially conservatives, are spearheading. States are trying to introduce bills encouraging the teaching of “all sides” of scientific issues. Conservative politicians are advocating for students to know “all the facts”. But nobody is fooled by these thinly veiled promotions of ignorance...


...Read the rest of this post on the Desipundit blog

A promising book falls apart

The atomic bombings of Hiroshima and Nagasaki were such horrific and singular historical events that any new retelling of them deserves to be read seriously. It was with such thoughts that I picked up Charles Pellegrino's "The Last Train From Hiroshima". The first few pages were enough to glue me to my chair. In an almost poetically clinical manner Mr. Pellegrino describes the effects of the bomb on human beings in the first few seconds after the detonation. His accounts of people evaporating and the "iron in their blood separating" while their friends who were protected in "shock bubbles" that were mere feet away were absolutely riveting.

Yet in spite of this promising start I could not shake off the gnawing feeling that something was wrong. For instance I have read my fair share of atomic history and so I was astonished to not find absolutely any mention of William "Deke" Parsons in the book. Parsons was a physicist and naval captain who played a part in designing the 'gun type' Little Boy and was instrumental in arming the Hiroshima bomb on flight. Earlier his hands had almost bled from practicing the arming, which had to occur at a precise given time twenty five thousand feet up in the air on the 'Enola Gay'. There is a superb account of him in Stephen Walker's "Shockwave: Countdown to Hiroshima". In response to a comment I made on Amazon, Mr. Pellegrino replied that he did not mention Parsons simply because he has already been part of so many accounts, which to me does not seem a good enough reason for the exclusion. Apart from this omission I also noted Mr. Pellegrino's statement that Stanley Miller and his advisor Harold Urey won a Nobel Prize for their classic experiment pioneering origin of life research. Urey won a Nobel, but for his discovery of deuterium. Miller was nominated for the prize a few times, and in my opinion should have won it.

Alas, the riveting start of the book and the author's accounts have now virtually fallen apart. In two New York Times articles it has been reported that the most egregious error in the book consists of the story of one Joseph Fuoco who was supposed to be on one of the planes. Mr. Fuoco makes several appearances in the book, and I had found myself scratching my head when I read his accounts, having never heard of him before. The New York Times and other resources discovered that Mr. Fuoco never took part in the bombing missions. Instead the relevant man is one Charles Corliss who has not been mentioned in the book. Astonishingly, Mr. Fuoco seems to have completely duped the author as Mr. Pellegrino himself admitted; he submitted several photographs and letters to Mr. Pellegrino as proof of his role in the mission, including a letter of commendation from President Truman. Clearly Mr. Fuoco proved to be a remarkably facile con man.

But sadly, this and many other errors have cast serious doubt on the validity of the book. This is a pity since Mr. Pellegrino is an interesting writer who has written books on diverse topics ranging from Jesus's tomb to Atlantis . As of now the publisher (Henry Holt) has a blurb on the Amazon page saying that further printing and shipping of the book has been halted (which makes me cherish my first printing copy). Even Mr. Pellegrino's PhD. from Victoria University in New Zealand is being questioned. As usual, an otherwise fine author seems to have sullied his name by sloppy writing on an important topic.