Rejected by the New England Journal of Medicine in 2015.
The text below is more expansive than the version submitted.

Case 22-2015 [1] marks a sad nadir for the Journal’s clinicopathological conferences. The main problem is that the discussant, after a two-paragraph differential diagnosis, used an Internet search engine to extend the differential, justifying this maneuver because it was “a challenging case.”

While physicians often do need help, and should not be afraid to seek it, it’s easy to see why this case’s approach ill suits a teaching exercise…. Every large hospital has at least one gray-haired master diagnostician on its staff who serves as a walking, talking “search engine” for tough cases. Asking that diagnostician to help with a challenging case is no different than asking a computer search engine, but this is not the strategy on which CPCs are based. No CPC in the past has ever had the discussant give up after just two paragraphs and ask a master diagnostician to bail him out. Yet that is what happened here.

Perhaps the editors believe that comments from the patient’s attending physician served as a replacement for the traditional diagnostic discussion. Of course this cannot be true. In a diagnostic-type of CPC (there are now many types of CPC), the whole point of the discussion is to have a clinician deconstruct the case in a prospective vein. Otherwise, the exercise becomes merely a memoir for the attending physician, and that is what we have here: entire categories of disease eliminated by weak heuristics (e.g. no infection because no response to antibiotics – systemic mycosis, anyone?) with little of the intellectual rigor that makes the diagnostic CPCs so great, and none of the nuance associated with disease entities that makes the CPCs so interesting.

There are multiple other unfortunate aspects to this CPC.

First, by employing a deus ex machina (literally) to reach the right diagnosis, the NEJM editors and the discussant forgot the main purpose of the CPCs, as stated more than 50 years ago by Castleman and Dudley: “The clinicopathological conferences remain an exercise in deductive reasoning and clinicopathological correlation. It is less important to pinpoint the correct diagnosis than to present a logical and instructive analysis of the pertinent conditions involved” [2]. The present CPC not only has comparatively miniscule teaching value, but it actually negates the leadership role that CPCs have in the past served. It serves only as an exemplar of intellectual laziness.

Second, and worse, the discussant’s diagnostic approach was fundamentally flawed. When the search engine’s first 10 results all pointed to the same disorder, the discussant abandoned the search for other explanations, claiming “there are no other obvious diagnostic considerations” and committing the single most common cognitive error in diagnosis: premature closure [3]. Medicine has great mimics that one ignores at one’s peril [4]. There is also the ever-present possibility that Occam’s razor fails, and that two disease entities are at work. Moreover, if 10 of the first 10 search engine results point to the same diagnosis, then the skill in using a search engine in this case would have been using it to identify a second and third item for the differential. The discussant was too lazy to overcome any of these pitfalls.

Third, the discussant’s lazy approach meant that relevant information related to the case was omitted from the CPC discussion. For example:

  • He picked hyperferritinemia as one of the key terms presented to the search engine. Although the literature on adult onset Still disease does indeed frequently mention high ferritin levels, the discussant should have clarified that ferritin is simply acting as an acute phase reactant, meaning that several other lab tests could yield the same diagnostic tip-off [5]. It would also have been useful to note the sensitivity and specificity of hyperferritinemia.

  • How did the discussant pick the terms to present to the search engine? Supplying a different set of terms, picked from the patient’s many clinical abnormalities, leads to much different search engine results. Such a “sensitivity analysis” was an obvious topic for discussion.

  • The discussant did not address the fact that some search engines (e.g. Google) adjust the search results presented to a user based on the user’s past search history [6]. So, a rheumatologist is going to bias Google to return rheumatology results. It may not have mattered much in this case, but any person in medicine who uses a search engine for clinical purposes should know of this phenomenon.

Fourth, the diagnostic approach cannot be replicated in non-English languages because on-line resources in other languages will not only be different, but less comprehensive. Medicine is a universal profession and until now the CPCs have been universal teaching tools when translated into other languages. Marginalizing a large fraction of the world’s physicians is good for neither patients nor the profession.

Fifth, and most disheartening, the discussant described clinical reasoning as a “diagnostic test,” as if it were as far outside the reach of bedside medicine as an MRI scan or a laparotomy.

I can’t decide whether the NEJM published this CPC as a gimmick, or to serve notice that we are in a brave new world where careful thought is unnecessary in clinical medicine, or simply because they have never had a case of adult onset Still disease in a CPC and needed a novel mechanism to make it happen (because no pathologist involvement is present).

Although it was a game effort, the central mistake was forgetting the heritage of CPCs. As Castleman and Dudley also stated in 1960: “The clinicopathological conference has been adversely termed a `guessing game,’ but this is not true if the case has been selected wisely. The properly chosen case lends itself to a discussion of the differential diagnosis.” In this instance, there was effectively no discussion of the differential.

[1] Hunt DP, Scheske JA, Dudzinski DM, Arvikar SL. Case 22-2015. A 20-Year-Old Man with Sore Throat, Fever, Myalgias, and a Pericardial Effusion. N Engl J Med. 2015 Jul 16;373(3):263-71.   PubMed 26176384

[2] Castleman, Benjamin, M.D. and H. Robert Dudley, M.D., editors, Clinicopathological Conferences of the Massachusetts General Hospital, Selected Medical Cases, Little, Brown and Co., Boston, 1960, p. viii.

[3] Graber ML, Franklin N, Gordon R. Diagnostic Error in Internal Medicine. Arch Intern Med. 2005;165(13):1493-1499.

[4] Sotos JG. Zebra Cards: An Aid to Obscure Diagnosis. Philadelphia: American College of Physicians, 1991. Card GE-000. See and specifically card GE-000.



First published on on April 28, 2015

Think of all the trouble that computer hackers cause. Now imagine what DNA hackers could do.

In the future, DNA hackers won’t sneak viruses into your laptop and crash websites. Instead, they’ll sneak viruses into your body and crash you, and maybe billions of other people, too. They’ll do this by designing DNA sequences that code for new, never-before-seen, living viruses that spread from person to person as easily as measles, and that kill (or sicken) as inevitability as rabies.

Truly monstrous hackers will ensure your doctor cannot help you fight the virus, by engineering it so that off-the-self medicines and vaccines are ineffective. Medical science, caught flat-footed, will have only weeks to develop, test, produce, and distribute new vaccines and medicines before the exponential spread of the virus collapses social order world-wide. (Witness last year’s penetrating anxieties when just two people caught Ebola inside the U.S.)

With today’s science, engineering an Armageddon virus may still be impossible. But the progress of DNA technology in the 40 years since its invention has been spectacular and is accelerating. Remember the national-scale effort needed to sequence one human genome 15 years ago? Within a year it will cost you $500. By mail order. So, certainly, 40 years in the future, things that are now very hard or impossible will be easy.

And hackers are going to love DNA. Fundamentally, DNA is just a programming language for living tissues. DNA hackers will write programs for living cells to run, just like computer hackers write programs for computers to run. Today’s most leading-edge scientists have only started doing this, and there is no telling where it will go.

But when such techniques mature, zealots —– or brilliant but disturbed high-school students – will realize they can make self-propagating bioweapons targeting only redheads. Or blood members of the British Royal family. Or Basques. … Or dark-skinned people. Many testified that the apartheid South African government sought precisely such weapons in the 1980s, but that era’s rudimentary biotechnology stymied it. Not for much longer.

What to do? Scientists today are debating whether experiments on this path should be performed, but this responsible approach will not stop malevolent forces unconcerned with law or morals. Containing the technology will be impossible: unlike atomic weapons, our bodies contain all the elements needed to manufacture viruses.

There is only one solution: build a defense better than the offense – a defense that can detect, characterize and counter, on a national scale, any new viral or bacterial threat within 30 days of its appearance. Make it so hard to beat our defense that assembling the capital and talent needed to do so cannot occur surreptitiously.

This will be hard. Unbelievably hard. The aim is nothing less than the neutralization of every infectious disease, known and unknown. But it is an ambition matched by need, and it is science, not hubris.

Fortunately, cost is not a showstopper. Even if only partially successful, such a program – let us call it the New Apollo program, because Apollo was also the god of plagues – would generate so many wealth-producing discoveries in all branches of medicine that the overall cost of the program would be largely offset, not to mention the lives it would save directly.

Finally, consider the alternative, in which the continued existence of our planetary civilization depends on the sound judgment of teenagers. To avoid certain doom, the defense must get ahead and stay ahead, and we must start now.

First published on on March 24, 2015
In response to the question: What health policy would you like Washington to adopt?

In medical practice today, 99.99% of the experience that physicians gain in treating disease is flushed down the toilet. The government should adopt policies to capture that experience and make it available to all.

Experience is the bedrock of medical practice. In any given situation, doctors are most confident in their decisions if several other doctors have previously faced the same situation, and have carefully tabulated what they tried and how the patient fared.

Now that many physician practices have moved to electronic medical records – a mixed blessing, to be sure – the next and most important step is enabling clinical queries of the national experience in treating specific subsets of patients.

This would help someone like my friend Jeff, who must wear oxygen just to walk, because his heart is beating irregularly and too fast (“atrial fibrillation”). Jeff is 80, has significant lung disease from past smoking, has a stiff heart muscle, lives at an elevation of 6000 feet, and has psoriasis. All of those characteristics could be driving his disease in one way or another, but no medical textbook or clinical study in the world tells doctors how a man with all those characteristics is best treated for atrial fibrillation – because the situation is too detailed. Medical science has never been able to assemble and study a group of 100 men (or even 5) with atrial fibrillation who are 80-ish, have lung disease, have a stiff heart, live at 6000 feet, and have psoriasis.

A national query-system would allow Jeff’s doctors to instantly review the course of men just like Jeff, and understand which of the many possible treatments for atrial fibrillation has the best chance of success. Lacking such a system, Jeff’s doctors are trying one treatment after another, hunting for one that works for him – a slow process.

Full patient records are the key to this system, especially the evolution of a patient’s illness over time (a feature often lacking in patient “registries” compiled today).

Records would, of course, be anonymized before abstraction into the national system. For those who believe it still exists in the digital realm, privacy is a concern because it is sometimes possible to identify specific individuals inside a small collection of anonymized medical records. In those situations, access could be limited to physicians.

Participation by patients should be voluntary, but opt-out. Compassion for the sick would make opt-outs uncommon. Government oversight is best because no one wants their medical record “monetized,” as a corporate overlord would inevitably be driven to do… A national query-system would be of the people, by the people, and for the people.

This system would complement, not replace, today’s gold-standard source of clinical information, the randomized trial. Unfortunately, randomized trials can answer only simple questions, and are often blind to subsets of patients who react in exceptional ways. Medical practice contains few simple questions, and identifying exceptions to general rules is a central physician function.

In short, a national query system would make every doctor smarter about his or her patient’s specific illness – and it is hard to argue against having smarter doctors.

You wouldn’t have had to watch too many episodes of my old TV show, House, MD, to hear mention of “sexually transmitted disease.” And you wouldn’t have to sit through too many medical school lectures before you heard about a “mosquito-transmitted disease,” like malaria, or a “tick-transmitted disease,” like Lyme disease.

Nowhere, however, would you ever hear about a “compassion-transmitted disease.” Yet, that’s exactly what Ebola virus disease is in humans.

With few exceptions, a person catches Ebola only through an act of compassion toward another person who has the virus.

For example, Thomas Eric Duncan, the man who died from Ebola in Dallas, picked up the virus when he helped a sick, infected woman get to a clinic in Liberia. The doctors and nurses who have contracted Ebola got it while delivering medical care to Ebola patients. Of course, lab technicians and a cleaning crew are part of the medical enterprise, too. And most of the thousands of people in west Africa who have gotten the disease were helping care for a loved one at home, or were performing post-mortem rituals as a token of benevolent love for the deceased.

Sure, there are exceptions to the compassion rule. The first patient to get the disease in any Ebola epidemic acquires it, most likely, from an animal. And perhaps there are a few cases where someone is exposed to infected body fluids while not coming to the aid of a fellow human. But, children excepted, there is no indication that disease is occurring in the current outbreak after only a coldly inadvertent exposure to body fluids.

There are two tragic ironies to the centrality of compassion.

First, for adults, callousness is effectively an excellent vaccine against Ebola virus disease. <sarcasm>So if you’re being a callous jerk, then congratulations, you’re protected from the disease.</sarcasm> (It’s fortunate that Ebola is rare in human history, otherwise evolution might have removed compassion from the population.)

Second, the entire epidemic could be ended very quickly if everyone in the affected regions immediately and completely discarded their compassion. In that compassionless world, any person who had a symptom or sign of Ebola virus disease would be instantly dumped into a well. Human-to-human transmission of the virus would immediately stop, and the epidemic would be over in a month… easy as pie.

That the compassionless scenario is both grossly repugnant and utterly impossible is an indication of how deeply compassion runs in humans. And maybe that is the inextinguishable good news in this epidemic.

First published on on Sept. 18, 2014
In response to the question: What’s the most harmful misconception about health and medicine seen in popular culture?

“I can’t have a heart attack, because no one in my family ever has.”

“Everyone in my family has diabetes, so why bother trying to avoid it?”

I have no idea where beliefs such as these originated, but they span many diseases and are astonishingly common, even among the well-educated – my cousins included.

To my cousins and non-cousins: The world is just not that simple, nor that deterministic. Although family history certainly influences the odds of developing specific diseases, it is never the whole story. Even a disease that arises solely from a genetic cause, e.g. Huntington disease, is inherited, statistically, by only 50% of an affected parent’s children.

Instead, the odds of disease come from a combination of four factors: genetics, environment, behavior, and random luck. The good news is that the factor most amenable to change – behavior – matters a lot, especially in the major diseases that afflict Americans today.

The bad news is that, as medical science learns more about preventing disease, new preventive actions will be added to the already-long list of fun-spoiling behaviors that physicians will encourage.

What will be interesting is to see is whether insurers expand the practice of raising premiums for people who engage in anti-healthy behaviors. No doubt, plans are already afoot to raise rates for anyone who tweets their love of bratwurst.