Tuskegee tactics vs. the cohort problem

Let's try this again.

In my last post, I responded to Hillary Johnson's essay likening of the CDC's mishandling of ME/CFS to the infamous Tuskegee syphilis experiment. For those unfamiliar with the history, Tuskegee medical researchers studied almost 400 black men with syphilis, didn't tell their subjects that they were infected, and didn't treat them for it—all so they could study the natural course of the disease.

I said that even with all the nasty politics surrounding ME/CFS, it was easier for me to believe that the CDC was simply clueless and biased than to believe they were pulling another Tuskegee.

A commenter felt my skepticism was naive, saying that I must be unfamiliar with the CDC's history. I'm not. But upon rereading my post, I realize that I came across as more of an apologist than I intended.

So, just a little bit of the history.

Back in 1996, a congressional investigation revealed that the Centers for Disease Control and Prevention had diverted funds meant for ME/CFS to other diseases.

Since then, the CDC has diluted its definition for what it considers "chronic fatigue syndrome"—it includes many patients who are likely suffering from depression or some other disease, but not ME/CFS. Using the diluted definition, they have focused almost exclusively on behavioral treatments. And that's where the problems begin.

They'll test the effects of cognitive behavioral therapy and graded exercise therapy, using subjects that may or may not actually have ME/CFS.

The real ME/CFS patients will experience post-exertional morbidity as a result of the graded exercise therapy, and they'll be much more likely than the others to drop out of the study.

The researchers won't count the dropouts when calculating their results.

They have continued to skew their results in this fashion despite criticism from other ME/CFS researchers.

Why? Maybe they really are just biased toward thinking that ME/CFS is a psychological disorder instead of a neuroimmune disease. I'm not ruling the possibility out. Not entirely. But if another congressional investigation revealed something more nefarious—influence from insurance companies, for instance—let's just say I wouldn't fall over from the shock.

So why am I skeptical that they're pulling another Tuskegee?

The facts don't fit.

We're horrified by the Tuskegee study today because the scientists treated human beings like lab rats. Because they let patients infect other human beings, suffer, and die in the name of science.

What they didn't do was study patients who had, say, schizophrenia, and lump them in with the syphilis patients.

If the CDC wanted to study the natural course of ME/CFS in the same way that Tuskegee did for syphilis, they'd want to actually study people with ME/CFS.

We wouldn't have the cohort problem.

Tuskegee #3?

Interesting essay by Hillary Johnson up on Osler's Web about the discovery of a "Tuskegee 2":

Inmates in a Guatemalan penitentiary, patients in insane asylums and soldiers in an army barracks were deliberately infected with syphilis or gonorrhea. According to [Susan] Reverby, infected prostitutes were recruited to infect Guatemalan prisoners. Reverby reported that ultimately 696 men and women were infected. According to records, the point of the project was to study the efficacy of penicillin, but Reverby reported that not everyone was cured.

Reverby linked the Guatemalan experiment of the 1940s with the notorious Tuskegee syphilis experiment that began in 1932 in Alabama. In this widely chronicled event, scientists at what would become the Centers for Disease Control identified 400 impoverished black men in Tuskegee with syphilis and denied them and their contacts treatment for the next four decades, purportedly to study the "natural history" of syphilis. In spite of the fact that treatment became available, and that the natural history of syphilis was already well-known, the CDC allowed blacks in Tuskegee to grow ill and to infect their spouses and even infants, who contracted the disease at birth. The Guatemalan debacle was headed by John Cutler, a Public Health Service doctor who was also involved in the Tuskegee experiment.

Johnson contemplates the possibility that the CDC has been treating ME/CFS in a similar fashion—deliberately allowing an infectious disease to spread so they could study its course.

Even with all the nasty politics surrounding ME/CFS, this speculation strikes me as a little paranoid. I find it easier to believe that the CDC is simply biased, and that its bias leads it to do very bad science.

The sad thing? If you're an ME/CFS patient, the world looks the same to you either way.

Dueling studies: One down

On Tuesday, we learned that the publication of two contradictory XMRV studies were on hold. Today, we finally have published results ... of the CDC paper.

I could speculate about why the NIH study is still awaiting release, but all the information has been confusing and contradictory, so I'll hold off for now. Instead, let's look at the results of the CDC study. Did they fail to detect a link because there isn't one, or because their methods were flawed?

The cohort problem

The CDC defines ME/CFS very broadly. As a result, their previous research includes many people who probably don't have ME/CFS. Though this paper is touted as a replication study of the Whittemore Peterson Institute's research, they didn't define their population using the same criteria. Here's an excerpt (all emphasis mine):

The 1994 International CFS case definition [used by the CDC] and the Canadian Consensus Criteria [used by the Whittemore Peterson Institute] are different and do not necessarily identify similar groups of ill persons. Most notably, the Canadian Criteria include multiple abnormal physical findings such as spatial instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy.

These are all common symptoms of ME/CFS.

Detection techniques

According to Dr. Suzanne D. Vernon, the CDC did not replicate the WPI study's techniques:

[T]he samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types. So the explanation for not finding XMRV in these samples is simple – this was a study designed to not detect XMRV using a hodge-podge sample set.

You can read Vernon's critique at CFIDS Association of America's site. It's worth noting that the CFIDS Association of America is regarded with suspicion among many members of the ME/CFS community, who view it as the CDC's lapdog. In other words, the criticisms that the CAA now levels at the CDC are in no way knee-jerk responses to news it didn't want to hear.

So, it seems as though the CDC paper has some serious issues. Now we need to convince the powers that be to release the NIH study. Only then will we be able to see if it holds up to similar scrutiny.

XMRV papers on hold

We're going to have to wait to see the results of the latest XMRV studies.

Last week, the FDA and NIH announced that they had independently confirmed the Whittemore Peterson Institute's original findings linking ME/CFS with the retrovirus XMRV. And there was much rejoicing among all of us who hope the link will lead to treatment, even a cure someday.

The CDC had also wrapped up an XMRV study. Though they didn't officially announce their results, CFS Central reported that they were negative. Disappointing, but not surprising to anyone familiar with the history. The CDC defines ME/CFS very broadly, and their research likely includes patients who don't actually have the disease.

There was nothing to do but wait for the release of both studies. Then we could examine the methodology and draw conclusions about the discrepancies.

According to the Wall Street Journal, however, both reports are being held from publication.

Kuan-Teh Jeang, editor-in-chief of Retrovirology, said the Switzer paper went through peer review and was accepted for publication when he got a call from the authors earlier this month. They asked that the Retrovirology paper be held.

"My understanding was HHS [Department of Health and Human Services] wanted to get it straightened out. Both reports are from different branches of the government," Dr. Jeang said.

In an email between scientists familiar with the situation, viewed by the Wall Street Journal, a researcher said the two teams were asked to put their papers on hold because senior public-health officials wanted to see consensus—or at least an explanation of how and why the papers reached different conclusions, said the people familiar with the situation.

Entire article here.

I don't want to don the tinfoil hat and immediately call shenanigans. I do want to know what's going on. Both of these papers were peer-reviewed; both were accepted by their respective journals. For the government to suddenly step in and suppress the results is a little bizarre, and it makes me nervous.

Reeves out

William C. Reeves, head of the Chronic Fatigue Syndrome Research Program at the CDC, is moving on. Effective February 14, he'll become senior advisor for a another department within the agency. Dr. Elizabeth Unger will temporarily replace him.

Those of you who have ME/CFS have probably heard about this already, and almost certainly know why it's cause for celebration. For everybody else, here's the deal.

Reeves has led the CDC's CFS program for around a decade. During that time, he has done nothing to bring us closer to a cure, or even marginally effective treatment. Instead ...

• He has diluted the definition of ME/CFS to include people who instead suffer from clinical depression.
  
  
• Armed with the new, diluted definition, he has promoted the belief that childhood trauma and sexual abuse are linked to ME/CFS. The 2009 paper supporting this assertion fails to cite an earlier study, which found that people with ME/CFS are less likely to report such abuse.
  
  
• He has championed cognitive behavioral therapy and graded exercise therapy, which may have small benefits for people with clinical depression, but do nothing for people with ME/CFS. In fact, graded exercise therapy can actually harm people with the disease.

In October of last year, the Whittemore Peterson Institute for Neuro Immune Disease announced that it had found a strong link between ME/CFS and a retrovirus called XMRV. The discovery shone a bright light on Reeves' biases. Immediately following the announcement, he told the New York Times that "We and others are looking at our own specimens and trying to confirm it. If we validate it, great. My expectation is that we will not."

Will Reeves' move represent a significant change in the way the CDC deals with the disease? Will they take the program in a different direction? No idea.

It's possible that the CDC saw which way the wind was blowing in the wake of the XMRV discovery and decided to make Reeves the fall guy. Maybe they intend to go back to business as usual after he leaves, hoping that his removal alone will appease angry sufferers and advocates.

If that's the case, they're very wrong. It won't appease us. But it is still cause for celebration.

I like the way the wind is blowing.

ME/CFS unfiltered

A little over a week ago, Atlanta Unfiltered ran a brief story about the Centers for Disease Control and its role in ME/CFS research:

A possible research breakthrough — the discovery of a correlation between CFS and a retrovirus related to the AIDS virus — has fired up the medical community in recent weeks. “This is going to create an avalanche of subsequent studies,” Dr. William Schaffner, an infectious disease expert at Vanderbilt University, told the New York Times this month.

But will the Centers for Disease Control and Prevention play a role in that research? It hasn’t so far. Advocates have been pushing the Atlanta-based CDC for years to fund outside research into a possible viral explanation for the debilitating disease, which afflicts as many as 1 million Americans — maybe more.

The full article succinctly outlines the specific criticisms. If you're unfamiliar with the long saga of the CDC and ME/CFS, this will give you a quick grasp of the basics.

Something that struck me about the story was that I'd never seen it reported by the news media before. There exists a very well-researched book, a documentary, and numerous websites/blogs on the subject, but conventional newspapers and magazines haven't touched it.

Comments are overwhelmingly positive and still coming in. Many can be summarized, "Thanks for being the first to tell everybody else what we already know."

Now, here's what really got me.

One of the commenters suggested further avenues of investigation that Atlanta Filtered should pursue. Editor Jim Walls replied:

I plan to work on a few more stories (next priority would seem to be the blood supply), but I gotta make a living and have been distracted by work for which I am actually paid.

I had to read that a couple of times before the full meaning sunk in.

There’s a certain poetic symmetry at work here. After the CDC ignores and denies the true nature of ME/CFS for decades, they’re shown up by an institute that hasn’t existed long enough to have its own building. After the mainstream media fails to pick up on this story for decades, it’s scooped by a newspaper that can’t afford to pay its reporters.

ME/CFS is not just being really tired

Last month I posted a link to Pamela Weintraub's article about why recent research on ME/CFS is bogus. The study found that experiencing sexual abuse in childhood puts one at greater risk for ME/CFS. Weintraub argued that the methodology was highly flawed, and that the study was part of an ongoing effort on the part of CDC to misclassify ME/CFS as a psychological disorder.

In response, a commenter pointed out:

It should be kept in mind, however, that it is well possible there is a link between trauma and CFS/ME - and it does not in any way indicate that the illness is psychiatric or psychosomatic in origin (or that it could be treated with psychotherapy), even though that's what the media often makes out of it. It's well-known that in lab animals trauma early in their life causes irrepairable damage to the HPA axis.

This is a reasonable argument, and it's true. Stressors do affect the immune system, and exploring these kinds of mind/body connections doesn't necessarily imply that the resulting diseases are all in the patient's head.

So what's the problem with this study, and others like it?

Many of the subjects don't actually have ME/CFS.

People with ME/CFS feel crushing fatigue, significant pain, and post-exertional malaise. The latter term means that any exertion -- even just walking to the bathroom and back -- causes them to feel much, much worse. The CDC's definition, however, only includes pain and post-exertional malaise as possible symptoms.

This is important. There are a lot of conditions that can make people feel chronically tired for a long time. One of them is clinical depression. If you're looking for the effects of childhood sexual abuse, and you include subjects who have clinical depression but not true ME/CFS, you're going to seriously skew your results.

It's not simply that they've funded a study focusing on a psychological cause. It's that they've extended the definition of ME/CFS to include people who might be suffering from clinical depression instead.

I'll conclude with another quote from Weintraub's original article:

Perhaps the most notable thing about the Emory study, Johnson points out, is that it fails to cite a study performed in 2001 that asked the identical question. That study demonstrated that people with CFS actually have a lower incidence of childhood abuse and trauma than controls.