Ten Years of PubMed Central: a Good Thing that’s Only Going to Get Better.

26 05 2010

PubMed Central (PMC) is a free digital archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH’s National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM) (see PMC overview).
PMC is a central repository for biomedical peer reviewed literature in the same way as NCBI’s GenBank is the public archive of DNA sequences. The idea behind it “that giving all users free access to the material in PubMed Central is the best way to ensure the durability and utility of the electronical archive as technology changes over time and to integrate the literature with other information resources at NLM”.
Many journals are already involved, although most of them adhere to restrictions (i.e. availability after 1 year). For list see http://www.ncbi.nlm.nih.gov/pmc/journals/

PMC, the brain child of Harold Varmus, once the Director of the National Institutes of Health, celebrated its 10 year anniversary earlier this year.

For this occasion Dr. Lipman, Director of the NCBI, gave an overview of past and future plans for the NIH’s archive of biomedical research articles. See videotape of the Columbia University Libraries below:

more about “Ten Years of PubMed Central | Scholar…“, posted with vodpod

The main points raised by David Lipman (appr. time given if you want to learn more about it; the text below is not a transcription, but a summary in my own words):

PAST/PRESENT

  • >7:00. BiomedCental (taken over by Spinger) and PLoS ONE show that Open Access can be a sustaining way in Publishing Science.
  • 13:23 Publisher keeps the copyright. He may stop depositing but the content already deposited remains in PMC.
  • 13:50 PMC is also an obligatory repository for author manuscripts under various funding agencies mandates, like the NIH and the UK welcome trust.
  • 14:31 One of the ideas from the beginning was to crosslink the literature with the underlying molecular and other databases. For instance NCBI is capable of mining out the information in the archived text and connecting it to the compound and the protein structure database.
  • 16:50 There is a back issue digitization for the journals that are participating, enabling to find research that you wouldn’t have easily found otherwise.
  • PMC has become international (not restricted to USA)
  • The PMC archive becomes more useful if it becomes more comprehensive
  • Before PMC you could do a Google Scholar search and find a paper in PubMed, that appeared funded by NIH, but then you had to pay $30 for it in order to get it. That’s hard to explain to the taxpayers (Lipman had a hard time explaining it to his dad who was looking for medical information online). This was the impetus for making the results of NIH-sponsored results freely available.

PRESENT/FUTURE

  • 23:00 Discovery initiative: is the use of tracking tools to find out which changes to the website work for users and which don’t. Thus modifications should lead to alterations in users behavior (statistics is easy with millions of users). Discovery initiative led to development and improvement of sensors, like sensors for disease names, drug names, genes and citations. What is being measured is if people click through (if it isn’t interesting, they usually don’t) and how quickly they find results. Motto: train the machine, not the users.
  • 30:37 We changed the looks of PMC. Planning to make a better presentation on the i-phone and on broad monitors.
  • 31:40. There are almost 2 million articles in PubMed Central, 585 journals fully participate in PMC
  • 32.30 It takes very long to publish a paper, even in Open Access papers. Therefore a lot of people are not publishing little discoveries, which are not important enough to put a lot of time in. Publishing should be almost as easy as writing a blog, but with peer review. This requires a new type of journal, with peer review, but with instant feedback from readers and reviewers and rapid response to comments. The Google Knol authoring system offers a fast and simple authoring system where authors (with a Google profile) can collaborate and compose the article on the server. Uploading of documents and figures is easy, the article updates are simple and fast, there is a simple workflow for moderators. After the paper is accepted you press a button, the paper is immediately available and the next day PMC automatically gets the XML content. There is also a simple Reference Manager included to paste citations.
  • Principle: How you can start a journal with this system (see Figure). Till now: 60 articles in PLOS Currents Influenza. There are also plans for other journals: the CDC is announcing a Systematic Reviews journal, for instance.

QUESTIONS (>39:30):

  • Process by which “KNOL-journal” is considered for inclusion in NLM?
    • Decide: is it in scope?, implicit policy (health peer review being done), who are the people involved, look at a dozen articles.
  • As the content in PMC increases, will it become possible to search in the full text, just like in Google Scholar?
    • Actually the full text is searchable in PMC as apposed to PubMed, but we are not that happy with the full text retrieval. Even with a really good approach, searching full text works just a little bit better than searching PubMed.
      We are incorporating more of the information of PMC into PubMed, and are working on a separate image database with all the figures from books and articles in PMC (with other search possibilities). Subsets of book(chapter)s (like practice guidelines) will get PubMed abstracts and become searchable in PubMed as well.
  • Are there ways to track a full list of our institutions OA articles in PMC (not picking up everything in PubMed)
    • Likely NIH will be contacting offices responsible for research to let them know what articles are out of compliance,  get their assistance in making sure that those get in.
    • Authors can easily update the electornic My Bibliography (in My NCBI in PubMed).
    • Author ID project, involves computational disambiguation. Where you are asked if you are the author of a paper if you didn’t include it. It may also be possible to have automatic reporting to the institutions.
  • What did it took politically to get the appropriation bill passed (PMC initiative)?
    • Congress always pushed more open access, because it was already spending money on the research. Most of the initiative came more from librarians (i.e. small libraries not having sufficient access) and government, than from the NIH.
  • Is there way to narrow down to NIH, free full text papers from PMC?
    • In PubMed, you can filter free full text articles in general via the limits.
  • Are all the articles deposited in PMC submitted the final manuscript?
    • Generally, yes.

HT: @bentoth on Twitter





Reclaim your Privacy on Facebook using a Simple Bookmarklet

20 05 2010

Of all social networking sites, Facebook causes the greatest privacy concerns. Certainly since it has changed its privacy options over time.

In the beginning, Facebook restricted the visibility of a user’s personal information to just their friends and their “network”, but the default privacy settings have become much more permissive, as you can see in the video below.
This short video is based on a visualization made by Matt McKeon and gives only an impression of a work-in-progress
(for up to date info check the original animation at http://mattmckeon.com/facebook-privacy/).

The reason? According Facebook founder Mark Zuckerberg the controversial new default and permanent settings just reflect the way the world has changed, becoming more public and less private (see ReadWriteWeb).

“Default” is the key to the problems. You have to opt out to protect your privacy. However to fully protect your privacy on Facebook, you have to navigate through 50 settings with more than 170 options (see great charts at the NY Times!). Facebook’s privacy policy is longer than the American constitution!!!

Shocked by the results of the ACLU’s Facebook Quiz (see Mashable), I already changed my privacy settings last summer. Doing a simple quiz on Facebook meant everything on your profile (whether you use privacy settings or not), is available to the quiz. Even more worrying, when your friends do a quiz, everything on your profile is made available to the developers as well.

Since the default privacy settings have changed, my settings needed to be adapted again. But where were the leaks in the 170 options?

Luckily there is a very simple bookmarklet Reclaim Privacy that can check and fix your profile in 2 minutes (see Mashable.com) It is very easy.

1. First go to Reclaim Privacy and drag the bookmarklet to your web browser bookmarks bar
(in the example I dragged the bookmarklet into Chrome’s bookmarks (upper arrow)

2. Go to your Facebook privacy settings and then click that bookmark (Scan for Privacy, see arrow) once you are on Facebook.

3. You will see a series of privacy scans that inspect your privacy settings and warn you about settings that might be unexpectedly public.
In my case my friends could still accidentally share my personal information. This is indicated by a red sign: “insecure.

4. So I clicked “prevent friends from sharing your data”, and in seconds this was the result:

5. I tweaked the contact information a bit (caution) by changing my contact settings, but I still would allow everyone to add me as a friend (I still have to approve, don’t I?)

Piece of cake!





When #Twitter Gets Creepy: People Who Force you to #Autofollow

18 05 2010

The third Twitter post in a row. But this one ain’t positive.

It is about privacy and spam.

Let’s first explain some basic things about Twitter.

People can follow you without your approval, at least if you  have a public account. You can follow them back if you like.

You just have to click on the follow button, that is all!
Everyone with a Twitter account can follow Barack Obama, for instance.

If Barack Obama followed me (whether I followed him or not), I could dm (direct message) him. He (or rather his staff) will receive a private message from me in his inbox.

Only people you follow, are able to dm you. This is to protect you against dm’s from whichever fool, Spam and Bots.

Barack Obama has many followers:  3,964,789. This is no surprise, because he is the president of the United States and everyone wants to know what he has to say.

Some people especially in the marketing sector find the numbers of followers that important that they will do anything to assure a lot of followers. They are even willing to pay for it.

There are several companies who specialize in it. Here is a list of paid Twitter services and their rates (from http://zacjohnson.com/buy-twitter-followers/).

  • BuyTwitterFriends.com = 10,000 Followers for $49.99 (0.0049 each)
  • TweetSourcer.com = 10,000 Followers for $60.00 (0.006 each)
  • UnlimitedTwitterFollowers.com = 10,000 Followers for $74.95 (0.0074 each)
  • Twitter1k.com = 5,000 Followers for $104.97 (0.0209 each)
  • SocialKik.com = 10,000 Followers for $150.00 (0.015 each)
  • USocial.net = 10,000 Followers for $447.30 (0.044 each)
  • Tweetcha.com = 10,000 Followers for $474.99 (0.047 each)
  • PurchaseTwitterFollowers.com = 5,000 Followers for $249.99 (0.049 each)

Buying followers….. that is rather shortsighted. My mother always used to say: “You can’t buy friends” (no real friends anyway).

What are followers worth who don’t follow you because you’re tweets are so interesting, or the stuff you sell is so good, etc… Do these followers really ‘follow’ you, in the sense that they follow what you say? And do they keep following you?

Moreover how are those followers recruited? Are they asked to do so? Are they offered money?

Well I don’t think so. There must be easier money strategies.

But how can you make people follow without asking?

Well there may be a sneaky way to force people to do so, without them being aware of it.

At least I think that has happened to me.

Saturday I got this dm:

I was alarmed.

  • First, somebody sends me a dm with a link to a marketing gift. I never click such links, you never know where they lead to. Even if it comes from someone I trust, it may be that his/her account has been hacked, so I have learned…
  • Second,  I’m not following this guy, at least not any longer….
  • Third I have blocked him before, after a similar dm.

The first time I got a dm of @jonathanvolk I thought I made the mistake by accidentally following him. But now (having blocked him before) I was sure that that wasn’t the case.

Out of curiosity (and to block him) I checked his Twitter account. Here I found several people complaining to him about the very same thing (the first tweet appeared later in response to my tweets).

@SorbetDigital appeared to have similar problems, not only with @jonathanvolk, but also with @JohnChow (see her post).

@JohnChow did ring a bell. Didn’t I block him in the past and didn’t I see his tweets rolling by lately?

I quickly checked Friend or Follow, a fantastic program, that shows you the people you follow and don’t follow you in return (following), your fans (who only follow you) and your friends (reciprocal relationship).

And who did I see there? John Chow, plus another guy that I presumably didn’t follow voluntarily: @MrGatherSuccess.
[The 2nd robot to the upper left also isn't kosher, as I found out today.]

Their Twitter pages ((below in blue and pink) have texts according to expectations.
Their follower/following ratio is absolutely skewed (557:1 and 1090:1 respectively)  so apparently their approach works in the sense that they got more followers, probably recruited in much the same way as they “recruited” me.

Strikingly@jonathanvolk and @Shoemoney are among the 100 people John Chow has chosen to follow. @Shoemoney (follower/-following ratio of 1355:1) and @Chow are also almost the only people followed by @MrGatherSuccess. By the way there is also “College Pages”, that links to Online Colleges, you know the site I warned you about on several occasions (Beware of Top 50 “Great Tools to Double Check your Doctor” or whatever Lists and “Vanity is the Quicksand of Reasoning: Beware of Top 100 and 50 lists!”)

Oh and “the robot” tweeted this today

Common features of these people:

  • they are  all Internet marketers,
  • All have let me follow them, (without following me back)
  • Some have sent me dm’s
  • they have many followers, some having skewed follower/following ratios
  • they “know” each other and may refer to each other

Strikingly @jonathanvolk has a post in which he explains how to get 25,000 Twitter followers with “Twitter Followers for Sale”. Juicy detail: Shoemoney gave him the tip. Vice versa at shoemoney.com, Shoemoney advocates to download the affiliate marketing guide of Jonathan.

Are these the guys behind the link services?

Not necessarily. In a recent post (Something Fishy Goin’ On Here… Paid Twitter Followers) @Jonathanvolk seems sincerely surprised about the pissed of reaction of his forced followers. Quote:

The other week I made a post about Paid twitter followers.

In the post I outline a few methods I have used to essentially pay for twitter followers and how much it has cost me per follower. With the methods like paying twittercounter.com, for example, you know exactly where your twitter followers are coming from.

Recently my follower count has been increasing steadily (and fairly rapidly) without me paying for any more services.

I’ve received a few @ messages before saying the person didn’t follow me and they were unsure how they did. I usually brushed it off as a… how can I put it lightly… computer illiterate person.(emphasis mine)

I think however that one of the services I used is using some sort of application access to automatically make users follow those who pay for the service.

The only problem is, I’m not sure which service is doing it… or if it’s just someone trying to get my account banned.

Since I have no way of know knowing… I have no way of stopping it.

Kinda crazy. Either way, be careful buying followers unless you know explicitly where the users are coming from!

——————

Kinda bullshitSince I have no way of know knowing… I have no way of stopping it.” …. Booh!

Let me give you one tip, guys (assuming that you are honest about this): go sit around the table and see which follower-robbering service you share, and do something about it!!

How people can force you to follow is a technical issue, I know little about. Jonathan refers to a follow bug in Twitter that they have found but should have been fixed.

Indeed @librarianbe told me the same in response to my “tweets for help”. He referred to an article in Gizmodo explaining how to force anyone to follow you on Twitter. Apparently the bug was not fixed (yet?), or there is another leak still to be discovered.

Twitter handled the p @  r  n-spam well. I hope it will find a solution to these problems too.

For such forced following and marketing dm’s are not only annoying, and an intrusion on our privacy, they are also bad for the credibility of a tool like Twitter.

So I’m going to block these guys (of course) and report them to Twitter using the ticket file @mrgunn advised me.

Similar problems? Here is the link to file a ticket with Twitter: http://help.twitter.com/requests/new

Meanwhile I advise you marketer guys to reassess the value of your followers. Do you only care about the size of the flock? Is it just the number of sheep? Do you want to impress by numbers? Or do you care about by whom you are being followed? And if what you’re tweeting does matter to them? Because only then you will have value as a twitterer and deserve to be followed. Otherwise, how can I put it lightly…you’re  a bit sheepish.

Added 18-05-2010

According to Twitter Status the bug that permitted a user to “force” other users to follow them was resolved & cleaned up May 10th. However Jonathan send the dm May 15th (although he might have forced me to follow him longer ago).

If you are still seeing folks you are following who you didn’t choose to follow, Twitter advises to use the block or unfollow tools as a remedy.

However, these buttons do not work effectively as @jonathanvolk and @johnchow keep resurrecting again after a total block.

@jonathanvolk reappeared in the Following Tab of Friend or Follow this very night, about 3 days after blocking (see comment).

Twitter, I hope you listen…





A Quantitave Study suggests that Twitter is not Primarily a Social Networking Site

13 05 2010

A lot can be said about Twitter, Facebook, Linkedin and other social media. What is the best, the most useful, the most popular the most social (and has the least privacy-issues, hehe Facebook)?

You know I love Twitter. Twitter is a social networking and microblogging service that enables its users to send and read messages known as tweets. The tweets don’t exceed 140 characters, so your message must be very concise. For me Twitter is a very rich source of information and a useful networking site. But it is hard to explain that to others.

Some Most people think that individuals who twitter are just parroting others (hé this is called retweeting, guys!) or are just egocentric bores (“I eat cornflakes for dinner”).

Well, a recent quantitative study by a group of researchers at Korea’s Advanced Institute of Science and Technology suggest that they might just be right. … Or at least their data suggest Twitter may be less of a social site and more of a news site.

According to Haewoon Kwak et al this is the first quantitative Twitter study ever.

The researchers crawled the entire Twitter site and obtained 41.7 million user profiles, 1.47 billion social relations, 4,262 trending topics, and 106 million tweets. They looked at the follower-following topology, looked at the ranking by number of followers and by PageRank, analyzed the retweets and the tweets of top trending topics.

You can read the main conclusions in the power presentation below and their abstract for Proceedings of the 19th International World Wide Web (WWW) Conference, April 26-30, 2010, Raleigh NC (USA). Below the abstract you can also find links to two download files, enabling you to reanalyze the data
Going Social Now and ReadWriteWeb also give a nice overview.

What are their main conclusions:

  • Twitter is not very “social”
    • It is “I follow you”, not “lets become friends” and you don’t have to approve or follow back. Following thus means that you “just subscribe” to the tweets of that person.
    • Only 22.1% of the relationships are reciprocal, thus 77.9% of the relationships is one way, just one of two is following the other. Surprisingly, 67.6% of users on Twitter are not followed by any of the people they follow.
    • this low reciprocity is unlike all other human social networks.
  • For most tweople, Twitter is primarily a source of information, not a social networking or information dissemination platform.
    • The Majority of topics (54,3%) are headline topics
    • Few users reach a large audience directly.
    • The average path length between two people on Twitter is 4.12. This is much shorter than Stanley Milgram’s original experiment uncovering the “six degrees of separation” phenomena.
    • Any retweeted tweet is to reach an average of 1,000 users no matter what the number of followers is of the original tweet.
    • Once retweeted, a tweet gets retweeted almost instantly on next hops, signifying fast diffusion of information after the 1st retweet.

It is a beautiful study that highlights the topological characteristics of Twitter.

One word of caution. Twitter is analyzed as a whole. There are many subpopulations with their own kinetics and goals. So the majority of people may follow the news, and fans may follow a celebrity by the million, but there are (relatively) small niches on Twitter, like health and medicine (or science) that may not follow the same rules.
I daresay (guess) that more people in this niche follow each other and do use Twitter both as a source of information and as as  network for social communication.
But these small niches are outnumbered by others (news sites, CEOs, celebrities).
At least that is my hypothesis.

Who is going to test this??

Many different Twitter birds in a flock

Credits





Three Studies Now Refute the Presence of XMRV in Chronic Fatigue Syndrome (CFS)

27 04 2010

ResearchBlogging.org.“Removing the doubt is part of the cure” (RedLabs)

Two months ago I wrote about two contradictory studies on the presence of the novel XMRV retrovirus in blood of patients with Chronic Fatigue Syndrome (CFS).

The first study, published in autumn last year by investigators of the Whittemore Peterson Institute (WPI) in the USA [1], claimed to find XMRV virus in peripheral blood mononuclear cells (PBMC) of patients with CFS. They used PCR and several other techniques.

A second study, performed in the UK [2] failed to show any XMRV-virus in peripheral blood of CFS patients.

Now there are two other negative studies, one from the UK [3] and one from the Netherlands [4].

Does this mean that XMRV is NOT present in CFS patients?

No, different results may still be due do to different experimental conditions and patient characteristics.

The discrepancies between the studies discussed in the previous post remain, but there are new insights, that I would like to share.*

1. Conflict of Interest, bias

Most CFS patients seem “to go for” WPI, because WPI, established by the family of a chronic fatigue patient, has a commitment to CFS. CFS patients feel that many psychiatrists, including authors of the negative papers [2-4] dismiss CFS as something “between the ears”.  This explains the negative attitude against these “psych-healers” on ME-forums (i.e. the Belgium forum MECVS.net and http://www.forums.aboutmecfs.org/). MECVS even has a section “faulty/wrong” papers, i.e. about the “failure” of psychiatrists to demonstrate  XMRV!

Since a viral (biological) cause would not fit in the philosophy of these psychiatrists, they might just not do their best to find the virus. Or even worse…

Dr. Mikovits, co-author of the first paper [1] and Director of Research at WPI, even responded to the first UK study as follows (ERV and Prohealth):

“You can’t claim to replicate a study if you don’t do a single thing that we did in our study,” …
“They skewed their experimental design in order to not find XMRV in the blood.” (emphasis mine)

Mikovits also suggested that insurance companies in the UK are behind attempts to sully their findings (ERV).

These kind of personal attacks are “not done” in Science. And certainly not via this route.

Furthermore, WPI has its own bias.

For one thing WPI is dependent on CFS and other neuro-immune patients for its existence.

WPI has generated numerous press releases and doesn’t seem to use the normal scientific channels. Mikovits presented a 1 hr Q&A session about XMRV and CFS (in a stage where nothing has been proven yet). She will also present data about XMRV at an autism meeting. There is a lot of PR going on.

Furthermore there is an intimate link  between WPI and VIP Dx, both housed in Reno. Vip DX is licensed by WPI to provide the XMRV-test. Vipdx.com links to the same site as redlabsusa.com, for Vip Dx is the new name of the former RedLabs.

Interestingly Lombardi (the first author of the paper) co-founded Redlabs USA Inc. and  served as the Director of Operations at Redlabs, Harvey Whittemore owns 100% of VIP Dx, and was the company President until this year and  Mikovits is the Vice President of VIP Dx. (ME-forum). They didn’t disclose this in the Science paper.

TEST_RQN_Feb_2010

Vip/Dx offers a plethora of tests, and is the only RedLab -branch that performs the WPI-PCR test, now replaced by the “sensitive” culture test (see below). At this stage of controversy, the test is sold as “a reliable diagnostic tool“(according to prohealth). Surely their motto “Removing the doubt is part of the cure” appeals to patients. But how can doubt be removed if the association of XMRV with CFS has not been confirmed, the diagnostic tests offered have yet not been truly validated (see below), as long as a causal relationship between XMRV and CFS has not been proven and/or when XMRV does not seem that specific for CFS: it has also been found in people with prostate cancer, autism,  atypical multiple sclerosis, fibromyalgia, lymphoma)(WSJ).

Meanwhile CFS/ME websites are abuzz with queries about how to obtain tests -also in Europe- …and antiretroviral drugs. Sites like Prohealth seem to advocate for WPI. There is even a commercial XMRV site (who runs it is unclear)

Project leader Mikovits, and the WPI as a whole, seem to have many contacts with CSF patients, also by mail. In one such mail she says (emphasis and [exclamations] mine):

“First of all the current diagnostic testing will define with essentially 100% accuracy! XMRV infected patients”. [Bligh me!]….
We are testing the hypothesis that XMRV is to CFS as HIV is to AIDS. There are many people with HIV who don’t have AIDS (because they are getting treatment). But by definition if you have ME you must have XMRV. [doh?]
[....] There is so much that we don’t know about the virus. Recall that the first isolation of HIV was from a single AIDS patient published in late 1982 and it was not until 2 years later that it was associated with AIDS with the kind of evidence that we put into that first paper. Only a few short years later there were effective therapies. [...]. Please don’t hesitate to email me directly if you or anyone in the group has questions/concerns. To be clear..I do think even if you tested negative now that you are likely still infected with XMRV or its closest cousin..

Kind regards, Judy

These tests costs patients money, because even Medicare will only reimburse 15% of the PCR-test till now. VIP Dx does donate anything above costs to XMRV research, but isn’t this an indirect way to support the WPI-research? Why do patients have to pay for tests that have not proven to be diagnostic? The test is only in the experimental phase.

I ask you: would such an attitude be tolerated from a regular pharmaceutical company?

Patients

Another discrepancy between the WPI and the other studies is that only the WPI use the Fukuda and Canadian criteria to diagnose CFS patients. The Canadian  criteria are much more rigid than those used in the European studies. This could explain why WPI has more positives than the other studies, but it can’t fully explain that WPI shows 96% positives (their recent claim) against 0% in the other studies. For at least some of the European patients should fulfill the more rigid criteria.

Regional Differences

Patients of the positive and negative studies also differ with respect to the region they come from (US and Europe). Indeed, XMRV has previously been detected in prostate cancer cells from American patients, but not from German and Irish patients.

However, the latter two reasons may not be crucial if the statement in the open letter* from Annette Whittemore, director of the WPI, to Dr McClure**, the virologist of the second paper [2], is true:

We would also like to report that WPI researchers have previously detected XMRV in patient samples from both Dr. Kerr’s and Dr. van Kuppeveld’s cohorts prior to the completion of their own studies, as they requested. We have email communication that confirms both doctors were aware of these findings before publishing their negative papers.(……)
One might begin to suspect that the discrepancy between our findings of XMRV in our patient population and patients outside of the United States, from several separate laboratories, are in part due to technical aspects of the testing procedures.

Assuming that this is true we will now concentrate on the differences in the PCR -procedures and results.

PCR

All publications have used PCR to test the presence of XMRV in blood: XMRV is present in such low amounts that you can’t detect the RNA without amplifying it first.

PCR allows the detection of a single or few copies of target DNA/RNA per milligram DNA input, theoretically 1 target DNA copy in 105 to 106 cells. (RNA is first reverse transcribed to DNA). If the target is not frequent, the amplified DNA is only visible after Southern blotting (a radioactive probe “with a perfect fit to” the amplified sequence) or after a second PCR round (so called nested PCR). In this second round a set of primers is used internal to the first set of primers. So a weak signal is converted in a strong and visible one.

All groups have applied nested PCR. The last two studies have also used a sensitive real time PCR, which is more of a quantitative assay and less prone to contamination.

Twenty years ago, I had similar experiences as the WPI. I saw very vague PCR bands that had all characteristics of a tumor-specific sequence in  normal individuals, which was contrary to prevailing beliefs and hard to prove. This had all to do with a target frequency near to the detection limit and with the high chance of contamination with positive controls. I had to enrich tonsils and purified B cells to get a signal and sequence the found PCR products to prove we had no contamination. Data were soon confirmed by others. By the way our finding of a tumor specific sequence in normal individuals didn’t mean that everyone develops lymphoma (oh analogy)

Now if you want to proof you’re right when you discovered something new you better do it good.

Whether a PCR assay at or near the detection limit of PCR is successful depends on:

  • the sensitivity of the PCR
    • Every scientific paper should show the detection limit of the PCR: what can the PCR detect? Is 1 virus particle enough or need there be 100 copies of the virus before it is detected? Preferably the positive control should be diluted in negative cells. This is called spiking. Testing a positive control diluted in water doesn’t reflect the true sensitivity. It is much easier for primers to find one single small piece of target DNA in water than to find that piece of DNA swimming in a pool of DNA from 105 cells. 
  • the specificity of the PCR.
    • You can get aspecific bands if the primers recognize other than the intended sequences. Suppose you have one target sequence competing with a lot of similar sequences, then even a less perfect match in the normal genome has every chance to get amplified. Therefore you should have a negative control of cells not containing the virus (i.e. placental DNA), not only water. This resembles the PCR conditions of your test samples.
  • Contamination
    • this should be prevented by rigorous spatial separation of  sample preparation, PCR reaction assembly, PCR execution, and post-PCR analysis. There should be many negative controls. Control samples should be processed the same way as the experimental samples and should preferably be handled blinded.
  • The quality and properties of your sample.
    • If XMRV is mainly present in PBMC, separation of PBMC by Ficoll separation (from other cells and serum) could make the difference between a positive and a negative signal. Furthermore,  whole blood and other body fluids often contain inhibitors, that may lead to a much lower sensitivity. Purification steps are recommended and presence of inhibitors should be checked by spiking and amplification of control sequences.

Below the results per article. I have also made an overview of the results in a Google spreadsheet.

WPI
The PCR conditions are badly reported in the WPI paper, published in Science[1]. As a matter of fact I wonder how it ever came trough the review.

  • Unlike XMRV-positive prostate cancer cells, XMRV infection status did not not correlate with the RNASEL genotype.
  • The sensitivity of the PCR is not shown (nor discussed).
  • No positive control is mentioned. The negative controls were just vials without added DNA.
  • Although the PCR is near the detection limit, only first round products are shown (without confirmation of the identity of the product). The positive bands are really strong, whereas you expect them to be weak (near the detection limit after two rounds). This is suggestive of contamination.
  • PBMC have been used as a source and that is fine, but one of WPI’s open letters/news items (Feb 18), in response to the first UK study, says the following:
    • point 7. Perhaps the most important issue to focus on is the low level of XMRV in the blood. XMRV is present in such a small percentage of white blood cells that it is highly unlikely that either UK study’s PCR method could detect it using the methods described. Careful reading of the Science paper shows that increasing the amount of the virus by growing the white blood cells is usually required rather than using white blood cells directly purified from the body. When using PCR alone, the Science authors found that four samples needed to be taken at different times from the same patient in order for XMRV to be detected by PCR in freshly isolated white blood cells.(emphasis mine)
  • But carefully reading the methods,  mentioned in the “supporting material” I only read:
    • The PBMC (approximately 2 x 107 cells) were centrifuged at 500x g for 7 min and either stored as unactivated cells in 90% FBS and 10% DMSO at -80 ºC for further culture and analysis or resuspended in TRIzol (…) and stored at -80 ºC for DNA and RNA extraction and analysis. (emphasis mine)

    Either …. or. Seems clear to me that the PBMC were not cultured for PCR, at least not in the experiments described in the science paper.

    How can one accuse other scientists of not “duplicating” the results if the methods are so poorly described and the authors don’t adhere to it themselves??

  • Strikingly only those PCR-reactions are shown, performed by the Cleveland Clinic (using one round), not the actual PCR-data performed by WPI. That is really odd.
  • It is also not clear whether the results obtained by the various tests were consistent.
    Suzanne D. Vernon, PhD, Scientific Director of the CFIDS Association of America (charitable organization dedicated to CFS) has digged deeper into the topic. This is what she wrote [9]:
    Of the 101 CFS subjects reported in the paper, results for the various assays are shown for only 32 CFS subjects. Of the 32 CFS subjects whose results for any of the tests are displayed, 12 CFS subjects were positive for XMRV on more than one assay. The other 20 CFS subjects were documented as positive by just one testing method. Using information from a public presentation at the federal CFS Advisory Committee, four of the 12 CFS subjects (WPI 1118, 1150, 1199 and 1125) included in the Science paper were also reported to have cancer – either lymphoma, mantle cell lymphoma or myelodysplasia. The presentation reported that 17 WPI repository CFS subjects with cancer had tested positive for XMRV. So how well are these CFS cases characterized, really?

The Erlwein study was published within 3 months after the first article. It is simpler in design and was reviewed in less then 3 days. They used whole blood instead of PBMC and performed nested PCR using another set of primers. This doesn’t matter a lot, if the PCR is sensitive. However, the sensitivity of the assay is not shown and the PCR bands of the positive control look very weak, even after the second round (think they mad a mistake in the legend as well: lane 9 is not a positive control but a base pair ladder, I presume). It also looked like they used a “molecular plasmid control in water”, but in the comments on the PLoS ONE paper, one of the authors states that the positive control WAS spiked into patient DNA.(Qetzel commenting to Pipeline Corante) Using this PCR none of the 186 CSF samples was positive.

Groom and van Kuppeveld studies
The two other studies use an excellent PCR approach[3,4]. Both used PBMC, van Kuppeveld used older cryoperserved PBMC. They first tried the primers of Lombardi using a similar nested PCR, but since the sensitivity was low they changed to a real time PCR with other optimized primers. They determined the sensitivity of the PCR by serially diluting a plasmid into PBMC DNA from a healthy donor. The limit of sensitivity equates to 16 and 10 XMRV-gene copies in the UK and the Dutch study respectively. They have appropriate negative controls and controls for the integrity of the material (GAPDH, spiking normal control cDNAs in negative DNA to exclude sample mediated PCR inhibition[1], phocine distemper virus[2]), therefore also excluding that cryopreserved PBMC were not suitable for amplification.

The results look excellent, but none of the PCR-samples were positive using these sensitive techniques. A limitation of the Dutch study is the that numbers of patients and controls were small (32 CSF, 43 controls)

Summary and Conclusion

In a recent publication in Science, Lombardi and co-authors from the WPI reported the detection of XMRV-related, a novel retrovirus that was first identified in prostate cancer samples.

Their main finding, presence of XMRV in peripheral blood cells could not be replicated by 3 other studies, even under sensitive PCR conditions.

The original Science study has severe flaws, discussed above. For one thing WPI doesn’t seem to adhere to the PCR to test XMRV any longer.

It is still possible that XMRV is present in amounts at or near the detection limit. But it is equally possible that the finding is an artifact (the paper being so inaccurate and incomplete). And even if XMRV was reproducible present in CFS patients, causality is still not proven and it is way too far to offer patients “diagnostic tests” and retroviral treatment.

Perhaps the most worrisome part of it all is the non-scientific attitude of WPI-employees towards colleague-scientists, their continuous communication via press releases. And the way they try to directly reach patients, who -i can’t blame them-, are fed up with people not taking them serious and who are longing for a better diagnosis and most of all a better treatment. But this is not the way.

Credits

*Many thanks to Tate (CSF-patient) for alerting me to the last Dutch publication, Q&A’s of WPI and the findings of Mrs Vernon.
- Ficoll blood separation. Photo [CC] http://www.flickr.com/photos/42299655@N00/3013136882/
- Nested PCR: ivpresearch.org

References

  1. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.), 326 (5952), 585-9 PMID: 19815723
  2. Erlwein, O., Kaye, S., McClure, M., Weber, J., Wills, G., Collier, D., Wessely, S., & Cleare, A. (2010). Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008519
  3. Groom, H., Boucherit, V., Makinson, K., Randal, E., Baptista, S., Hagan, S., Gow, J., Mattes, F., Breuer, J., Kerr, J., Stoye, J., & Bishop, K. (2010). Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome Retrovirology, 7 (1) DOI: 10.1186/1742-4690-7-10
  4. van Kuppeveld, F., Jong, A., Lanke, K., Verhaegh, G., Melchers, W., Swanink, C., Bleijenberg, G., Netea, M., Galama, J., & van der Meer, J. (2010). Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort BMJ, 340 (feb25 1) DOI: 10.1136/bmj.c1018
  5. McClure, M., & Wessely, S. (2010). Chronic fatigue syndrome and human retrovirus XMRV BMJ, 340 (feb25 1) DOI: 10.1136/bmj.c1099
  6. http://scienceblogs.com/erv/2010/01/xmrv_and_chronic_fatigue_syndr_5.php
  7. http://scienceblogs.com/erv/2010/01/xmrv_and_chronic_fatigue_syndr_6.php
  8. http://scienceblogs.com/erv/2010/03/xmrv_and_chronic_fatigue_syndr_11.php
  9. http://www.cfids.org/xmrv/022510study.asp
Sensitivity of PCR screening for XMRV in PBMC DNA. VP62 plasmid was serially diluted 1:10 into PBMC DNA from a healthy donor and tested by Taqman PCR with env 6173 primers and probe. The final amount of VP62 DNA in the reaction was A, 2.3 × 10-2 ng, B, 2.3 × 10-3 ng, C, 2.3 × 10-4 ng, D, 2.3 × 10-5 ng, E, 2.3 × 10-6 ng, F, 2.3 × 10-7 ng or G, 2.3 × 10-8 ng. The limit of sensitivity was 2.3 × 10-7 ng (shown by trace F) which equates to 16 molecules of VP62 XMRV clone.




Silly Saturday #22 – A Picture is Worth a 1000 Words.

17 04 2010

This post is my submission for the Grand Rounds to be hosted at Sterile Eye.
This upcoming edition has the theme VISUAL COMMUNICATION.

You know I love visualizations, they are so easy to understand.

No lengthy post here, because a picture is worth a 1000 words…..

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I

250lbs versus 120 lbs

The body scans side by side of 250 lb. woman versus 120 lb. woman.
Source: Bored Panda

Hattip: @EvidenceMatters, @rlbates & @streetanatomy who referred to a repost on LikeCool

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II

Planes or Volcano?

We were wondering this today (April 16, 2010)

Source: Information is Beautiful

Hattip: Bitethedust & @mpesce “Turns out that a little volcanic action is surprisingly good for planet Earth They referred to a repost at The Daily Wh.at.

I’m a real fan of Information is Beautiful with its beautiful visualizations. See previous post on evidence for health supplements

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III

Real Eyeballing

Source: Wolfram Demonstrations Project

Contributed to Sterile Eye ;) : An interactive project showing hows the interaction between an eyeball and two of the muscles connected to it. Muscles deform as the eyeball rotates. You can download a live version.





Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease

10 04 2010

ResearchBlogging.orgApril 8th is Cushing’s Awareness Day. This day has been chosen as a day of awareness as it is the birthday of Dr. Harvey Cushing, a neurosurgeon, who discovered this illness.

Cushing’s disease is a rare hormone disease caused by prolonged exposure to high levels of the stress hormone cortisol in the blood, whereas Addison’s disease is caused by the opposite: the lack of cortisol. For more background information on both see this previous post. Ramona Bates MD, of Suture for a Living, has written an excellent review (in plain language) about Cushing’s Disease on occasion of Cushing Awareness Day at EmaxHealth.

From this you can learn that Cushing’s disease can be due to the patient taking cortisol-like glucocorticoids, such as prednisone for asthma (exogenous cause), but can also arise because people’s bodies make too much of cortisol itself.  This may be due to a tumor on the pituitary gland, the adrenal gland, or elsewhere in the body.

Symptoms of Cushing’s disease are related to the effects of high levels of cortisol or other glucocorticoids on the immune system, the metabolism and  the brain. Symptoms include rapid weight gain, particularly of the trunk and face (central obesity, “moon face” and buffalo neck), thinning of the skin and easy bruising, excessive hair growth, opportunistic infections, osteoporosis and high blood pressure.

Less emphasized than the clinical features are the often very disabling cognitive deficits and emotional symptoms that accompany Cushing’s disease. Cushing patients may suffer from various psychological disturbances, like insomnia, mood swings, depression and manic depression, and from cognitive decline. Several studies have shown that these glucocorticoid induced changes are accompanied by atrophy of the brain, and in particular of the  hippocampal region, leading to hippocampal volume loss and a profound loss of synapses [2]. This hippocampal loss seems reversible [2], but are neurological and psychological defects also restored? This is far more important to the patient than anatomic changes.

If we listen to Cushing patients, who are “cured” and have traded Cushing’s disease for Addison’s disease, we notice that they feel better after their high levels of cortisol have normalized, but not fully cured (see two examples of ex-Cushing patients with longlasting if not irreversible health) problems in my previous post here. [added 2010-04-17)
To realize how this affects daily life, I recommend to read the photo-blog 365 days with Cushing by Robin (also author of Survive the Journey). Quite a few of her posts deal with the continuous weakness (tag muscle atrophy), tiredness (tag fatigue), problems with (short-term) memory (see tag memory)  or both (like here and here).

Scientifically the question is to which extent ex-Cushing patients score worse than other healthy individuals or chronically ill people and, if so, whether this can be attributed to the previous high levels of glucocorticoids.

A recent study by endocrinologists (and one neurologists) from the Leiden University Medical Center assessed the cognitive functioning of patients  after long-term cure of their Cushing's disease (caused by a ACTH producing pituitary adenoma, that induces overproduction of cortisol (hypercortisolism) by the adrenals [1]. Previous studies had contradictory outcomes and/or were too small to draw conclusions.

The authors first compared a group of 74 Cushing patients (with a previous pituitary tumor) with matched healthy controls (selected by the patients themselves). Matched means that these controls had the same characteristics as the Cushing patients with respect to gender (male/female: 13/61), age (52 yr) and education.
Cushing patients were on average 13 years in remission and were followed for another 3 years (total 16 yrs follow-up). Cushing’s disease  had been established by clinical signs and symptoms and by appropriate biochemical tests. All patients were treated by transsphenoidal surgery (surgery via the nostrils), if necessary followed by repeat surgery and/or radiotherapy (27%). Cure of Cushing’s disease was defined by normal overnight suppression of plasma cortisol levels after administration of dexamethasone and normal 24-h urinary excretion rates of cortisol. 58% of the patients had at least one form of hypopituitarism (deficiency of one or more hormones) and half of the patients needed hydrocortisone replacement therapy.

Long after their cure, 62% of the Cushing patients reported memory problems, and 47% reported problems in executive functioning. The Hospital Anxiety and Depression Scale (HADS)-score (10.5)  indicated no clinical depression or anxiety. Patients with long-term cure of Cushing’s disease did not perform worse on measures of global cognitive functioning. However, these patients had several other cognitive impairments, mainly in the memory domain.
Only a single test result (FAS, measures verbal mental flexibility and fluency) was significantly different between patients with short and long-term remission.

From direct comparison with healthy controls it is not clear what causes these cognitive alterations in Cushing patients.

Therefore the cognitive function of Cushing patients was compared to that of patients previously treated for non-functioning pituitary macroadenomas (NFMA).
NFMA patients were chosen, because they have undergone similar treatments (transsphenoidal surgery (100%), with repeat surgery and/or radiotherapy (44%) as the Cushing patients. They also shared hypopituitarism and the need for hydrocortisone substitution in half of the cases. NFMA patients, however, have never been exposed to prolonged excess of cortisol.

Cushing patients could not be directly compared to NFMA-patients, because these patient groups differed with regard to age and gender.

Thus Cushing patients were compared to matched healthy controls and NFMA to another set of healthy controls, matched to these NFMA patients (Male/Female: 30/24  and mean age: 61 yr).

To compare Cushing patients with NFMA patients the Z-scores* were calculated for each patient group in relation to their appropriate control group. A general linear model was used to compare the Z-scores.

Overall Cushing patients performed worse than NFMA patients. In the memory domain, patients cured from Cushing’s disease had a significantly lower MQ measured with the Wechsler Memory Scale compared with patients with NFMA in the subscales concentration and visual memory. On the Verbal Learning Test of Rey, patients cured from Cushing’s disease recalled fewer words in the imprinting, the immediate and delayed recall trials. Furthermore, on the Rey Complex Figure, patients with cured Cushing’s disease scored worse on both trials when compared with NFMA patients. In tests measuring executive function, patients cured from Cushing’s disease made fewer correct substitutions on the Letter-Digit Substitution Test and came up with fewer correct patterns on the Figure Fluency Test compared with treated NFMA patients.

These impairments were not merely related to pituitary disease in general and/or its treatment, because these patients with long-term cure of Cushing’s disease also revealed subtle impairments in cognitive function compared with patients previously treated for NFMA. These are most likely caused by the irreversible effects of previous glucocorticoid excess on the central nervous system (because this is the main difference between the two).

Sub-analysis indicated that hypopituitarism was associated with mildly impaired executive functioning** and hydrocortisone dependency** and additional radiotherapy were negatively associated with memory and executive functioning, whereas the duration of remission positively influenced memory and executive functioning.

The main point of criticism, apparently raised during the review process and discussed by the authors, is the presentation of the data without adjustments for multiple comparisons. When more than one test is used, the chance of finding at least one test statistically significant due to chance increases. As the authors point out, however, the positive significant results were not randomly distributed among the different variables. Furthermore, the findings are plausible given the irreversible effects of cortisol excess on the central nervous system in experimental animal and clinical studies.

Although not addressed in this study, similar cognitive impairments would be expected in patients having continuous overexposure to exogenous glucocorticosteroids, like prednison.

* Z-scores: The z score for an item, indicates how far and in what direction, that item deviates from its distribution’s mean, expressed in units of its distribution’s standard deviation. The z score transformation is especially useful when seeking to compare the relative standings of items from distributions with different means and/or different standard deviations (see: http://sysurvey.com/tips/statistics/zscore.htm).

** This makes me wonder whether Addison patients with panhypopituitarism have lower cognitive functions compared to healthy controls as well.

Hattip: Hersenschade door stresshormoon lijkt onomkeerbaar (2010/04/08/) (medicalfacts.nl/)

References

  1. Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, & Romijn JA (2010). Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease. The Journal of clinical endocrinology and metabolism PMID: 20371667
  2. Patil CG, Lad SP, Katznelson L, & Laws ER Jr (2007). Brain atrophy and cognitive deficits in Cushing’s disease. Neurosurgical focus, 23 (3) PMID: 17961025 Freely available PDF, also published at Medscape




The University Library (UBA) goes Mobile.

4 04 2010
UBA mobielOur Medical Library at the AMC hospital is one of main (autonomous) libraries of the UBA, the University Library of the University of Amsterdam.

The UBA developed the Spoetnik (library 23 things-like) course -inspiring the start of this blog-, has a library-coach with chat function, a library blog (UBA-e), and is now on Twitter as @bibliotheekuva.
Plus, as I just learned, a small team of the UBA recently launched a mobile version of the library website.

I like their approach. This team consisting of Driek Heesakkers (project leader), Lukas Koster, Gre Ootjers, Roxana Popistasu en Alice Doek, realized this “perpetual beta version” in no more than 7 weeks (from first meeting till launch at April 1st). There aim was not to strive for perfection, but to develop a version first and to learn from their mistakes and the feedback from the users. Thus highly interactive.

Another excellent principle was that they designed ONE mobile app for all smart phones.

This is what UBA mobile offers right now:

  • The library catalog (searching; reserve items; renew loans)
  • Opening hours and addresses of library locations
  • Locations (on a map)
  • Contact phone numbers
  • Questions, feedback
  • News via @bibliotheekuva-tweets

The most important feature, full access to the digital library (with link to all subscriptions) is not yet realized.

I hope our medical library will follow this shining example. Many medical students and doctors use smart-phones and I’m sure a digital version of our medical library website would surely be appreciated by our clients.

Mobile is the future. What do you think?

Below a short and clear presentation by Lukas Koster at UGUL (UGame ULearn) 2010.

The web address of the mobile site is: http://cf.uba.uva.nl/mobiel.

Short notice about UBA mobile at the news section of the UBA.

Janneke Staaks (librarian for: Psychology, Cultural Anthropology and Pedagogical and Educational Sciences) has dealt more in depth with this subject. See this post at her (Dutch) blog FMG Library.





Health Care Reform 2010- Obama, USA, Bill, Dutch, Plan, Doctors, Letterman, Pills, $ & other Random Thoughts

30 03 2010

“I do believe the only way we can end all preventable deaths and the suffering of millions is to provide decent health care to all.”
Hilary Benn, 2006
———————

The next Grand Rounds will be hosted by Evan Falchuk at SEE FIRST (Insights into the Uncertain World of Healthcare).  Evan’s theme is Health Care Reform.

How will it affect your life, your medical practice, your experience as a patient, as an insured, an employer, an employee, someone without insurance?  What are your reactions to the politics, and what do you think will happen next?  I’m asking for your candid views on health care reform seen from whatever perspective you bring.  Medicine, politics, business, humor, left, right, center, up, down, you name it.

Health Care Reform has been a theme more than once in this Grand Rounds, i.e. February 10th at the Health Care Blog, and at Obama’s inauguration day (Ten Suggestions For Healthcare Reform) by Val Jones, MD.

The question is which health care reform? Because after all, this is an international Grand Round with bloggers from the US, Europe, Africa, Australia & Asia.
Probably, just as Google.nl (Dutch) already suggests the theme is meant to be about the USA health care bill of Obama, the future plan, and its costs (see Google Fig).

Since I’m from the Netherlands my non-US readers probably need an introduction first:

Recently  the Patient Protection and Affordable Care Act (known as the “Senate bill”) became law on March 23, 2010 and was shortly thereafter amended by the Health Care and Education Reconciliation Act of 2010 and passed by both houses on March 25 without any support from republicans (source: Wikipedia).  Please see Reuters and CNN for an overview of the March 2010 reforms and the year in which they take effect  and the New York Times [1] for the effect per types of household (i.e. Fig. at the right)

The legislation will tighten regulation of insurance companies and is expected to extend medical coverage to more than 30 million uninsured Americans. As explained by Barack Obama in the CNN-video [2] below, it will take 4 years to implement fully may of these reforms, but some desperately needed reforms will take effect right away.  For instance, having a child with a pre-existing medical condition will no longer be the basis for denial of coverage or higher premiums in the old system.


more about “Health Care:What happens when”, posted with vodpod

As a Dutch citizen, I simply can’t imagine that an insurance would be refused because my girl has asthma and I would to have pay a lot more because I happen to have a chronic disease. I can’t imagine that so many people (from a rich country) are uninsured.

As of January 2006 Our Dutch Health Care has been reformed as well. (Officially) there is no longer a fragmented system with compulsory social insurance for the majority and private health care insurance for people with a higher income. Now there is a standard insurance for all, where the insurers have to accept all patients, with no difference in premium, and no surcharges. Children up to the age of 18 years are insured for free.
Both employer and  government will contribute to the Health Insurance fund, and the insured will pay a nominal premium for their standard insurance directly to the health insurer. People with a low income can apply for a care allowance.
To avoid that health insurers seek to avoid less healthy clients, insurers are entitled to compensation for expensive customers. Although not as ideal as conveyed by the Dutch Government in their commercial-like video [3] (a too central role for the insurers, considerably less covered by the basic health insurance) it still is a pretty good and affordable health care system.

more about “MinVWS | The new health care system i…“, posted with vodpod [press T for English translation]

It is often difficult to imagine how things work in another country unless you’ve been there or hear it through somebody else.

A Dutch correspondent in the US, Tom-Jan Meeus wrote a eye-opening article in the Dutch NRC newspaper [4] about the US health care.

When Meeus collected his first prescriptions from a US pharmacy, he had to pay six times as much for the same pills (same brand, logo, packing) as in the Netherlands. And he was even more surprised that the prices were negotiable. But he got used to the US health care system: he gets an expensive check-up each 2 months instead of the once yearly (when needed) doctor visit back in Holland. In this way his doctor safeguards himself against health insurance claims. Furthermore, his doctor “has to keep the pot boiling too”.
This man knows many influential people and has valuable inside information, i.e. about the health status (botox, psychoses) of some of the key players in the health care system. In addition, he was one of the doctors who thwarted Clintons Health Reform: his glory years. This friendly conservative doctor wants freedom of choice, for himself and his patients. When Meeus objects that this freedom of choice becomes a little expensive, the doctor argues that top health care costs a little (US doctors know they are “the best in the world”)  and continues: “do you really think the health care becomes any cheaper when Obama subsidizes 30 million people to get insured? Hanky Panky, that is what it is.” But he knows a way to circumvent the rules. He cut the ties with two insurance companies that reimburse too little. “Perhaps, we can’t stop Obama, but we can undermine him. Why should we help people when we don’t make money out of it…”.

Hopefully not all the doctors think this way (I’m sure the blogging doctors that I know, don’t), but lets give a moments thought to two statements: That the US Healthcare is “the best” (as it is) and that the new health care system costs too much.

We first have to find out whether the money was well spend before the health care renewal.

I’ve shown the figures before (see [5] and [6]), but here are some other representations.

1. According to the Organization for Economic Cooperation and Development (OECD), the US spent 15.3 percent of its GDP on health care in 2006 and this number is rising. As you can see this is far more than the other countries spend.

This trend was already visible in the early eighties: the last 10-20 years the US spend far more money on health care than other rich countries..


And although the U.S. Medicare coverage of prescription drugs began in 2006, most patented prescription drugs are more costly in the U.S. than in most other countries. Factors involved are the absence of government price controls (Wikipedia).

Perhaps, surprisingly, the higher health expenditure hasn’t lead o a higher life expectancy. (78 years in the US versus 82 years in Japan in 2007). The differences are huge if one plots health spending per capita against life expectancy at birth.

Just like the international comparison, higher health care expenditures in different parts of America don’t result in a better health care for all this extra spending. Miami spends 3 times as much money per person health care than Salem (Oregon). Many doctors in Miami, for instance, perform a bunch of tests, like ECG’s, after chest complaints, because they have the necessary devices, not because all these tests have proven useful. Despite all expensive tests and treatments, Miami (and comparable great spenders)  has the worst death rate following a heart attack.* [ source, video in ref 5 and the Organisation for Economic Co-operation and Development's Health Data 2009 site.]

And this is how the US health care works:  simply more treatments and tests are available, but the incentives are wrong: physicians are paid for the quantity of care not the quality.

Just like the doctor of Tom-Jan Meeus, who did a two-monthly unnecessary check-up.

Or as the internist Lisa Bernstein suggests in the New York Times [7]:

For instance, if an asymptomatic, otherwise healthy, patient comes to me wanting a whole-body CT scan to make sure they do not have something bad hiding inside of them, I would decline and educate him or her that there is no data to show that this test has any significant benefit to offset the potential radiation or other harm and the major medical societies do not recommend this test.”

Mind you this is the situation before the current health care reform.

But there is another thing not yet addressed: the expectations of the US-citizens. Americans (and more and more Europeans too) want those check-ups and screenings, because it gives them a (false) feeling of security and because they feel they have the right. That is why it is so difficult for people to give up unnecessary CT-scans, PSA-screening and mammograms.

One reason why Americans have a higher risk for certain diseases (diabetes, overweight, cardiovascular diseases) might be their lifestyle. And lifestyle is something you can change to a certain extent and can have great effects on your health. Lifestyle is also something you can learn. You can learn to enjoy good food, you can avoid the 3 times daily coca cola  and it can be fun to do some exercise or for children to play outside. But still some people rather have a pill to stay healthy or  undergo all kind of (poor performing) tests to see how they’re doing.

Am I exaggerating?

No. This is reality. A few days ago. I saw Letterman in his show [8] telling Jamie Oliver (on his crusade to change the US diet habits) that “he believed diet pills were the only successful way to lose weight in the U.S. and that he expected humans to ‘evolve to the point where 1,000 years from now we all weigh 500-600lbs and it will be OK’ and that “If you would go to doctor they would be happy to give you as many pills as you need and you weight 80 pounds”

Do I fail to see Lettermans warped sense of humor?

Does he really belief this? And, more important, does the majority of Americans believe this?

For here is much to gain, both in health and health care costs.

* As far as I can tell these are only associations; other possible reasons are not taken into consideration: busy live in a metropolis or the population composition might also play a role.

Main References (all accessed 29 March 2010)

  1. NY-Times (2010/03/24) How Different Types of People Will Be Affected by the Health Care Overhaul.
  2. CNN.com (2010/03/23) Health care timeline (including video)
  3. Ministerie van VWS: The new health care system in the Netherlands
  4. NRC (2010/03/20) Tom-Jan Meeus: Mijn dokter won ook van Clinton (Dutch; subscription required).
  5. Laika’s MedLibLog (2009/09/10) Visualization of  paradoxes behind US Health Care.
  6. Laika’s MedLibLog (2009/09/25) Friday Foolery [4]: Maps & Mapping.
  7. NY Times.com (2010/03/27) health/27patient.html?src=twt&twt=nytimeshealth.
  8. The dail Mail UK (Last updated 210-03-25). Simon Cable. Don’t cry Jamie! Now David Letterman lectures Oliver and says his healthy eating crusade won’t work in America

Photo Credits

This map shows the ability of the health service of each territory to provide good basic health care to a number of people. The health service quality score for 1997 was applied to the population. The world average score for health service quality was 72 out of 100. This means that the equivalent of 4.5 billion people had access to good basic health care.The populations with the poorest health care provision live in Sierra Leone and the Central African Republic. The Sierra Leonean health system scored 36 out of 100 – that is half the world average score. Note that only the most basic care is measured here.
“I do believe the only way we can end all preventable deaths and the suffering of millions is to provide decent health care to all.” Hilary Benn, 2006 Territory size shows the proportion of people worldwide who receive good basic health care that live there.




#SillySaturday #17 – Social Media Stats per Second

13 02 2010
more about “Garys Social Media Count“, posted with vodpod

Some time ago I saw the above Real Time Social Media Stats Counter at Heidi Allen Online (see here), the blog of Heidi Allen. The live stats meter is actually from Gary Hayes at Personalize Media (see post: Garys Social Media Count).

You can find the embed code at Gary Hayes post. I used the above Vodpod video, because WordPress won’t allow flash.

Yesterday, I saw a similar stats counter (in Dutch) at the excellent Dutch Education Blog  Trendmatcher tussen ICT en Onderwijs (see here) of @trendmatcher (Willem Karrsenberg). Willem saw these real time stats presented in a powerpoint presentation by Toine Maes, director of  “Kennisnet” (~”Knowledge network”). Later he asked Toine how he managed to get these dynamic stats in his slide. Of course it is great to show such a slide in a class room, or at other occasions.

At his blog Willem explains what it takes to make a slide with real life counters yourself. You need the Cortona 3D viewer (download here), that can be embedded in a browser or in Powerpoint. And you need the definition file with the actual formulas.  He made an example of a presentation and has made all files public (download here).

For people (like me) who find this all too complicated he made a simple one minute Flickr-video (FF) you can use instead. I converted this again to a Vodpod video, which easily picks up the embed code (Add-on in FireFox) and can be directly imported into WordPress.

Willem  notes that he doesn’t know if the actual figures are correct. Bas Jonkers of Kennislink commented that the numbers are based on recent data, mostly from indirect sources. With the Cortona 3D viewer you can see the updated data here

Gary Hayes at Personalize Media shares his sources at his blog. The dates are less recent because his post dates from September 2009, but he will update the data from time to time.

For instance:

  • 20 hours of video uploaded every minute onto YouTube (source YouTube blog Aug 09)
  • Facebook 600k new members per day, and photos, videos per month, 700mill & 4 mill respectively (source Inside Facebook Feb 09)
  • Twitter 18 million new users per year & 4 million tweets sent daily (source TechCrunch Apr 09)
  • 900 000 blogs posts put up every day (source Technorati State of the Blogosphere 2008)
  • UPDATE: YouTube 1Billion watched per day SMH (2009)- counter updated!
  • Flickr has 73 million visitors a month who upload 700 million photos (source Yahoo Mar 09)
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#NotSoFunny #16 – Ridiculing RCTs & EBM

1 02 2010

I remember it well. As a young researcher I presented my findings in one of my first talks, at the end of which the chair killed my work with a remark, that made the whole room of scientists laugh, but was really beside the point. My supervisor, a truly original and very wise scientist, suppressed his anger. Afterwards, he said: “it is very easy ridiculing something that isn’t a mainstream thought. It’s the argument that counts. We will prove that we are right.” …And we did.

This was not my only encounter with scientists who try to win the debate by making fun of a theory, a finding or …people. But it is not only the witty scientist who is to *blame*, it is also the uncritical audience that just swallows it.

I have similar feelings with some journal articles or blog posts that try to ridicule EBM – or any other theory or approach. Funny, perhaps, but often misunderstood and misused by “the audience”.

Take for instance the well known spoof article in the BMJ:

“Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials”

It is one of those Christmas spoof articles in the BMJ, meant to inject some medical humor into the normally serious scientific literature. The spoof parachute article pretends to be a Systematic Review of RCT’s  investigating if parachutes can prevent death and major trauma. Of course, no such trial has been done or will be done: dropping people at random with and without a parachute to proof that you better jump out of a plane with a parachute.

I found the article only mildly amusing. It is so unrealistic, that it becomes absurd. Not that I don’t enjoy absurdities at times, but  absurdities should not assume a live of their own.  In this way it doesn’t evoke a true discussion, but only worsens the prejudice some people already have.

People keep referring to this 2003 article. Last Friday, Dr. Val (with whom I mostly agree) devoted a Friday Funny post to it at Get Better Health: “The Friday Funny: Why Evidence-Based Medicine Is Not The Whole Story”.* In 2008 the paper was also discussed by Not Totally Rad [3]. That EBM is not the whole story seems pretty obvious to me. It was never meant to be…

But lets get specific. Which assumptions about RCT’s and SR’s are wrong, twisted or put out of context? Please read the excellent comments below the article. These often put the finger on the spot.

1. EBM is cookbook medicine.
Many define EBM as “make clinical decisions based on a synthesis of the best available evidence about a treatment.” (i.e. [3]). However, EBM is not cookbook medicine.

The accepted definition of EBM  is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” [4]. Sacket already emphasized back in 1996:

Good doctors use both individual clinical expertise and the best available external evidence, and neither alone is enough. Without clinical expertise, practice risks becoming tyrannised by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient. Without current best evidence, practice risks becoming rapidly out of date, to the detriment of patients.


2. RCT’s are required for evidence.

Although a well performed RCT provides the “best” evidence, RCT’s are often not appropriate or indicated. That is especially true for domains other than therapy. In case of prognostic questions the most appropriate study design is usually an inception cohort. A RCT for instance can’t tell whether female age is a prognostic factor for clinical pregnancy rates following IVF: there is no way to randomize for “age”, or for “BMI”. ;)

The same is true for etiologic or harm questions. In theory, the “best” answer is obtained by RCT. However RCT’s are often unethical or unnecessary. RCT’s are out of the question to address whether substance X causes cancer. Observational studies will do. Sometimes cases provide sufficient evidence. If a woman gets hepatic veno-occlusive disease after drinking loads of a herbal tea the finding of  similar cases in the literature may be sufficient to conclude that the herbal tea probably caused the disease.

Diagnostic accuracy studies also require another study design (cross-sectional study, or cohort).

But even in the case of  interventions, we can settle for less than a RCT. Evidence is not present or not, but exists on a hierarchy. RCT’s (if well performed) are the most robust, but if not available we have to rely on “lower” evidence.

BMJ Clinical Evidence even made a list of clinical questions unlikely to be answered by RCT’s. In this case Clinical Evidence searches and includes the best appropriate form of evidence.

  1. where there are good reasons to think the intervention is not likely to be beneficial or is likely to be harmful;
  2. where the outcome is very rare (e.g. a 1/10000 fatal adverse reaction);
  3. where the condition is very rare;
  4. where very long follow up is required (e.g. does drinking milk in adolescence prevent fractures in old age?);
  5. where the evidence of benefit from observational studies is overwhelming (e.g. oxygen for acute asthma attacks);
  6. when applying the evidence to real clinical situations (external validity);
  7. where current practice is very resistant to change and/or patients would not be willing to take the control or active treatment;
  8. where the unit of randomisation would have to be too large (e.g. a nationwide public health campaign); and
  9. where the condition is acute and requires immediate treatment.
    Of these, only the first case is categorical. For the rest the cut off point when an RCT is not appropriate is not precisely defined.

Informed health decisions should be based on good science rather than EBM (alone).

Dr Val [2]: “EBM has been an over-reliance on “methodolatry” - resulting in conclusions made without consideration of prior probability, laws of physics, or plain common sense. (….) Which is why Steve Novella and the Science Based Medicine team have proposed that our quest for reliable information (upon which to make informed health decisions) should be based on good science rather than EBM alone.

Methodolatry is the profane worship of the randomized clinical trial as the only valid method of investigation. This is disproved in the previous sections.

The name “Science Based Medicine” suggests that it is opposed to “Evidence Based Medicine”. At their blog David Gorski explains: “We at SBM believe that medicine based on science is the best medicine and tirelessly promote science-based medicine through discussion of the role of science and medicine.”

While this may apply to a certain extent to quack or homeopathy (the focus of SBM) there are many examples of the opposite: that science or common sense led to interventions that were ineffective or even damaging, including:

As a matter of fact many side-effects are not foreseen and few in vitro or animal experiments have led to successful new treatments.

At the end it is most relevant to the patient that “it works” (and the benefits outweigh the harms).

Furthermore EBM is not -or should not be- without consideration of prior probability, laws of physics, or plain common sense. To me SBM and EBM are not mutually exclusive.

Why the example is bullshit unfair and unrealistic

I’ll leave it to the following comments (and yes the choice is biased) [1]

Nibu A George,Scientist :

First of all generalizing such reports of some selected cases and making it a universal truth is unhealthy and challenging the entire scientific community. Secondly, the comparing the parachute scenario with a pure medical situation is unacceptable since the parachute jump is rather a physical situation and it become a medical situation only if the jump caused any physical harm to the person involved.

Richard A. Davidson, MD,MPH:

This weak attempt at humor unfortunately reinforces one of the major negative stereotypes about EBM….that RCT’s are required for evidence, and that observational studies are worthless. If only 10% of the therapies that are paraded in front of us by journals were as effective as parachutes, we would have much less need for EBM. The efficacy of most of our current therapies are only mildly successful. In fact, many therapies can provide only a 25% or less therapeutic improvement. If parachutes were that effective, nobody would use them.
While it’s easy enough to just chalk this one up to the cliche of the cantankerous British clinician, it shows a tremendous lack of insight about what EBM is and does. Even worse, it’s just not funny.

Aviel Roy-Shapira, Senior Staff Surgeon

Smith and Pell succeeded in amusing me, but I think their spoof reflects a common misconception about evidence based medicine. All too many practitioners equate EBM with randomized controlled trials, and metaanalyses.
EBM is about what is accepted as evidence, not about how the evidence is obtained. For example, an RCT which shows that a given drug lowers blood pressure in patients with mild hypertension, however well designed and executed, is not acceptable as a basis for treatment decisions. One has to show that the drug actually lowers the incidence of strokes and heart attacks.
RCT’s are needed only when the outcome is not obvious. If most people who fall from airplanes without a parachute die, this is good enough. There is plenty of evidence for that.

EBM is about using outcome data for making therapeutic decisions. That data can come from RCTs but also from observation

Lee A. Green, Associate Professor

EBM is not RCTs. That’s probably worth repeating several times, because so often both EBM’s detractors and some of its advocates just don’t get it. Evidence is not binary, present or not, but exists on a heirarchy (Guyatt & Rennie, 2001). (….)
The methods and rigor of EBM are nothing more or less than ways of correcting for our
imperfect perceptions of our experiences. We prefer, cognitively, to perceive causal connections. We even perceive such connections where they do not exist, and we do so reliably and reproducibly under well-known sets of circumstances. RCTs aren’t holy writ, they’re simply a tool for filtering out our natural human biases in judgment and causal attribution. Whether it’s necessary to use that tool depends upon the likelihood of such bias occurring.

Scott D Ramsey, Associate Professor

Parachutes may be a no-brainer, but this article is brainless.

Unfortunately, there are few if any parallels to parachutes in health care. The danger with this type of article is that it can lead to labeling certain medical technologies as “parachutes” when in fact they are not. I’ve already seen this exact analogy used for a recent medical technology (lung volume reduction surgery for severe emphysema). In uncontrolled studies, it quite literally looked like everyone who didn’t die got better. When a high quality randomized controlled trial was done, the treatment turned out to have significant morbidity and mortality and a much more modest benefit than was originally hypothesized.

Timothy R. Church, Professor

On one level, this is a funny article. I chuckled when I first read it. On reflection, however, I thought “Well, maybe not,” because a lot of people have died based on physicians’ arrogance about their ability to judge the efficacy of a treatment based on theory and uncontrolled observation.

Several high profile medical procedures that were “obviously” effective have been shown by randomized trials to be (oops) killing people when compared to placebo. For starters to a long list of such failed therapies, look at antiarrhythmics for post-MI arrhythmias, prophylaxis for T. gondii in HIV infection, and endarterectomy for carotid stenosis; all were proven to be harmful rather than helpful in randomized trials, and in the face of widespread opposition to even testing them against no treatment. In theory they “had to work.” But didn’t.

But what the heck, let’s play along. Suppose we had never seen a parachute before. Someone proposes one and we agree it’s a good idea, but how to test it out? Human trials sound good. But what’s the question? It is not, as the author would have you believe, whether to jump out of the plane without a parachute or with one, but rather stay in the plane or jump with a parachute. No one was voluntarily jumping out of planes prior to the invention of the parachute, so it wasn’t to prevent a health threat, but rather to facilitate a rapid exit from a nonviable plane.

Another weakness in this straw-man argument is that the physics of the parachute are clear and experimentally verifiable without involving humans, but I don’t think the authors would ever suggest that human physiology and pathology in the face of medication, radiation, or surgical intervention is ever quite as clear and predictable, or that non-human experience (whether observational or experimental) would ever suffice.

The author offers as an alternative to evidence-based methods the “common sense” method, which is really the “trust me, I’m a doctor” method. That’s not worked out so well in many high profile cases (see above, plus note the recent finding that expensive, profitable angioplasty and coronary artery by-pass grafts are no better than simple medical treatment of arteriosclerosis). And these are just the ones for which careful scientists have been able to do randomized trials. Most of our accepted therapies never have been subjected to such scrutiny, but it is breathtaking how frequently such scrutiny reveals problems.

Thanks, but I’ll stick with scientifically proven remedies.

parachute experiments without humans

* on the same day as I posted Friday Foolery #15: The Man who pioneered the RCT. What a coincidence.

** Don’t forget to read the comments to the article. They are often excellent.

Photo Credits

ReferencesResearchBlogging.org

  1. Smith, G. (2003). Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials BMJ, 327 (7429), 1459-1461 DOI: 10.1136/bmj.327.7429.1459
  2. The Friday Funny: Why Evidence-Based Medicine Is Not The Whole Story”. (getbetterhealth.com) [2010.01.29]
  3. Call for randomized clinical trials of Parachutes (nottotallyrad.blogspot.com) [08-2008]
  4. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, & Richardson WS (1996). Evidence based medicine: what it is and what it isn’t. BMJ (Clinical research ed.), 312 (7023), 71-2 PMID: 8555924
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are very well edged off




Haiti still needs help

21 01 2010

Usually, I don’t grant requests for help “to get the word out”. But I will make an exception for a good cause: Haiti.

You could help Haiti by supporting the International Medical Corps (IMC).

The IMC is a global, humanitarian, nonprofit organization, founded by volunteer doctors and nurses in 1984 and dedicated to saving lives and relieving suffering through relief and development programs. Their emergency response team is in Haiti responding in force, but there are still thousands of patients seeking treatment of which approximately 80% are in need of surgery and are running out of time – especially with the tremendous aftershocks still devastating this country. The team is treating crush injuries, trauma, substantial wound care, shock and other critical cases with the few available supplies – And they’re in it for the long haul.

You can help by donating funds, volunteering in Haiti, or just spreading the word (i.e. putting a widget on your site or or Tweeting this )

Want to know more about IMC’s rescue efforts, see:  http://www.imcworldwide.org/haiti

Here you can also donate to help people of Haiti.

Donating $10 to help the people of Haiti is as simple as sending a text message of the word “haiti” to 85944. But other ways are also possible, i.e. click on the red widget on the left.

Importantly, IMC is highly efficient as 92% of their resources go directly to program activities.

————————————
Nederlanders kunnen ook deze internationale organisatie ondersteunen.

Daarnaast kunt ook terecht bij het oude vertrouwde noodhulp gironummer 555, dat nu speciaal opengesteld is voor Haiti (zie bijvoorbeeld NRC-next). U steunt daarmee wel andere organisaties, die noodhulp geven.

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NOT ONE RCT on Swine Flu or H1N1?! – Outrageous!

16 12 2009

Last week doctorblogs (Annabel Bentley) tweeted: “Outrageous- there isn’t ONE randomised trial on swine flu or #H1N1

Annabel referred to an article at Trust the Evidence, the excellent blog of the Centre for Evidence-Based Medicine (CEBM) in Oxford, UK.

In the article “Is swine flu the most over-published and over-hyped disease ever?Carl Heneghan first showed the results of a quick PubMed search using the terms ‘swine flu’ and ‘H1N1’: this yielded 4,475 articles on the subject, with approximately one third (1,437 articles) published in the last 7 months (search: November 27th). Of these 107, largely news articles, were published in the BMJ, followed by the Lancet and NEJM at 35 each.

Top News stories on H1N1 generated appr. 2000 to 4000 news articles each (in Google). Items included outbreak of a new form of ‘swine flu’ which prompted the United States and the World Health Organization to declare a public health emergency (April), Southern Hemisphere being mostly spared in the swine flu epidemic (May), Tamiflu, i.e. the effects of Tamiflu in children in the BMJ (co-authored by Carl) in August and the availability of the vaccine H1N1 vaccine clinics to offer seasonal flu shots in November.

According to Heneghan this must be the most over-hyped disease ever, and he wonders: “are there any other infections out there?”

Finally he ends with: Do you know what the killer fact is in all of this? There isn’t one randomized trial out there on swine flu or H1N1 – outrageous.”

My first thoughts were: “is H1N1 really so over-published compared to other (infectious) diseases?”, “Is it really surprising that there are no RCTs yet? The H1N1-pandemics just started a few months ago!” and even “are RCT’s really the study designs we urgently need right now?”

Now the severity of the H1N1 flu seems less than feared, it is easy to be wise. Isn’t is logic that there are a lot of “exploratory studies” first: characterization of the virus, establishing the spread of H1N1 around the world, establishing mortality and morbidity, and patterns of vulnerability among the population? It is also understandable that a lot of news articles are published, in the BMJ or in online newspapers. We want to be informed. In the Netherlands we now have a small outbreak of Q-fever, partly because the official approach was slow and underestimated the public health implications of Q-fever. So the public was really underinformed. That is worse than being “overexposed”.

News often spreads like wildfire, that is no news. When I google “US Preventive Services Task Force” (who issued the controversial US breast cancer screening guidelines last month) 2,364 hits still pop up in Google News (over the last month). All papers and other news sources echo the news. 2,000 hits are easily reached.

4,475 PubMed articles on ‘swine flu’ and ‘H1N1’ isn’t really that much. When I quickly search PubMed for the rather “new” disease Q-fever I get 3,752 hits, a search for HPV (Alphapapillomavirus OR papilloma infections OR HPV OR human papilloma virus) gives 19,543 hits (1,330 over the last 9 months), and a quick search for (aids) AND “last 9 months”[edat] yields 4,073 hits!

The number of hits alone doesn’t mean much, certainly not if news, editorials and comments are included. But lets go to the second comment, that there is “not ONE RCT on H1N1.”

Again, is it reasonable to expect ONE RCT published and included in PubMed over a 9 month period? Any serious study takes time from concept to initiation, patient-enrollment, sufficient follow-up, collection of data, writing and submitting the article, peer review, publication, inclusion in PubMed and assignment of MeSH-terms (including the publication type “Randomized Controlled Trial”).

Furthermore RCTs are not always the most feasible or appropriate study designs for answering certain questions. For instance for questions related to harm, etiology, epidemiology, spreading of virus, characteristics, diagnosis and prognosis. RCTs may be most suitable to evaluate the efficacy of treatment or prevention interventions. Thus in case of H1N1 the efficacy of vaccines and of neuraminidase inhibitors to prevent or treat H1N1 flu. However, it may not always be ethical to do so (see below).

I’ve repeated the search, and using prefab “My NCBI filters” for RCTs discussed before I get the following results:

Using the Randomized Controlled Trials limits in PubMed I do get 7 hits, and using broader filters, like the Therapy/Narrow Filter under  Clinical Queries I even find 2 more RCTs that have not yet been indexed by PubMed. With the Cochrane Highly sensitive Filter even more hits are obtained, most of which are “noise”, inherent to the use of a broad filter.

The found RCTs are safety/immunogenicity/stability studies of subunit or split vaccines to H1N1, H3N2, and B influenza strains. This means they are not restricted to H1N1, but this is true for the entire set of H1N1 publications. 40 of the 1443 hits are even animal studies. Thus the total number of articles dealing with H1N1 only -and in humans- is far less than 1443.
By the way, one of the 15 H1N1-hits in PubMed obtained with the SR-filter (see Fig) is a meta-analysis of RCTs in the BMJ, co-authored by Heneghan. It is not about H1N1, but contains the sentence: “Their (neuraminidase inhibitors) effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.”

More important, if studies have been undertaken in this field they are probably not yet published. Thus, the place to look is a clinical trials register, like Clinical trials.gov (http://clinicaltrials.gov/), The International Clinical Registry Platform Search Portal at the WHO (www.who.int/trialsearch) , national or pharmaceutical industry trials registers.

A search for H1N1 OR swine flu in Clinical trials.gov, that offers the best searching functions, yields 132 studies, of which 116 were first recieved this year.

Again, most trials concern the safety and efficacy of H1N1 vaccines and include the testing of vaccines on subgroups, like pregnant women, children with asthma and people with AIDS. 30 trials are phase III.
Narrowing the search to H1N1
OR swine flu | neuraminidase inhibitors OR oseltamivir OR zanamivir (treatment filled in in the filed “Interventions”) yields 8 studies. One of the studies is a phase III trial.

This yield doesn’t seem bad per se. However, numbers of trials don’t mean a lot and a more pertinent issue is, whether the most important and urgent questions are investigated.

Three issues are important with respect to interventions:

  1. Are H1N1 vaccines safe and immunogenic? in subpopulations?
  2. Do H1N1 vaccines lower morbidity and mortality due to the H1N1 flu?
  3. Are neuraminidase inhibitors effective in preventing or treating H1N1 flu?
Question [1] will be answered by current trials.
Older Cochrane Reviews on the seasonal influenza flu (and updates) cast doubt on the efficacy of [2] vaccines (see the [poor*] Atlantic news article) ànd [2] neuraminidase inhibitors in children (Cochrane 2007 and BMJ 2009) ànd adults  (Cochrane 2006, update 2008 and BMJ 2009) against symptoms or complications of the seasonal flu. The possibility has even been raised that seasonal flu shots are linked to swine flu risk.
However, the current H1N1 isn’t a seasonal flu. It is a sudden, new pandemic that requires different actions. Overall H1N1 isn’t as deadly as the regular influenza strains, but it hits certain people harder: very young kids, people with asthma and pregnant women. About the latter group, Amy Tuteur (obstetrician-gynecologist blogging at The Skeptical OB) wrote a guest post at Kevin MD:
(…) the H1N1 influenza has had an unexpectedly devastating impact among pregnant women. According to the CDC, there have been approximately 700 reported cases of H1N1 in pregnant women since April.** Of these, 100 women have required admission to an intensive care unit and 28 have died. In other words, 1 out of every 25 pregnant women who contracted H1N1 died of it. By any standard, that is an appalling death rate. (……)
To put it in perspective, the chance of a pregnant woman dying from H1N1 is greater than the chance of a heart patient dying during triple bypass surgery. That is not a trivial risk.
The H1N1 flu has taken an extraordinary toll among pregnant women. A new vaccine is now available. Because of the nature of the emergency, there has not been time to do any long term studies of the vaccine. Yet pregnant women will need to make a decision as soon as possible on whether to be vaccinated. (Emphasis mine)
…. Given the dramatic threat and the fact that we know of no unusual complications of vaccination, the decision seems clear. Every pregnant woman should get vaccinated as soon as possible.
Thus the anticipated risks must be balanced against the anticipated benefits, Amy urges pregnant women to get vaccinated, even though no one can be sure about side effects ànd about the true efficacy of the vaccine.
For scientific purposes it would be best to perform a double randomized trial with half of a series of pregnant women receiving the vaccine, and the other half a placebo. This would provide the most rigid evidence for the true efficacy and safety of the vaccine.
However it would not be ethical to do so. As “Orac” of Orac Knows explains so well  in his post “Vaccination for H1N1 “swine” flu: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter?” RCTs are only acceptable from an ethical standpoint if we truly do not know whether one treatment is superior to another or a treatment is better than a placebo. There is sufficient reason to believe that vaccination for H1N1 will be more efficacious than “doing nothing”. Leaving a control group unvaccinated will certainly mean that a substantial percentage of pregnant women is going to die. To study the efficacy of the H1N1 among pregnant women observational studies (like cohort studies) are also suitable and more appropriate.
Among the studies found in ClinicalTrials.gov there are a few H1N1 Vaccine Clinical Studies in Pregnant Women, including RCTs. But these RCT’s never compare vaccinated women with a non-vaccinated women. All pregnant women are vaccinated, but the conditions vary.
In one Danish study the arms (study groups) are as follows:
Thus two doses of H1N1 with adjuvant are compared with a higher dose H1N1 without adjuvant. As a control non-pregnant women are vaccinated with the adjuvant H1N1.*** The RCT is performed within a prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. As a natural control women pregnant in the H1N1 season (Q4) will be compared with women outside the season. Please note that the completion date of this study will be 2012, thus we will have to wait a number of years before the study describing the results will be found in PubMed….
To give an impression of the idea behind the study, here is the summary of that trial in the register (not because it is particularly outstanding, but to highlight the underlying thoughts):
“Pregnant women are at particular risk during the imminent H1N1v influenza pandemic. The new H1N1v virus requires urgent political and medical decisions on vaccination strategies in order to minimize severe disease and death from this pandemic. However, there is a lack of evidence to build such decisions upon. A vaccine will be provided in the fourth quarter of 2009, but there is little knowledge on the immunogenicity. Particularly its clinical effectiveness and duration of immunity in pregnant women and their newborn infants is unknown. Therefore, it will be important to study the optimal vaccination regimens with respect to dosing and use of adjuvant to decide future health policies on vaccination of pregnant women. We have a unique possibility to study these aspects of H1N1v infection in pregnant women in our ongoing unselected, prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. Pregnant women from East-Denmark are being enrolled during the 2nd trimester and their infant will undergo a close clinical follow-up. The H1N1v pandemic is expected to reach Denmark Q4-2009. The timing of this enrollment and the imminent pandemic allows for an “experiment of nature” whereby the first half of the mothers completes pregnancy before the H1N1v pandemic. The other half of this cohort will be pregnant while H1N1v is prevalent in the community and will require H1N1v vaccination.The aim of this randomized, controlled, trial is to compare and evaluate the dose-related immune protection conferred by vaccine and adjuvant (Novartis vaccine Focetria) in pregnant women and non-pregnant women. In addition the protocol will assess the passive immunity conferred to the newborn from these vaccine regimes. The study will provide evidence-based guidance for health policies on vaccination for the population of pregnant women during future H1N1v pandemics.”
Although with regard to H1N1-vaccination, appropriate studies are being done, it is feasible that certain measures might not be appropriate on basis of what we know. For instance, pretreating people in the non-risk groups (healthy young adults) with neuraminidase-inhibitors, because they are “indispensable employees”. Perhaps Heneghan, who as you remember is a co-author of the BMJ paper on neuraminidase -inhibitors in children with the seasonal flu, was thinking of this when writing his post.
If Heneghan would have directed his arrows at certain interventions in certain circumstances in certain people he might have had a good point, but now his arrows don’t hit any target. Revere from Effect Measure and Orac from Orac Knows might well have diagnosed him as someone who suffers from “methodolatry,” which is, as Revere puts it, the “profane worship of the randomized clinical trial as the only valid method of investigation.”
Notes
* But see the excellent post of Orac who trashes the Atlantic paper in Flu vaccination: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter? (scienceblogs.com). He also critiques the attitude of the Cochrane author Jefferson, who has a different voice in the media compared to the Cochrane Reviews he co-authors. Here he is far more neutral.
** There is no direct link to the data in the post. I’m not sure whether all pregnant women in the US are routinely tested for H1N1. (if not the percentage of H1N1 deaths among H1N1 infected pregnant women might be overestimated)
***In the US, vaccins given to pregnant women are without adjuvant.

45,982

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Empathy

13 12 2009

The next Grand Rounds will be hosted by Barbara Olson of Florence dot com. The theme will be Simplify, identical to the theme of the annual conference of the Institute for Healthcare Improvement in Orlando. We are invited to share what’s on our mind about any healthcare-related topic indicating with one word why it is important.

My word is Empathy, because it is a versatile,  important skill doctors should have (besides knowledge and technical expertise to name a few other important skills). Empathy is especially important with vulnerable patients, the old and very young.

It strikes me that pediatricians are often very kind and pleasant doctors. They know how to ‘handle’ kids. GP’s also have to deal with kids a lot, but they’re often less patient and kind. At least that applies to our GP. I have had various issues with him, although never outspoken. He is a good doctor, but can be rude at times.

This is a funny story.

Once upon a time, we had to regularly visit our doctor, because my daughter, then 4 to 5 years old, had all kinds of small complaints.

Once she had (innocent) warts. He had to scrape them, but because my daughter found this painful, we had to pretreat the warts with EMLA plasters that numb the skin. I had to do that at home, but the plaster at the inner side of her knee had loosened after a half our walk to the doctor’s practice. He grumbled that I didn’t do it right and that I had to come back another time, meanwhile hard-handedly removing the other warts, forgetting half of them. My daughter didn’t enjoy the scrapings, the corners of her mouth trembling in her attempts not to cry.

After most of the warts had been removed, the doctor took a big flat box with all kinds of little presents, he obviously gave to children at the end of the ordeal.

“Here. You can choose a present!”

My daughter looked at all the minute presents, pondering which one to choose.

There were a lot of rings, with blue stones, red stones, pink stones. There were necklaces, little toys, games….

“Choose one”.

She choose a ring with a pink stone. But wait, that blue ring was nicer and she returned the ring with the pink stone .

But the little patience my doctor had was at an end.

He grabbed something from the box and put it into my daughter’s hand: “Here!”

It was a simple round cardboard with the most silly sheep drawing I have ever seen. With open mound my daughter received the present. Speechless she stared at the gift.

The doctor gestured we could leave the room. He apparently met his obligations with the gift.

With the door handle in my hand, I saw my daughter making a sudden turn. She took one last look at the sheep to throw it as an experienced pitcher straight at the doctor’s desk.

We heard a loud “Well, I never!”, when we left the room.

Added 2009-12-15:

Summary by Barbara at Florence.dot.com:

Jacqueline at Laika’s MedLibLog captures the arachnoid spirit, giving her post a one word title: empathy. The post shows how much we long for care that considers more about who we are than our “chief complaint” often reveals. If Jacqueline had been in the mood to spin longer, she could have called this post, “What comes around, goes around!”
Hit the nail on the head, Barbara!

Photo Credits:

“You are a lamb”, adapted from: http://www.flickr.com/photos/onegoodbumblebee/ / CC BY-NC-SA 2.0

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