P C R : Publish, Cite Cyagen and get a Reward of $100 or more !?

Thursday I got an odd mail from Cyagen.

Cyagen offered me $100 or more in reward for citing their animal model services in an article. Even more surprising the reward was dependent on the impact factor of the journal I was publishing in.

Cyagen gives the following example:

If you published a paper in Science (IF = 30) and cite Cyagen Biosciences, you will be entitled to a voucher with a face value of $3,000 upon notification of the publication (PMID).

Thus the higher the impact factor the higher the reward.

Click to enlarge

First I thought this was link bait, because the mail was send from vresp.com. (spam reputation) and not cyagen.com.

But tweets from @doctorsdilemma and @PhytophthoraLab pointed me to this advertorial at Cyagen’s website.

It was real.

This doesn’t feel right, because it “smells like a conflict of interest”.

In clinical research we all know where conflicts of interest can lead to: biased results. Or according to Corollary 5 in the famous Iaonnides paper “Why Most Published Research Findings Are False”:

“The greater the financial and other interests and prejudices in a scientific field, the less likely the research findings are to be true.”

We expressed our concerns on Twitter but it took a while for Cyagen to respond to our concern (see Facebook-Q&A *).

@laikas @doctorsdilemma @PhytophthoraLab @bengoldacre @rvosa Thank you for being patient while we respond. https://t.co/ieQvO3yCCe

— Cyagen Biosciences (@CyagenBio) August 14, 2015

Meanwhile Ben Goldacre from BadScience and Retraction Watch wrote a post about Cyagen’s “pay-for-citation program”.

Ben Goldacre emphasizes the COI-problem:

I would imagine that this is something journal editors will be interested in, and concerned by. We worry about “conflict of interest” a lot in science, and especially medicine: if someone has shares in a company, or receives money from it, and their publication discusses that company’s products, then this needs to be declared in the paper. If you get funding for a study then, again, you must declare it. If you have received payment for making an academic citation, then in my view this is clearly a source of funds that should be declared.

The most problematic point, according to Goldacre, is that (part of) the researchers “have received funds from Cyagen, in exchange for an academic citation.”  He keeps an archive of the 164 papers that cite Cyagen, so one can always check whether “any one of them has declared receiving money from the company”.
(because in his opinion they should)

Some of the commenters to Goldacres’ post go even further and state:

“It’s one thing to fund a study. It’s another thing entirely to pay someone to write what you want — that’s not science, it’s PR. You’re not being puritanical at all, this is corruption, plain and simple.”

and

“This is an old and very well researched problem. TV makers get paid to have the popular detective drive a certain make of car, scoff a certain brand of drink and so on. That this kind of advertising is not innocent and that it works is beyond doubt. The media have established firm rules about this, science journals need just copy them.”

Although Retraction Watch lets both sides be heard, the title of its post “Researchers, need $100? Just mention Cyagen in your paper!” suggests researchers are being bribed by Cyagen to mention its product anywhere in the paper.

I agree that the Cyagen incentive is a (very curious) marketing trick, but  it has nothing to do with ghostwriting or corruption and IMHO the authors of the 164 papers are not to blame and need not declare anything.

Let me explain why.

• First, as everybody familiar with benchwork knows, authors are required to mention the brand and source of the used reagents and tools (including strains of mice). This is for transparency and reproducibility. There can be huge differences between products and it is important to know which enzyme, primer or mouse strain someone has used.
• Authors only MENTION the products, reagents etc. that they have used. Mentioning a brand doesn’t mean an endorsement, although you probably wouldn’t choose a product if you thought it worked suboptimal.
  Indeed the first two papers on the Cyagen citations list both mentionCyagen only ONCE in the materials and methods where it belongs
• The product itself is not being tested, it is just being used, something else is being tested. (it would be different if the discount was for a diet supplement that was being tested)
• The authors don’t receive money, they receive a discount on their next purchase. This is common practice in the lab when you are a regular customer.
• You don’t write COI’s for getting (normal) discounts.

Still, I do think that this incentive is rather inappropriate and not a very wise thing to do (even from a marketing point of view).

It is not the discount that is problematic, neither is the mention of the product’s name and brand in the articles (as this is required).

It is the coupling of the discount (erroneously called “reward”) to “a mention” (erroneously called “citation”) that is not a proper thing to do and even more so, the coupling of the height of the discounts to the impact factor of a journal.

The idea behind it is that Cyagen not only wants to thank its customers, it wants to “increase the number of publications featuring Cyagen as a product or service provider to add strength to our company’s reputation and visible experience”. 

Of course, Cyagen’s reputation is not linearly dependent on the number of the publications and certainly not the citation score. Reputation depends on other things, like the quality of your product, client satisfaction and …  your reputatIon.

It now seems that the entire marketing campaign will just have the opposite effect: it will harm Cyagen’s reputation (and perhaps also that of the researchers).

My advice to Cyagen is to directly remove the incentive from their website and stop the unsolicited mailing.

And please, Cyagen, stop to defend your P(C)R-tactics, just admit it was a wrong approach and learn from it.

* Later I found out that the a Q&A on Facebook had been extracted from an interview a blogger was still in the process of doing with a product manager of Cyagen. Apparently social media etiquette is another thing Cyagen doesn’t master very well.

Update post:2015-08-16

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Diane-35: Geen Reden tot Paniek!

Dear english-speaking readers of this blog.

This post is about the anti-acne drug Diane-35 that (with other 3rd and 4th generation combined oral contraceptives (COCs)) has been linked to the deaths of several women in Canada, France and the Netherlands. Since there is a lot of media attention (and panic) in the Netherlands, the remainder of this post is in Dutch. Please write in the comments (or tweet) if you would like me to summarize the health concerns of these COCs in a separate English post.

————————-

Mediaophef 

Er is de laatste tijd nogal veel media-aandacht voor Diane-35. Het begon allemaal in Frankrijk, waar de Franse toezichthouder op geneesmiddelen ANSM Diane-35* eind januari van de markt wilde halen omdat in de afgelopen 25 jaar 4 vrouwen na het gebruik ervan waren overleden. In beroep werd dit afgewezen, waarna de ANSM de EMA (European Medicines Agency) verzocht om de veiligheid van Diane en 3e/4e generatie orale combinatie anticonceptiepillen (OAC) nog eens te onderzoeken.

In januari overleed ook een 21-jarige gebruikster van Diane-35 in Nederland. Met terugwerkende kracht ontving het Nederlandse Bijwerkingscentrum Lareb 97 meldingen van bijwerkingen van Diane-35. Hieronder waren 9 sterfgevallen uit 2011 en eerder.** Overigens werden ook sterfgevallen gemeld van vrouwen die vergelijkbare (3e en 4e generatie) orale anticonceptiemiddelen hadden gebruikt, zoals Yasmin.

Alle vrouwen zijn overleden aan bloedproppen in bloedvaten (trombose dan wel longembolie).  Totaal waren er  89 meldingen van bloedstolsels, wat altijd (ook zonder dodelijke afloop) een ernstige bijwerking is.

Aanleiding voor Canada en België, om ook in de statistieken te duiken. In Canada bleken sinds 2000 11 vrouwen die Diane-35 slikten te zijn overleden en in België zijn er sinds 2008 29 meldingen van trombose door het gebruik van de 3e/4e generatiepil (5 door Diane-35, geen doden)

Dit nieuws sloeg in als een bom. Veel mensen raakten in paniek. Of zijn boos op Bayer*, het CBG (College ter Beoordeling van Geneesmiddelen) en/of minister Schippers die het naar hun idee laten afweten. Op Twitter zie ik aan de lopende band tweets voorbijkomen als:

“Diane-35 pil: heet deze zo omdat je er niet altijd de 35 jaar mee haalt?“.

“Tonnen #rundvlees halen we uit de handel om wat #paardenvlees. Maar doden door de Diane 35 #pil doet de regering niks mee.

Oud Nieuws

Dergelijke reacties zijn sterk overdreven. Er is absoluut geen reden tot paniek.

Echter waar rook is, is vuur. Ook al gaat het hier om een klein brandje.

Maar wat betreft Diane-35 is die rook er al jaren…. Waarom roept men nu ineens: “Brand!”?

De meeste sterfgevallen zijn van vòòr dit jaar. Dat de Fransen authoriteiten nu zoveel daadkracht tonen komt waarschijnlijk omdat hen laksheid verweten werd bij recente schandalen met PIP-borstimplantaten en Mediator, dat meer dan 500 sterfgevallen veroorzaakt heeft. [Reuters, zie ook het blog van Henk Jan Out]

Verder was allang bekend dat Diane-35 de kans op bloedstolsels verhoogde.

Niet alleen Diane-35

Men kan de risico’s van Diane-35 niet los zien van de risico’s van orale anticonceptiemiddelen (OAC’s) in het algemeen.

Diane-35 lijkt qua samenstelling erg op de 3e generatie OAC.  Het is echter uniek omdat het in plaats van een 3e generatie progestogeen cyproteronacetaat bevat. ‘De pil’ bevat levonorgestrel, dit is een 2e generatie progestogeen. Al de OAC combinatiepillen bevatten daarnaast (tegenwoordig) een lage dosering ethinylestradiol.

Zoals gezegd, is al jaren bekend dat alle OAC’s, dus ook ‘de pil’, de kans op bloedstolsels in bloedvaten licht verhogen[1,2,3]. Op zijn hoogst verhogen 2e generatie OAC’s (met levonorgestrel) die kans met een factor 4. Derde generatie pillen lijken die kans verder te verhogen. Met hoeveel precies, daarover verschillen de meningen. Voor wat beteft Diane-35, ziet de een géén tot nauwelijks effect [4], de ander een 1,5 [5]  tot 2 x [3] sterker effect.  Het totaalplaatje ziet er ongeveer als volgt uit:

Absolute en relatieve kans op VTE (Veneuze trombo-embolie).
Uit: http://www.anticonceptie-online.nl/pil.htm

Risico’s in Perspectief

Een 1,5-2 x groter risico vergeleken met de “gewone pil”, lijkt een enorm groot risico. Dit zou ook een groot effect zijn als trombo-embolie vaak voorkwam. Stel dat 1 op de 100 mensen trombose krijgt per jaar, dan zouden op jaarbasis 2-4 op de 100 mensen trombose krijgen na de ‘pil’ en 3-8 mensen na Diane-35 of een 3e of 4e generatiepil. Dit is een groot absoluut risico. Dat risico zou je normaal niet nemen.

Maar trombo-embolie is zeldzaam. Het komt voor bij 5-10 op de 100.000 vrouwen per jaar. En totaal zal 1 op miljoen vrouwen daaraan overlijden. Dat is een heel minieme kans.Vier tot zes keer een kans van iets meer dan 0 blijft een kans van bijna 0. Dus in absolute zin, brengen Diane-35 en OAC’s weinig risico met zich mee.

Daarbij komt dat trombose niet direct door de pil veroorzaakt hoeft te zijn. Roken, leeftijd, (over)gewicht, erfelijke aanleg voor stollingsproblemen kunnen ook een (grote) rol spelen. Verder kunnen deze factoren samenspelen. Om deze reden worden OAC’s (ook de pil) afgeraden aan risicogroepen (oudere vrouwen die veel roken, aanleg voor trombose e.d.)

Het aantal bijwerkingen, dat mogelijk samenhangt met het gebruik van Diane-35, geeft eigenlijk aan dat dit een relatief veilig middel is.

@Net_Arts @medicalfacts @laikas @jopinie Zijn er überhaupt medicijnen waar de afgelopen 25 jaar minder dan 10 mensen aan zijn overleden?

— Hugo van der Wedden (@hugovdwedden) March 7, 2013

Aanvaardbaar risico?

Om het nog meer in perspectief te plaatsen: zwangerschap geeft een 2x hoger risico op trombose dan Diane-35, en in de 12 weken na de bevalling is de kans nog weer 4-8 keer hoger dan in de zwangerschap (FDA). Toch zullen vrouwen het daarvoor niet laten om zwanger te worden. Het krijgen van een kind weegt meestal (impliciet) op tegen(kleine) risico’s (waarvan trombose er één is).

Men kan de (kans op) risico’s dus niet los zien van de voordelen. Als het voordeel hoog is zal men zelfs een zeker risico op de koop toe willen nemen (afhankelijk van de ernst van de aandoening en eht nut). Aan de andere kant wil je zelfs een heel klein risico niet lopen, als je geen baat hebt bij een middel of als er even goede, maar veiliger middelen zijn.

Maar mag de patiënte die overweging niet zelf met haar arts maken?

Geen plaats voor Diane-35  als anticonceptiemiddel

Diane-35 heeft een anticonceptiewerking, maar het is hiervoor niet (langer) geregistreerd. De laatste anticonceptie-richtlijn van de nederlandse huisartsen (NHG) uit 2010 [6] zegt expliciet dat er geen plaats meer is voor de pil met cyproteronacetaat. Dit omdat de gewone ‘pil’ even goed zwangerschap voorkomt én (iets) minder kans geeft op trombose als bijwerking. Dus waarom zou je een een potentieel hoger risico lopen, als dat niet nodig is? Helaas is de NHG-standaard minder expliciet over 2e en 3e generatie OAC’s.

In andere landen denkt men vaak net zo (In de VS is Diane-35 echter niet geregistreerd).

Dit zegt bijv de RCOG (Royal College of Obstetricians and Gynaecologist, UK) in hun evidence-based richtlijn die specifiek gaat over OAC’s en kans op trombose [1]

Diane-35 als middel tegen ernstige acne en overbeharing.

Omdat het cyproteron acetaat in Diane-35 een sterk anti-androgene werking heeft kan het worden ingezet  bij ernstige acné en overbeharing (dat laatste met name bij vrouwen met PCOS, een gynecologische aandoening). Desgewenst kan het dan tevens dienst doen als anticonceptiemiddel: 2 vliegen in één klap.

Clinical Evidence, dat een heel mooie evidence based bron is die voor-en nadelen van behandelingen tegen elkaar afzet, concludeert dat middelen met cyproteron acetaat ondanks hun prima werking, bij ernstige overbeharing (bij PCOS) niet de voorkeur verdienen boven middelen als metformine. Het risico op trombose is in deze overweging meegenomen.[7]

Volgens een Cochrane Systematisch Review hielpen alle OAC’s wel bij acné, maar OAC’s met cyproteron leken wat effectiever dan pillen met 2e of 3e generatie progestogeen. De resultaten waren echter tegenstrijdig en de studies niet zo erg sterk.[8]

Sommigen concluderen op basis van dit Cochrane Review dat alle OAC’s even goed helpen en dat de gewone pil dus voorkeur verdient (zie bijv. dit recente artikel van Helmerhorst in de BMJ [2], en de NHG standaard acne [9]

Maar in de meest recente Richtlijn Acneïforme Dermatosen [10] van de Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV) wordt er op basis van dezelfde evidence iets anders geconcludeerd:

De Nederlandse dermatologen komen dus met een positieve aanbeveling van Diane-35 ten opzichte van andere anticonceptiemiddelen bij vrouwen die ook anticonceptie wensen. Nergens in deze richtlijn wordt expliciet gerefereerd aan trombose als mogelijke bijwerking.

Het voorschrijfbeleid in de praktijk.

Als Diane-35 niet als anticonceptiemiddel voorgeschreven wordt, en het wordt slechts bij ernstige vormen van acne of overbeharing gebruikt, hoe kan dit middel met een zo’n laag risico dan zo’n omvangrijk probleem worden? De doelgroep èn de kans op bijwerkingen is immers heel klein. En hoe zit het met 3e en 4e generatie OAC’s die niet eens bij acné voorgeschreven zullen worden? Daar zou de doelgroep nog kleiner moeten zijn.

De realiteit is dat de omvang van het probleem niet zozeer door het on-label gebruik komt maar, zoals Janine Budding al aangaf op haar blog Medical Facts door off-label voorschrijfgedrag, dus voor een  andere indicatie dan waarvoor het geneesmiddel is geregistreerd. In Frankrijk gebruikt de helft van de vrouwen die OAC’s gebruiken, de 3e en 4e generatie OAC: dat is ronduit buitensporig, en niet volgens de richtlijnen.

In Nederland slikkten ruim 161.000 vrouwen Diane-35 of een generieke variant met exact dezelfde werking. Ook veel Nederlandse en Canadese gebruiken Diane-35 en andere 3e en 4e generatie OAC’s puur anticonceptiemiddel. Voor een deel, omdat sommige huisartsen het ‘in de pen’ hebben of denken dat een meisje dan gelijk van haar puistjes afgeholpen is. Voor een deel omdat, in  Nederland en  Frankrijk, Diane-35 vergoed wordt en de gewone pil niet. Er is, zeker in Frankrijk, een run op een ‘gratis’ pil.

Online bedrijven spelen mogelijk ook een rol. Deze lichten vaak niet goed voor. Eén zo’n bedrijf (met gebrekkige info over Diane op hun website) gaat zelfs zover het twitter account @diane35nieuws te creeeren als dekmantel voor online pillenverkoop.

Wat nu?

Hoewel de risico’s van Diane-35 allang bekend waren en gering lijken te zijn, en bovendien vergelijkbaar met die van de 3e en 4e generatie  OAC’s, is er een massaal verzet tegen Diane-35 op gang gekomen, die niet meer te stuiten lijkt. Niet de experts, maar de media en de politiek lijken de discussie te voeren.Erg verwarrend en soms misleidend voor de patiënt.

Mijn inziens is het besluit van de Nederlandse huisartsen, gynecologen en recent ook de dermatologen om Diane-35 voorlopig niet voor te schrijven aan nieuwe patiënten tot de autoriteiten een uitspraak hebben gedaan over de veiligheid***, gezien de huidige onrust, een verstandige.

Wat niet verstandig is om zomaar met de Diane-35 pil te stoppen. Overleg altijd eerst met uw arts wat voor u de beste optie is.

In 1995 heeft een vergelijkbare reactie op waarschuwingen over de tromboserisico’s van bepaalde OAC’s geleid tot een ware “pil scare”: vrouwen gingen massaal over op een andere pil of stopten er in het geheel mee. Gevolg: een piek aan ongewenste zwangerschappen (met overigens een veel hogere kans op trombose) en abortussen. Conclusie destijds [10]:

“The level of risk should, in future, be more carefully assessed and advice more carefully presented in the interests of public health.”

Kennelijk is deze les aan Nederland en Frankrijk voorbijgegaan.

Hoewel ik denk dat Diane-35 maar voor een beperkte groep echt zinvol is boven de bestaande middelen, is het te betreuren dat op basis van ongefundeerde reacties, patiënten straks mogelijk zelf geen keuzevrijheid meer hebben. Mogen zij zelf de balans tussen voor-en nadelen bepalen?

Het is begrijpelijk (maar misschien niet zo heel professioneel), dat dermatologen nogal gefrustreerd reageren, nu een bepaalde groep patienten tussen wal en schip raakt. Tevens moet men niet op basis van evidence en argumenten, maar onder druk van media en politiek, tot een ander beleid overgaan.

Want laten we wel wezen, sommige dermatologische en gynecologische patiënten hebben wel baat bij Diane-35.

Ik kreeg hem op mijn 14e voorgeschreven, acnévrij. RT @volkskrant: Waarom wordt #Diane35 niet in Nederland verboden? http://t.co/seZ5Z7V3hk

— Kiind (@KiindNL) March 7, 2013

en

@laikas great, completely agree (being on Diane-35 for 20 years 😉 )

— Esther van Zuuren (@Ezzoef) March 8, 2013

En tot slot een prachtige reactie van een acne-patiënte op een  blog post van Ivan Wolfers. Zij vat de essentie in enkele zinnen samen. Net als bovenstaande dames, een patient die zeer weloverwogen met haar arts beslissingen neemt op basis van de bestaande info.

Zoals het zou moeten…

Noten

* Diane-35 wordt geproduceerd door Bayer. Het staat ook bekend als Minerva, Elisa en in buitenland bijvoorbeels als Dianette. Er zijn verder ook veel merkloze preparaten met dezelfde samenstelling.

**Inmiddels heeft zijn er nog 4 dodelijke gevallen na gebruik van Diane-35 in Nederland bijgekomen (Artsennet, 2013-03-11)

***Hopelijk wordt de gewone pil dan ook in de vergelijking meegenomen. Dit is wel zo eerlijk: het gaat immers om een vergelijking.

Referenties 

• Venous Thromboembolism and Hormone Replacement Therapy – Green-top Guide line 40 (2010) Royal College of Obstetricians and Gynaecologists, 

  2011

• Helmerhorst F.M. & Rosendaal F.R. (2013). Is an EMA review on hormonal contraception and thrombosis needed?, BMJ (Clinical research ed.), PMID: 23471363
• van Hylckama Vlieg A., Helmerhorst F.M., Vandenbroucke J.P., Doggen C.J.M. & Rosendaal F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study., BMJ (Clinical research ed.), PMID: 19679614
• Spitzer W.O. (2003) Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation., Journal of obstetrics and gynaecology Canada : JOGC = Journal d’obstétrique et gynécologie du Canada : JOGC, PMID: 14663535
• Martínez F., Ramírez I., Pérez-Campos E., Latorre K. & Lete I. (2012) Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis., The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, PMID: 22239262

• NHG-Standaard Anticonceptie 2010 Anke Brand, Anita Bruinsma, Kitty van Groeningen, Sandra Kalmijn, Ineke Kardolus, Monique Peerden, Rob Smeenk, Suzy de Swart, Miranda Kurver, Lex Goudswaard.

• Cahill D. (2009). PCOS., Clinical evidence, PMID: 19445767
• Arowojolu A.O., Gallo M.F., Lopez L.M. & Grimes D.A. (2012). Combined oral contraceptive pills for treatment of acne., Cochrane database of systematic reviews (Online), PMID: 22786490
• Kertzman M.G.M., Smeets J.G.E., Boukes F.S. & Goudswaard A.N. [Summary of the practice guideline ‘Acne’ (second revision) from the Dutch College of General Practitioners]., Nederlands tijdschrift voor geneeskunde, PMID: 18590061
• Richtlijn Acneïforme Dermatosen, © 2010, Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV)
• Furedi A. The public health implications of the 1995 ‘pill scare’., Human reproduction update, PMID: 10652971

Of Mice and Men Again: New Genomic Study Helps Explain why Mouse Models of Acute Inflammation do not Work in Men

This post is update after a discussion at Twitter with @animalevidence who pointed me at a great blog post at Speaking of Research ([19], a repost of [20], highlighting the shortcomings of the current study using just one single inbred strain of mice (C57Bl6)  [2013-02-26]. Main changes are in blue

A recent paper published in PNAS [1] caused quite a stir both inside and outside the scientific community. The study challenges the validity of using mouse models to test what works as a treatment in humans. At least this is what many online news sources seem to conclude: “drug testing may be a waste of time”[2], “we are not mice” [3, 4], or a bit more to the point: mouse models of inflammation are worthless [5, 6, 7].

But basically the current study looks only at one specific area, the area of inflammatory responses that occur in critically ill patients after severe trauma and burns (SIRS, Systemic Inflammatory Response Syndrome). In these patients a storm of events may eventually lead to organ failure and death. It is similar to what may occur after sepsis (but here the cause is a systemic infection).

Furthermore the study only uses one single approach: it compares the gene response patterns in serious human injuries (burns, trauma) and a human model partially mimicking these inflammatory diseases (human healthy volunteers receiving  a low dose endotoxin) with the corresponding three animal models (burns, trauma, endotoxin).

And, as highlighted by Bill Barrington of “Understand Nutrition” [8], the researchers have only tested the gene profiles in one single strain of mice: C57Bl6 (B6 for short). If B6 was the only model used in practice this would be less of a problem. But according to Mark Wanner of the Jackson Laboratory [19, 20]:

 It is now well known that some inbred mouse strains, such as the C57BL/6J (B6 for short) strain used, are resistant to septic shock. Other strains, such as BALB and A/J, are much more susceptible, however. So use of a single strain will not provide representative results.

The results in itself are very clear. The figures show at a glance that there is no correlation whatsoever between the human and B6 mouse expression data.

Seok and 36 other researchers from across the USA  looked at approximately 5500 human genes and their mouse analogs. In humans, burns and traumatic injuries (and to a certain extent the human endotoxin model) triggered the activation of a vast number of genes, that were not triggered in the present C57Bl6 mouse models. In addition the genomic response is longer lasting in human injuries. Furthermore, the top 5 most activated and most suppressed pathways in human burns and trauma had no correlates in mice. Finally, analysis of existing data in the Gene Expression (GEO) Database showed that the lack of correlation between mouse and human studies was also true for other acute inflammatory responses, like sepsis and acute infection.

This is a high quality study with interesting results. However, the results are not as groundbreaking as some media suggest.

As discussed by the authors [1], mice are known to be far more resilient to inflammatory challenge than humans*: a million fold higher dose of endotoxin than the dose causing shock in humans is lethal to mice.* This, and the fact that “none of the 150  candidate agents that progressed to human trials has proved successful in critically ill patients” already indicates that the current approach fails.

[This is not entirely correct the endotoxin/LPS dose in mice is 1000–10,000 times the dose required to induce severe disease with shock in humans [20] and mice that are resilient to endotoxin may still be susceptible to infection. It may well be that the endotoxin response is not a good model for the late effects of  sepsis]

The disappointing trial results have forced many researchers to question not only the usefulness of the current mouse models for acute inflammation [9,10; refs from 11], but also to rethink the key aspects of the human response itself and the way these clinical trials are performed [12, 13, 14]. For instance, emphasis has always been on the exuberant inflammatory reaction, but the subsequent immunosuppression may also be a major contributor to the disease. There is also substantial heterogeneity among patients [13–14] that may explain why some patients have a good prognosis and others haven’t. And some of the initially positive results in human trials have not been reproduced in later studies either (benefit of intense glucose control and corticosteroid treatment) [12]. Thus is it fair to blame only the mouse studies?

dick mouse (Photo credit: Wikipedia)

The coverage by some media is grist to the mill of people who think animal studies are worthless anyway. But one cannot extrapolate these findings to other diseases. Furthermore, as referred to above, the researchers have only tested the gene profiles in one single strain of mice: C57Bl6, meaning that “The findings of Seok et al. are solely applicable to the B6 strain of mice in the three models of inflammation they tested. They unduly generalize these findings to mouse models of inflammation in general. [8]”

It is true that animal studies, including rodent studies, have their limitations. But what are the alternatives? In vitro studies are often even more artificial, and direct clinical testing of new compounds in humans is not ethical.

Obviously, the final proof of effectiveness and safety of new treatments can only be established in human trials. No one will question that.

A lot can be said about why animal studies often fail to directly translate to the clinic [15]. Clinical disparities between the animal models and the clinical trials testing the treatment (like in sepsis) are one reason. Other important reasons may be methodological flaws in animal studies (i.e. no randomization, wrong statistics) and publication bias: non-publication of “negative” results appears to be prevalent in laboratory animal research.[15–16]. Despite their shortcomings, animal studies and in vitro studies offer a way to examine certain aspects of a process, disease or treatment.

In summary, this study confirms that the existing (C57Bl6) mouse model doesn’t resemble the human situation in the systemic response following acute traumatic injury or sepsis: the genomic response is entirely different, in magnitude, duration and types of changes in expression.

The findings are not new: the shortcomings of the mouse model(s) were long known. It remains enigmatic why the researchers chose only one inbred strain of mice, and of all mice only the B6-strain, which is less sensitive to endotoxin, and only develop acute kidney injury (part of organ failure) at old age (young mice were used) [21]. In this paper from 2009 (!) various reasons are given why the animal models didn’t properly mimic the human disease and how this can be improved. The authors stress that:

“the genetically heterogeneous human population should be more accurately represented by outbred mice, reducing the bias found in inbred strains that might contain or lack recessive disease susceptibility loci, depending on selective pressures.” 

Both Bill Barrington [8] and Mark Wanner [18,19] propose the use of “diversity outbred cross or collaborative cross mice that  provide additional diversity.” Indeed, “replicating genetic heterogeneity and critical clinical risk factors such as advanced age and comorbid conditions (..) led to improved models of sepsis and sepsis-induced AKI (acute kidney injury). 

The authors of the PNAS paper suggest that genomic analysis can aid further in revealing which genes play a role in the perturbed immune response in acute inflammation, but it remains to be seen whether this will ultimately lead to effective treatments of sepsis and other forms of acute inflammation.

It also remains to be seen whether comprehensive genomic characterization will be useful in other disease models. The authors suggest for instance,  that genetic profiling may serve as a guide to develop animal models. A shotgun analyses of gene expression of thousands of genes was useful in the present situation, because “the severe inflammatory stress produced a genomic storm affecting all major cellular functions and pathways in humans which led to sufficient perturbations to allow comparisons between the genes in the human conditions and their analogs in the murine models”. But rough analysis of overall expression profiles may give little insight in the usefulness of other animal models, where genetic responses are more subtle.

And predicting what will happen is far less easy that to confirm what is already known….

NOTE: as said the coverage in news and blogs is again quite biased. The conclusion of a generally good Dutch science  news site (the headline and lead suggested that animal models of immune diseases are crap [6]) was adapted after a critical discussion at Twitter (see here and here), and a link was added to this blog post). I wished this occurred more often….
In my opinion the most balanced summaries can be found at the science-based blogs: ScienceBased Medicine [11] and NIH’s Director’s Blog [17], whereas “Understand Nutrition” [8] has an original point of view, which is further elaborated by Mark Wanner at Speaking of Research [19] and Genetics and your health Blog [20]

References

1. Seok, J., Warren, H., Cuenca, A., Mindrinos, M., Baker, H., Xu, W., Richards, D., McDonald-Smith, G., Gao, H., Hennessy, L., Finnerty, C., Lopez, C., Honari, S., Moore, E., Minei, J., Cuschieri, J., Bankey, P., Johnson, J., Sperry, J., Nathens, A., Billiar, T., West, M., Jeschke, M., Klein, M., Gamelli, R., Gibran, N., Brownstein, B., Miller-Graziano, C., Calvano, S., Mason, P., Cobb, J., Rahme, L., Lowry, S., Maier, R., Moldawer, L., Herndon, D., Davis, R., Xiao, W., Tompkins, R., , ., Abouhamze, A., Balis, U., Camp, D., De, A., Harbrecht, B., Hayden, D., Kaushal, A., O’Keefe, G., Kotz, K., Qian, W., Schoenfeld, D., Shapiro, M., Silver, G., Smith, R., Storey, J., Tibshirani, R., Toner, M., Wilhelmy, J., Wispelwey, B., & Wong, W. (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1222878110
2. Drug Testing In Mice May Be a Waste of Time, Researchers Warn 2013-02-12 (science.slashdot.org)
3. Susan M Love We are not mice 2013-02-14 (Huffingtonpost.com)
4. Elbert Chu  This Is Why It’s A Mistake To Cure Mice Instead Of Humans 2012-12-20(richarddawkins.net)
5. Derek Low. Mouse Models of Inflammation Are Basically Worthless. Now We Know. 2013-02-12 (pipeline.corante.com)
6. Elmar Veerman. Waardeloos onderzoek. Proeven met muizen zeggen vrijwel niets over ontstekingen bij mensen. 2013-02-12 (wetenschap24.nl)

7. Gina Kolata. Mice Fall Short as Test Subjects for Humans’ Deadly Ills. 2013-02-12 (nytimes.com)

8. Bill Barrington. Are Mice Reliable Models for Human Disease Studies? 2013-02-14 (understandnutrition.com)
9. Raven, K. (2012). Rodent models of sepsis found shockingly lacking Nature Medicine, 18 (7), 998-998 DOI: 10.1038/nm0712-998a
10. Nemzek JA, Hugunin KM, & Opp MR (2008). Modeling sepsis in the laboratory: merging sound science with animal well-being. Comparative medicine, 58 (2), 120-8 PMID: 18524169
11. Steven Novella. Mouse Model of Sepsis Challenged 2013-02-13 (http://www.sciencebasedmedicine.org/index.php/mouse-model-of-sepsis-challenged/)
12. Wiersinga WJ (2011). Current insights in sepsis: from pathogenesis to new treatment targets. Current opinion in critical care, 17 (5), 480-6 PMID: 21900767
13. Khamsi R (2012). Execution of sepsis trials needs an overhaul, experts say. Nature medicine, 18 (7), 998-9 PMID: 22772540
14. Hotchkiss RS, Coopersmith CM, McDunn JE, & Ferguson TA (2009). The sepsis seesaw: tilting toward immunosuppression. Nature medicine, 15 (5), 496-7 PMID: 19424209
15. van der Worp, H., Howells, D., Sena, E., Porritt, M., Rewell, S., O’Collins, V., & Macleod, M. (2010). Can Animal Models of Disease Reliably Inform Human Studies? PLoS Medicine, 7 (3) DOI: 10.1371/journal.pmed.1000245
16. ter Riet, G., Korevaar, D., Leenaars, M., Sterk, P., Van Noorden, C., Bouter, L., Lutter, R., Elferink, R., & Hooft, L. (2012). Publication Bias in Laboratory Animal Research: A Survey on Magnitude, Drivers, Consequences and Potential Solutions PLoS ONE, 7 (9) DOI: 10.1371/journal.pone.0043404
17. Dr. Francis Collins. Of Mice, Men and Medicine 2013-02-19 (directorsblog.nih.gov)
18. Tom/ Mark Wanner Why mice may succeed in research when a single mouse falls short (2013-02-15) (speakingofresearch.com) [repost, with introduction]
19. Mark Wanner Why mice may succeed in research when a single mouse falls short (2013-02-13/) (http://community.jax.org) %5Boriginal post]
20. Warren, H. (2009). Editorial: Mouse models to study sepsis syndrome in humans Journal of Leukocyte Biology, 86 (2), 199-201 DOI: 10.1189/jlb.0309210
21. Doi, K., Leelahavanichkul, A., Yuen, P., & Star, R. (2009). Animal models of sepsis and sepsis-induced kidney injury Journal of Clinical Investigation, 119 (10), 2868-2878 DOI: 10.1172/JCI39421

Health Experts & Patient Advocates Beware: 10 Reasons Why you Shouldn’t be a Curator at Organized Wisdom!! #OrganizedWisdom

Last year I aired my concern about Organized Wisdom in a post called Expert Curators, WisdomCards & The True Wisdom of @organizedwisdom.

Organized Wisdom shares health links of health experts or advocates, who (according to OW’s FAQ), either requested a profile or were recommended by OW’s Medical Review Board. I was one of those so called Expert Curators. However, I had never requested a profile and I seriously doubt whether someone from the a medical board had actually read any of my tweets or my blog posts.

This was one of the many issues with Organized Wisdom. But the main issue was its lack of credibility and transparency. I vented my complaints, I removed my profile from OW, stopped following updates at Twitter and informed some fellow curators.

I almost forgot about it, till Simon Sikorski, MD, commented at my blog, informing me that my complaints hadn’t been fully addressed and convincing me things were even worse than I thought.

He has started a campaign to do something about this “Unethical Health Information Content Farming by Organized Wisdom (OW)“.

While discussing this affair with a few health experts and patient advocates I was disappointed by the reluctant reactions of a few people: “Well, our profiles are everywhere”, “Thanks I will keep an eye open”, “cannot say much yet”. How much evidence does one need?

Of course there were also people – well known MD’s and researchers – who immediately removed their profile and compared OW’s approach with that of Wellsphere, that scammed the Health Blogosphere. Yes, OW also scrapes and steals your intellectual property (blog and/or tweet content), but the difference is: OW doesn’t ask you to join, it just puts up your profile and shares it with the world.

As a medical librarian and e-patient I find the quality, reliability and objectivity of health information of utmost importance. I believe in the emancipation of patients (“Patient is not a third person word”, e-patient Dave), but it can only work if patients are truly well informed. This is difficult enough, because of the information overload and the conflicting data. We don’t need any further misinformation and non-transparency.

I belief that Organized Wisdom puts the reputation of  its “curators” at stake and that it is not a trustworthy nor useful resource for health information. For the following reasons (x see also Simon’s blog post and slides, his emphasis is more on content theft)

1. Profiles of Expert Curators are set up without their knowledge and consent
Most curators I asked didn’t know they were expert curators. Simon has spoken with 151 of the 5700 expert curators and not one of those persons knew he/she was listed on OW. (x)

2. The name Expert Curator suggests that you (can) curate information, but you cannot.
The information is automatically produced and is shown unfiltered (and often shown in duplicate, because many different people can link to the same source). It is not possible to edit the cards.
Ideally, curating should even be more than filtering (see this nice post about Social Media Content Curators, where curation is defined as the act of synthesizing and interpreting in order to present a complete record of a concept.)

3. OW calls your profile address: “A vanity URL¹”.

Is that how they see you? Well it must be said they try to win you by pure flattery. And they often succeed….

¹Quote OW: “We credit, honor, and promote our Health Experts, including offering: A vanity URL to promote so visitors can easily share your Health Profile with others, e.g. my.organizedwisdom.com/ePatientDave.
Note: this too is quite similar to the Wellsphere’s approach (read more at E-patients-net)

4. Bots tap into your tweets and/or scrape the content off their website
(x: see healthcare content farms monetizing scheme)

5. Scraping your content can affect your search rankings (x)
This probably affects starting/small blogs the most. I checked two posts of well known blogs and their websites still came up first.

6.  The site is funded/sponsored by pharmaceutical companies.
 “Tailored” ads show up next to the so called Wisdom Cards dealing with the same topic. If no pharmaceutical business has responded Google ads show up instead.
See the form where they actually invite pharma companies to select a target condition for advertizing. Note that the target conditions fit the OW topics.

7. The Wisdom Cards are no more than links to your tweets or posts. They have no added value. 

8. Worse, tweets and links are shown out of context.
I provided various examples in my previous post (mainly in the comment section)

A Cancer and Homeopathy WisdomCard™ shows Expert Curator Liz Ditz who is sharing a link about Cancer and Homeopathy. The link she shares is a dangerous article by a Dr. who is working in an Homeopathic General Hospital, in India “reporting” several cases of miraculous cures by Conium 1M, Thuja 50M and other watery-dilutions. I’m sure that Liz Ditz, didn’t say anything positive about the “article”. Still it seems she “backs it up”. Perhaps she tweeted: “Look what a dangerous crap.”
When I informed her, Liz said:“AIEEEE…. didn’t sign up with Organized Wisdom that I know of”. She felt she was used for credulous support for homeopathy & naturopathy.

Note: Liz card has disappeared (because she opted out), but I was was surprised to find that the link (http://organizedwisdom.com/Cancer-and-Homeopathy/wt/med) still works and links to other “evidence” on the same topic.

9. There is no quality control. Not of the wisdom cards and not of the expert curators.
Many curators are not what I would call true experts and I’m not alone: @holly comments at a Techcrunch post: I am glad you brought up the “written by people who do not have a clue, let alone ANY medical training [of any kind] at all.” I have no experience with any kind of medical education, knowledge or even the slightest clue of a tenth of the topics covered on OW, yet for some reason they tried to recruit me to review cards there!?! )

The emphasis is also on alternative treatments: prevention of cancer, asthma, ADHD by herbs etc. In addition to “Health Centers”, there also Wellness Centers (Aging, Diet, Fitness etc) and Living Centers (Beauty, Cooking, Environment). A single card can share information of 2 or 3 centers (diabetes and multivitamins for example).

And as said, all links of expert curators are placed unfiltered, even when you make a joke or mention you’re on vacation. Whether you’re a  Top health expert or advocate (there is a regular shout-out) just depends on the number of links you share, thus NOT on quality. For this reason the real experts are often at lower positions.

Some cards are just link baits.

 

10.  Organized Wisdom is heavily promoting its site.
Last year it launched activitydigest, automatic digests meant to stimulate “engagement” of expert curators. It tries to connect with top health experts, pharma -people and patient advocates. Hoping they will support OW. This leads to uncritical interviews such as at Pixels and Pills, at Health Interview (Reader’s Digest + Organized Wisdom = Wiser Patients), Xconomy.com organizedwisdom recruits experts to filter health information on the web.

What can you do?

• Check whether you have a profile at Organized Wisdom here.
• Take a good look at Organized Wisdom and what it offers. It isn’t difficult and it doesn’t take much time to see through the facade.
• If you don’t agree with what it represents, please consider to opt out.
• You can email info@organizedwisdom.com to let your profile as expert curator removed.
• If you agree that what OW does is no good practice, you could do the following (most are suggestions of Simon):

• spread the word and inform others
• join the conversation on Twitter #EndToFarms
• join the tweetup on what you can do about this scandal and how to protect yourself from being liable. (more details will be offered by Simon at his regularly updated blogpost)
• If you don’t agree this Content Farm deserves HONcode certification, notify HON at  https://www.healthonnet.org/HONcode/Conduct.html?HONConduct444558

Please don’t sit back and think that being a wisdom curator does not matter. Don’t show off  with an Organized Wisdom badget, widget or link at your blog or website.  Resist the flattery of being called an expert curator, because it doesn’t mean anything in this context. And by being part of Organized Wisdom, you indirectly support their practice. This may seriously affect your own reputation and indirectly you may contribute to misinformation.

Or as Heidi’s commented to my previous post:

I am flabbergasted that people’s reputation are being used to endorse content without their say so.
Even more so that they cannot delete their profile and withdraw their support.*

For me those two things on their own signal big red flags:

The damage to a health professional’s reputation as a result could be great.
Misleading the general public with poor (yes dangerous) information another

Altogether unethical.

*This was difficult at that time.

Update May 10, 2011: News from Simon: 165 individuals & 5 hospitals have now spoken up about unfolding scandal and are doing something about it (Tuesday )

Update May 12, 2011: If I failed to convince you, please read the post of Ramona Bates MD (@rlbates at Twitter, plastic surgeon, blogger at Suture for a Living), called “More Organized Wisdom Un-Fair Play“. Ramona asked her profile to be removed from OW half a year ago).  Recommended pages at her blog seem to be written by other people.
She concludes:

“Once again, I encourage my fellow healthcare bloggers (doctors, nurses, patient advocates, etc) to remove yourself from any association with Organized Wisdom and other sites like them”

Related articles

• “Unethical Health Information Content Farming by Organized Wisdom (OW)” & how 5700 social media Curators participate in major ethical, legal, & moral violations without their knowledge (healthcaremarketingcoe.com/)
• No thanks, ‘Organized Wisdom’: I say NO to datamining, scraping & pharma funded health information:reminds me of Wellsphere-I dumped that too (bipolarsoupkitchen-stephany.blogspot.com)
• How the Health Blogosphere was scammed (getbetterhealth.com)
• Social Media Content Curators Are Not “Just Filters”  More at: jamiebeckland.com
• Organizedwisdom, the Mahalo for Health Raises 23 million (techcrunch.com -2008/06/19!)
• Can Curating Doctors’ Tweets Improve People’s Health? (theatlantic.com)
• OrganizedWisdom Recruits Experts to Filter Health Information on the Web (xconomy.com)
• Why social media gives your doctor an ulcer (news.cnet.com)
• Health Sites Try to Diagnose Growing Market (blogs.wsj.com)

FDA to Regulate Genetic Testing by DTC-Companies Like 23andMe

Direct-to-consumer (DTC) genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. [definition from NLM’s Genetic Home Reference Handbook]

Almost two years ago I wrote about 23andMe (23andMe: 23notMe, not yet),  a well known DTC company, that offers a genetics scan (SNP-genotyping) to the public ‘for research’, ‘for education’ and ‘for fun’:

“Formally 23andMe denies there is a diagnostic purpose (in part, surely, because the company doesn’t want to antagonize the FDA, which strictly regulates diagnostic testing for disease). However, 23andme does give information on your risk profile for certain diseases, including Parkinson”

In another post Personalized Genetics: Too Soon, Too Little? I summarized an editorial by Ioannides on the topic. His (and my) conclusion was that “the promise of personalized genetic prediction may be exaggerated and premature”. The most important issue is that predictive power to individualize risks is relatively weak. Ioannidis emphasized that despite the poor evidence, direct to consumer genetic testing has already begun and is here to stay. He proposed several safeguards, including transparent and thorough reporting, unbiased continuous synthesis and grading of the evidence and alerting the public that most genetic tests have not yet been shown to be clinically useful.

And now these “precautionary measures” actually seem to happen.
Last week the FDA sent 5 DTC-companies, including 23andMe a letter saying “their tests are medical devices that must receive regulatory approval before they can be marketed.” (ie. see NY-times article).

Alberto Gutierrez, who leads diagnostic test regulation at the FDA, wrote in the letters:

“Premarket review allows for an independent and unbiased assessment of a diagnostic test’s ability to generate test results that can reliably be used to support good health care decisions,”

These letters are part of an initiative to better explain the FDA’s actions by providing information that supports clinical medicine, biomedical innovation, and public health,” (May 19 New England Journal of Medicine commentary, source: see AMED-news)

Although it doesn’t look like the tests will be taken from the market, 23andMe does take a quite a rebellious attitude: one of its directors called the FDA “appallingly paternalistic.”

Many support this view: “people have the right to know their own genetic make-up”, so to say. Furthermore as discussed above, 23andMe denies that their genetic scans are meant for diagnosis.

In my view the latter is largely untrue. At least 23andMe suggests that knowing a scan does tell you something about your risks for certain diseases.
However, the risks are often not that straightforward. You just can’t “measure” the risk of a multifactorial disease like diabetes by “scanning” a few weakly predisposing  genes. Often the results are given in relative risk, which is highly confusing. In her TED-talk the 23andMe director Anne Wojcicki said her husband Sergey Brin (Google), had a 50% chance of getting Parkinson, but his relative risk (RR, based on the LRRK2-mutation, which isn’t the most crucial gene for getting Parkinson) varies from 20% to 80% , which means that this mutation increases his absolute risk of getting Parkinson from 2-5% (normal chance) to 4-10% at the most. (see this post).

Furthermore, as reported by Venture in Nature (October 8, 2009): For seven diseases, 50% or less of the predictions of two companies agreed across five individuals (i.e. for one disease: 23andMe : RR 4.02, and Navigenics RR: 1.25). On the other hand *fun* diagnoses could lead to serious concern in, or wrong/unnecessary decisions (removal of ovaries, changing drug doses) by patients.

There are also concerns with regard to their good-practice standards, as 23andMe just flipped a 96-wells plate of costumer DNA (see Genetic Future for a balanced post), which upset a mother noticing that her son didn’t have compatible genes. But lets assume that proper precautions will prevent this to happen again.

There are also positive aspects: results of a preliminary study showed that people who find out they have high genetic risk for cardiovascular disease are more likely to change their diet and exercise patterns than are those who learn they have a high risk from family history. (Technology Review: Genetic Testing Can Change Behavior).

Furthermore, people buy those tests themselves and, indeed, there genes are their own.

However, I agree with Dr. Gutierrez of the FDA saying: “We really don’t have any issues with denying people information. We just want to make sure the information they are given is correct.” (NY-Times). The FDA is putting the consumers first.

However, it will be very difficult to be consistent. What about total body scans in normal healthy people, detecting innocent incidentilomas? Or what about the controversial XMRV-tests offered by the Whittemore Peterson Institute (WPI) directly to CFS- patients? (see these posts) And one step further (although not in the diagnostic field): the ineffective CAM/homeopathic products sold over the counter?

I wouldn’t mind if these tests/products would be held up to the light. Consumers should not be misled by the results of unproven or invalid tests, and where needed should be offered the guidance of a healthcare provider.

But if tests are valid and risk predictions correct, it is up to the “consumer” if he/she wants to purchase such a test.

—————–

“What Five FDA Letters Mean for the Future of DTC Genetic Testing” at Genomics law Report is highly recommendable, but couldn’t be accessed while writing the post.

[Added: 2010-06-14 13.10]

• Problem assessing Genomics Law Report is resolved.
• Also recommendable: the post “FDA to regulate genetic tests as “devices”” at PHG Foundation. This post highlights that simply trying to classify the complete genomic testing service as “a device” is inadequate and will not address the difficult issues at hand. One of the biggest issues is that, while classifying DTC genetics tests as devices is certainly appropriate for assessing their analytical validity and direct safety, it does not and cannot provide an assessment of the service, thus of the predictions and interpretations resulting from the genome scans.  Although standard medical testing has traditionally been overseen by professional medical bodies, the current genomic risk profiling tests are simply not good enough to be used by health care services. (see post)

Related articles by Zemanta

• 23andMe Sends Wrong DNA Test Results To 96 Customers (techcrunch.com)
• F.D.A. Faults 5 Companies on Genetic Tests (nytimes.com)
• Gene test mix-up brings scrutiny to industry (sfgate.com)
• FDA Takes Issue With Genetic Tests From 5 Firms (abcnews.go.com)
• 23andMe swapped samples! (scienceroll.com)
• FDA wants safety, accuracy data on consumer genetic tests (arstechnica.com)

Kaleidoscope 2009 wk 47

Kaleidoscope is a new series, with a “kaleidoscope” of facts, findings, views and news gathered over the last 1-2 weeks.

Most items originate from Twitter, my Google Reader (RSS) and sometimes real articles (yeah!).

I read a lot, I bookmark a lot, but only some of those things end op in a post. Since tweets have a half-life of less than a week, I thought it would be nice to safeguard some of the tweets in a post. For me to keep, for you to read.

I don’t have the time and the discipline to post daily about health news and social media as Ves Dimov does. It looks more like the compilation at blogs of dr Shock’s (see example),  dr Bates shout-outs, Health Highlights of Highlight HEALTH and Rachel Walden’s Womens health News Round-ups, but less on one subject and less structured. It will just be a mix of old and new, Social Media and science, just a kaleidoscope. Or a potpourri  if you like.

I don’t know if this kaleidoscope will live a long live. I already wrote 2 3 4 5 6 editions, but didn’t have the time to finish them. Well, we will see, just enjoy this one.

Ooh and the beautiful kaleidoscope is made by RevBean and is called: Eyeballs divide like cells. Looks very much like the eyeball-bubblewrap of a previous post but that is thus coincidence. Here is the link (Flickr, CC)

Medical Grand Rounds

Louise Norris at Colorado Health Insurance Insider is this week’s host of Grand Rounds.(see here). There are many interesting posts again. As a mother of two teens I especially liked the insight Nancy Brown of Teen Health 411 brings us into what teens want when it comes to their relationships with their parents and the “would you rather…?” story that Amy Tenderich of Diabetes Mine shares with us. The punch line is great. Her 9 year old melts my heart.

At InsureBlog’s Hank Stern brings us an article about a British hospital that will no longer admit expectant mothers with a BMI of more than 34, because the hospital’s labor and delivery unit is not equipped to handle complicated births. Hank concludes: “Fear not, though, portly preggies have to travel but 20 miles to the next closest facility. Assuming, of course, that they can make it that far when contractions are minutes apart.”

Dr Charles of the The Examining Room wrote an in depth article about a cheerleader who was supposedly stricken with dystonia following a seasonal flu vaccine in August. Dr Charles not only highlights why (specialists) think it is not dystonia, but gives also background information about the efficacy of vaccins.

Recent editions of the Grand Rounds were at CREGRL, flight nurse (link), NonClinicalJobs (link) and Codeblog, tales of a nurse (link). You can always find previous and upcoming hosts at the Grand Rounds Archive at Blogborygmi.

Breast cancer screening

The update of the 2002 USPSTF recommendation statement on screening for breast cancer in the general population, published in the November issue of The Annals of Internal Medicine has led to heated discussions in the mainstream media (i.e. New York Times and MedPage Today). Based on current evidence, partly based on 2 other articles in the same journal (comparison screening schedules and an systematic review) the guidelines advise scaling back of the screening. The USPSTF recommends:

• against routine screening mammography in women aged 40 to 49 years
• against routine screening mammography of women 75 years or older.
• biennial (instead of annual) screening mammography for women between the ages of 50 and 74 years.
• against teaching breast self-examination (BSE).
• against either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities.

The two articles published in Ann Intern Med add to the evidence that the propagation of breast cancer self exam doesn’t save lives (see Cochrane review discussed in a previous post) and that the benefits of routine mammography in the young (<50) or old (>75) do not outweigh the harm (also covered by a  Cochrane review before). Indeed, as put forward by Gary Schwitzer at Schwitzer health news blog this is NOT a new debate. He refers to Slate who republishes a five-year old piece of Amanda Schaffer that does a good job of explaining the potential harms of screening. However it is difficult for women (and some doctors) to understand that “When it comes to cancer screening, more isn’t always better.” Indeed -as Kevin Pho at Kevin MD states, the question is whether “patients will accept the new, evidence-based, breast cancer screening guidelines”.

In the Netherlands it is already practice to start biannual routine mammography at the age of 50. The official breast cancer screening site of the RIVM even states that the US is now going to follow the Dutch guidelines 😉 (one of assessed guidelines in one the Ann Intern Med papers is Dutch). But people still find the  long established guidelines difficult to accept: coincidentally I saw tweets today asking to sign a petition to advance the age of screening ‘because breast cancer is more and more frequently observed at young age…(??)’ Young, well educated, women are very willing to sign…

No time to read the full articles, but interested to know more, then listen to the podcast of this Ann Intern Med edition:

Systematic Reviews, pharma sponsored trials and other publishing news

Cochrane reviews are regarded as scientifically rigorous, yet a review’s time to publication can be affected by factors such as the statistical significance of the findings. A study published in Open Medicine examined the factors associated with the time to publication of Cochrane reviews. A change in authors and updated reviews were predictive factors, but the favorability of the results was not.

Roy Poses of the Health Care Renewal Blog starts this blogpost as follows: “Woe to those of us who have been advocates for evidence-based medicine”. He mainly refers to a study published in the NEJM, that identified selective outcome reporting for trials of off-label use of gabapentin: for 8 of the 12 published trials, there was a disagreement between the definition of the primary outcome in the protocol and that in the published report. This seriously threatens the validity of evidence for the effectiveness of off-label interventions. Roy was surprised that the article didn’t generate much media attention. The reason may be that we have been overwhelmed by manipulation of data, ghostwriting and by the fact that pharma-sponsored trials rarely produce results that are unfavorable to the companies’ product (see previous posts about Ghostwriting (Merck/Elsevier, Conflict of Interest in Cancer Studies and David Tovey about Cochrane Reviews). At least two authors of the NEJM review (Bero and Dickersin) have repeatedly this to be the case [e.g. see here for an overview, and papers of Lisa Bero]. It is some relief that at least 3 of the 4 NEJM authors are also members of the Cochrane Collaboration. Indirectly better control of reporting, i.e. by clinical trials registries, can improve the reliability of pharma sponsored trials and thus systematic reviews summarizing them. As a matter of fact Cochrane authors always have to check these registries.

At Highlight Health Walter Jessen writes about Medical Journal Conflict of Interest Disclosure and Other Issues, which also discusses how money can taint objectivity in scientific publishing. Half of the post discusses the book The Trouble with Medical Journals, written in 2007 by Richard Smith, the former editor of the BMJ.
By the way, Walter just hosted MedLibs Round with the theme “Finding Credible Health Information Online”.

Good news in the Netherlands: right after international Open Access week and the launching of the Dutch Open Access website (www.openaccess.nl), the Netherlands Organization for Scientific Research (NWO) has announced that it is in favor of Open Access. (via PLOS-facebook).

The open access nature of PLOS itself gets out of hand: they even peer-review T-shirts (according to Bora Zivkovic of a Blog around the Clock, see here)

Other Health & Science News:

Medline Plus summarizes an article in the Journal of Nutrition, that states that Selenium supplements, may pose a heart risk.

Even Folic Acid and vitamin B12, when taken in large doses, have been reported to Increase Cancer Risk (WebMD)

Luckily WebMD also reports that dark chocolate seems to help against stress, that is it reduced stress hormones in the blood. However @evidencematters and @NHSChoices cast doubt on that :  “Chocolate cuts stress, says newspaper. Does the study really say that? And who paid for the study?…”

Scientists made the unexpected discovery (published in Molecular Cell) that BRAF, which is linked to around 70 per cent of melanomas and seven per cent of all cancers, is in fact controlled by a gene from the same RAF family called CRAF – which has also been linked to the disease. For the first time it is shown “how two genes from the same ‘family’ can interact with each other to stop cancer in its tracks” (Source: Info Cancer Research UK)

For the first time, scientists have successfully used exome sequencing to quickly discover a previously unknown gene responsible for Miller syndrome, a rare disorder. The finding demonstrates the usefulness of exome sequencing in studying rare genetic disorders. The exome is enriched for coding (thus functional) DNA, it is only 1% of the total DNA, but contains 85% of the mutations (Published in Nature Genetics, source: PhysOrg.com)

Web 2.0

For information regarding the FDA hearings on internet and social media see #FDASM: http://www.fdasm.com.

Read Write Web summarizes the new numbers released by analytics firm Postrank that indicate that reader engagement with blogs has changed dramatically over the last three years, primarily because of the rise of online social networks.

Twitter has began to relaunch the new retweet feature, although not without controversy. What do you think about the newest feature?

The Next Web gives an overview of which Twitter application is hot and which is not.

And Finally: Top 100 tools for learning, compiled by Jane Hart from the contributions of 278 learning professionals worldwide. You can see the lists here (HT: http://blogs.netedu.info/?p=1005)

The web 2.0 part is relatively short, but it is time to conclude this edition. Till next time!

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MEDLIB’s ROUND 1.6 (laikaspoetnik.wordpress.com)

Tool Talk: quick links re Facebook, GReader and GWave (socialfish.org)

NLM’s PillBox, a new pill identification system

The National Library of Medicine (NLM) not only launched a redesigned PubMed interface, but also another service (though still in beta): Pillbox beta for “rapid identification and reliable information.
The web address is http://pillbox.nlm.nih.gov/

Pillbox was developed to aid in the identification of unknown solid dosage pharmaceuticals. The system combines high-resolution images of tablets and capsules with FDA-approved appearance information (imprint, shape, color, size and scoring) to enable users to visually search for and identify an unknown solid dosage pharmaceutical. (see About-section).

This system is designed for use by emergency physicians, first responders, other health care providers, Poison Control Center staff, and concerned citizens.
David Hale from the National Library of Medicine (NLM), argued in his short presentation at the Medicine 2.0 congress that better medication identification can potentially prevent 6000 to 8000 deaths each year due to adverse events. David explained that while FDA data might be available in the public domain, there is a need to make the information more usable.

The interface is very clear and intuitive. You can choose the visual identification/exploration or the HTML screen reader compatible option to search.

Below I did a quick search with the latter option. (To show you the search options) I searched for 9mm white pills with the imprint West-ward 254, that can be broken in two and I get one result: a hydrocortisone pill (HC). That is neat. Only the imprint would have done, I guess, but without imprint there remain a lot of white pills to choose from.

The visual identification option is even easier to use.

As of September 2009 only 779 of the  5,693 records have images, but as the project of the NLM and FDA proceeds in making large-scale photos of prescription medications, verified by manufacturers, more images will be available.

Once a solid dosage form has been identified, additional information is provided, including brand/generic name, ingredients, and the National Drug File identification number. Links are provided to NLM drug information resources, such as FDA-approved label information (DailyMed) and the Drug Information Portal, which searches all NLM drug information resources (About).

The pills are sometimes difficult to discern. Perhaps because of my screen, and/or because white pills (on a black background) all look alike. The Figure left is 50% of the original (enlarged) picture: it is barely recognizable. So, at least in case of white pills, you do depend on correctly identified imprints.

Furthermore pillbox will not be suitable to identify “illicit drugs”, foreign drugs and pharmacy compounded dosage forms which are not in FDA databases.” For this an “open source” Pillbox where everyone can collaborate (globally) to develop a rapid data rich pill identification system would be the solution (David Hale).

It should be stresses that the PillBox is still in beta-phase. Feedback is welcomed at pillbox@mail.nih.gov.

Finally a presentation of David Hale at the US Pharmacopeia’s Annual Scientific Meeting.

and an interview with him during the Medicine 2.0 congress.

Hattip: @eagledawg and @rachel_w :see Tweet) and NLM_SIS (see Tweet)

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• Pillbox at US Pharmacopeia’s Annual Scientific Meeting (slideshare.net)
• A New Kind Of Pillbox (cenblog.org)

One Third of the Clinical Cancer Studies Report Conflict of Interest

While many of us just recovered from the news that Elsevier was paid to produce fake Journals to promote pharmaceutical products, another news item has appeared about “conflicts of interests in scientific publications”

This news is based on a new journal article from researchers from the University of Michigan’s Comprehensive Cancer Center in Ann Arbor, published in an early online edition of Cancer [1]

As mentioned in my previous post about the Elsevier “Fake Journals”, pharma-sponsored trials rarely produce results that are unfavorable to the companies’ products [e.g. see 3 for an overview, and many papers of Lisa Bero]. Concerned by these findings, the main medical journals now require researchers to disclose their potential conflicts of interest (COI).

The present study [1] analyzes the frequency of self-reported conflicts of interest (COI), source of study funding, and (their relationship with) other characteristics in original clinical cancer research (thus no reviews or basic research) published in 8 medical Journals in 2006. The 8 journals are high-impact clinical journals, 5 are oncology journals (Journal of Clinical Oncology, the Journal of the National Cancer Institute, Lancet Oncology,Clinical Cancer Research, Cancer) and 3 are core general medical journals (New England Journal of Medicine,JAMA, the Journal of the American Medical Association, Lancet).

In these medical journals 1534 original oncology studies were found. Twenty-nine percent of the oncology articles reported COI: 17% declared industrial funding and the remaining 12% of the studies had authors who were an employee of industry at the time of publication, or were funded by industry.

The study was thoroughly done: 2 students independently coded the articles and 2 other coders, blinded for the initial coding, assessed all randomized trials (within those 1543 papers) for the outcomes. They graded the authors’ subjective interpretations as positive (in favor of the intervention), neutral, or negative (in favor of the control arm). Overall survival was assessed quantitatively.

The main results:

• Conflicts of interest varied by discipline (P<.001). Studies that had a corresponding author from a medical oncology department or division were most likely to have conflicts (45%), and studies from diagnostic radiology were least likely to have conflicts (4%)
• Likewise the cancer type mattered, especially with regard to likelihood of industrial funding (P = .001). Studies on the male reproductive system and lung cancers scored highest and studies on neurological cancers scored lowest as to the likelihood of funding. (however there is some contradiction because gynecologic departments have a high score and gynecologic cancers have a relatively low score, conf. figures 1 and 2)
• Continental origin was also an important variable (P<.001). COI were observed in 33% of the North American studies, 27% of the European studies, 5% of the Asian studies, and 40% of the studies from other locations.
• COI was most likely in articles with male first and senior authors (P<.001).
• Industry funded studies were more likely to focus on treatment (P<.001), and less on epidemiology, prevention, risk factors for incidence, screening, or diagnostic methods.
• The randomized trials (n=124) that assessed survival were more likely to report positive survival outcomes when a COI was present (P=.04). (see below)

The paper has received a lot of media attention, initiated by the press release of the University of Michigan Health System itself. The data however are less shocking then they may seem. The main finding is that “conflicts of interest characterize a substantial minority of the clinically oriented cancer research published in high-impact medical journals”. This and the characteristics of the papers with COI (see above) add to earlier papers that report on the occurrence of COI in published articles, including papers in the field of clinical oncology.”

Some outcomes are not very surprising, such as that pharmaceutical industries and funding will be most involved in intervention studies in medical oncology studies (not so much in radiology or diagnostics).

In itself, COI does not mean that the results cannot be trusted or that they are plain wrong. Credibility could be questioned if only positive results are published or if the results are represented more positive then they really are.

Indeed, Jagsi et al show that “randomized trials with a COI were more likely to report positive survival outcomes (P=.04)”. However, the likelihood that the author interpretation was positive or more positive than the objective effect on overall survival wasn’t influenced by COI. And differences in industrial funding didn’t influence any of the blinded outcomes assessed. Also in this study, the non-neutral findings are emphasized. 😉

On the other hand, authors had to rely on the information given, i.e. not all conflicts of interests may have been reported. Another issue is that not all known COIs are disclosed to the public (i.e. medicalnewstoday)

The following conclusion of the lead author Reshma Jagsi seems most relevant:[2]

“Given the frequency we observed for conflicts of interest and the fact that conflicts were associated with study outcomes, I would suggest that merely disclosing conflicts is probably not enough. It’s becoming increasingly clear that we need to look more at how we can disentangle cancer research from industries”

References

1. Jagsi, R., Sheets, N., Jankovic, A., Motomura, A., Amarnath, S., & Ubel, P. (2009). Frequency, nature, effects, and correlates of conflicts of interest in published clinical cancer research Cancer DOI: 10.1002/cncr.24315
2. University of Michigan Health System (2009, May 13). 29 Percent Of Cancer Studies Report Conflict Of Interest. ScienceDaily. Retrieved May 14, 2009, from http://www.sciencedaily.com­ /releases/2009/05/090511090846.htm
3. Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med. 2005 May; 2(5): e138. Published online 2005 May 17. doi: 10.1371/journal.pmed.0020138.

You may also want to read:

• Merck’s Ghostwriters, Haunted Papers and Fake Elsevier Journals

Hattip: @sciencebase, Reinout Rietveld (via NRC-next)

Merck’s Ghostwriters, Haunted Papers and Fake Elsevier Journals

What is the purpose of publications? (…) The purpose of data is to support, directly or indirectly, the marketing of our product.” [1, 2]

It is well known that studies with significant positive results are easier to find than those with ‘negative’ results. This so called publication bias can arise from the tendency to submit or accept manuscripts that have a positive rather than a negative or neutral result. It can also be the consequence of deliberately overemphasizing positive results or even worse: the results can be “embellished”, (partly) faked or negative results can be “hidden”

In fact, pharma-sponsored trials rarely produce results that are unfavorable to the companies’ products [3, 4, 5]. For instance, none of the published 56 trials of  NSAIDs in arthritis identified by Rochon et al in 1994 [3] had outcomes that were unfavorable to the company that sponsored the trials. Another study showed that studies funded by a company were four times more likely to have results favorable to the company than studies funded from other sources [1, 4]

Ghostwriters, who write articles that are officially credited to another person, are part of the tactics. Ghostwriters may be hired by companies to write articles for medical journals that appear under the names of scientists who didn’t substantially contribute to the paper. In extreme cases pharmaceutical companies and their agents control or shape multiple steps in the research, analysis, writing, and publication of articles. This so called ghost management can be outsourced to MECC’s, medical education and communication companies.

All the above approaches, -and more- are said to have been used by Merck to sell their Vioxx (rofecoxib) pills, the blockbusting painkiller, that could cause heart attacks and strokes [6]. Merck knew, but didn’t disclose (all) these adverse effects*. Later it appeared that many Vioxx- manuscripts were prepared by sponsor employees (ghost writers), but attributed to academic investigators who did not always disclose industry financial support. Distancing himself from one such article, first author Jeffrey Lisse said in an interview that:

“Merck designed the trial, paid for the trial, ran the trial…Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing” [NY-times -[2005].

And although Merck has “voluntarily” withdrawn Vioxx from the market in 2004 and has agreed to pay billions to settle lawsuits in the US, the Vioxx-ghost keeps hunting Merck (and us).

In a few weeks 3 news-items have crossed my eyes.

A. The Guardian ( May 4) mentioned that Merck refused to compensate hundreds of Britons who have suffered serious cardiovascular  problems while on Vioxx.  Ministers apparently backed down from supporting these people after lobbying by the company.

B. May 1st NewsInferno com reported that Merck was accused of hiring a ghostwriter for a Circulation paper (2001) to minimize issues linked to Vioxx’s safety, while the well known cardiologist Dr. Marvin Konstam agreed to act as lead author. This was revealed by Prof. Jelinek during an Australian lawsuit against Merck.

C. The above news story was covered by Australian Newspapers including “the Australian“. In its article on the lawsuit, the Australian also devotes one sentence to a fake Elsevier/Merck journal. It says:

“The drug company also allegedly produced an entire journal — called The Australasian Journal of Bone and Joint Medicine — and passed it off as an independent peer review publication.”

It is this sentence that has caused a tsunami, starting with the Scientist, via blog.bioethics.net to  many other blogs of researchers, publishers, librarians and to newspapers. “Everybody” was alarmed.

What were the allegations? Are they all true? Who is to blame? Merck or Elsevier? Most importantly: is it an isolated incidence, something completely new and what is its impact?

Points addressed by the Scientist (mainly based on interviews, i.e. with George Jelinek)

1. Australasian Journal of Bone and Joint Medicine, is published by Exerpta Medica, a division of Elsevier
2. This Journal is not indexed in the MEDLINE database and has no website.
3. It had the looks of a peer-reviewed medical journal, but contained only reprinted or summarized articles
4. Most of the articles presented data favorable to the Merck products Fosamax (for osteoporosis) and Vioxx.
5. So called “review” articles only cited one or two references. Even a meta-analysis contained 2 references, one of which referring to a real meta-analysis.
6. The articles are “simply a summary of already published articles”
7. There are several ads for Fosamax and Vioxx.
8. It is unclear who wrote the editorials
9. One member of the editorial board, Peter Brooks said that he didn’t ever get manuscripts to review while on the board. Neither was he paid for his role.
10. There is no disclosure of company sponsorship.
11. Merck paid an undisclosed sum to Elsevier to produce several volumes (confirmed by Elsevier).

According to a statement of Merck (see pdf on their website):

“The Australasian Journal of Bone and Joint Medicine (..) was published by the medical publishing company Elsevier. Merck Sharp & Dohme Australia understood that Elsevier envisaged the complimentary publication would draw on the vast resources of Elsevier, publishers of many leading peer-reviewed journals including Lancet, Bone, Joint Bone Spine and others, to deliver novel and timely full-text articles and abstracts to physicians.”

In the same PDF Merck states that “ghostwriting” allegations concerning the 2001 Circulation paper about VIOXX [item B] are false and that professor Jelinek has witdrawn his accusation under cross examination. According to Merck, the lead author Dr. Marvin Konstam, was in fact very much involved in the study. Indeed, according to the Heartwire, Konstam maintained he acted properly. He  takes full responsibility for everything he has published.

Elsevier acknowledged the concern that the journal didn’t have the appropriate disclosures,” and although they said they had no plans in looking further into the matter, Elsevier disclosed today that in total 6 such fake Australasian Journals were produced (see Scientist).

Now what? An isolated blunder by staff of the Australian Branche of Elsevier who published a fake peer review while Elsevier headquartes and Merck were totally unaware?

First, although I don’t want to triviliaze the affair, obviously this Journal does not pretend to be a peer reviewed paper (i.e. see this pdf, obtained by the Scientist). Any doctor who even considers it to be a peer reviewed paper must have very little experience with critically reading of peer reviewed papers. It is clear from the start that all articles are just copied from other (Elsevier) Journals, the citations are given, articles are classed to type (in black boxes at the tope) and the so called meta-analyses just describes another meta-analysis, which is cited.

The editorial board is called “Honorary”. The advertorials and the repeated mentioning of Merck drugs makes it immediately clear that this Journal is just a so-called throwaway. True, it should have been disclosed at the front page and the Journal’s name and lay-out might suggest otherwise at first glance. And to me as a librarian it is particularly strange that there was an annual subscription for institutions of $250. Throw-aways are usually for free. Furthermore it is not included in Science Direct nor the usual bibliographic databases.

As a matter of fact, this Journal is what you would expect from an “Excerpta Medica Journal”: an excerpt of various articles. At least that’s what the name suggests and that’s what I remember from the old fashioned Excerpta Medica abstract journals I browsed as a post-doc.

But it is remarkable that “the reliable and authorative” Elsevier, publisher of journals like the Lancet, lends itself to a biased publication of articles that only serve as promotional material? Surely this is an exception?

Well, whereas Elsevier itself has dismayed the Lancet by sponsoring one of the largest military exhibitions in the world (CMAJ 2007), its medical and health sciences division Excerpta medica is clearly a separate business. On the Elsevier website 41 titles of Excerpta Medica are listed, but none of the Australian Excerpta clones. Here it says that:

Every journal contains bibliographic references and abstracts summarizing original articles from primary research and clinical journals. The records are carefully selected from 4,000 journals from 70 countries around the world, which makes the Excerpta Medica Abstract Journals very comprehensive.

The home page of Excerpta Medica states that it is an “Elsevier Business”, a strategical medical communications agency, partnering with their clients in the pharmaceutical and biotech industries to educate the global health care community to enable them to make well informed decisions (copied from EBM definition of Sackett, hé?)

Under the heading “strategic planning” it is written that “Our relationship with Elsevier allows us access to editors and editorial boards who provide professional advice and deep opinion leader networks” ….(!!)

I’m not the first one noticing this.

In 2007 the same link was given by the PLOS-paper about ghost management[1], discussed above..

Here Excerpta is mentioned as an example of a MECC.

And not only in this paper. Both a Medscape[7] and a Perspectives in Biology and Medicine article[2] mention the role of Excerpta as a MECC. A citation from the latter:

Recovered documents show that the pharmaceutical company Wyeth hired the MECC Excerpta/Medica to produce several scientific papers on the dangers of obesity and on obesity treatment as part of their marketing strategy for Fen-Phen. Mundy documents that Wyeth paid between $15,000 to $20,000 for Excerpta to prepare each article, of which $1,500 would go to the “named author” as an honorarium. Some completed papers, simply listed as “author to be determined,” lacked a “named author,” while others had made their way in to print or were under review. One doctor, Dr. Richard Atkinson, was so pleased with the arrangement for “Therapeutic Effects of Dexfenfluramine: A Review” that he wrote a thank you note to Excerpta/Medica saying,“Let me congratulate you and your writer. . . . Perhaps I can get you to write all of my papers for me” (Mundy 2002, p. 164).

And Medscape:

What made Excerpta Medica such an inspired choice is that it is a branch of the academic publisher, Reed Elsevier Plc., which publishes many of the world’s most prestigious science journals. Excerpta Medica manages two journals itself: Clinical Therapeutics and Current Therapeutic Research. According to court documents, Excerpta Medica planned to submit most of the articles it produced to Elsevier journals. In the actual event, Excerpta managed to publish only two articles before Fen-Phen was withdrawn from the market in 1997. One appeared in Clinical Therapeutics, the other in the American Journal of Medicine (another Elsevier journal). In neither case did the authors of the articles disclose that they were paid by Excerpta Medica. So clean was the laundering operation, in fact, that many of the authors did not even realize that Wyeth was involved.

By the way Fen_Phen was not particularly effective, and was linked to valvular heart disease, leading to the death of hunderds of people. Even after withdrawal Wyeth spent $100 million on public relations to convince the public that the response had been overblown.

Hereby I do not want to suggest that Excerpta has played a similar role in the Vioxx case, but it does illustrate that Excerpta is a MECC with dangerous principles as it organized the ghostwriting for Wyatt elaborately, using its connections with Elsevier in a very nontransparent way.

I also don’t want to suggest that the followed procedure is unique for Excerpta. Several other MECC’s follow the same approach. For many other examples see the references below, especially [1, 2, 7]. It is really tarnishing. And worth a reading.

However, In my opinion we have to fear more from the strategic publication planning of the MECCs in authentic journals then the fake Australian Excerpta series. Firstly, because the known Journals are far more trustworthy and have far more impact than the throwaways. Secondly because the phenomenon of ghostwriting is widespread, also among “first class Journals”. A conservative benchmark for ghostwriting of papers published in biomedical journals is roughly 10%[2], but in particular cases the percentage may be much higher [1]. This has caused Richard Smith, former editor of the BMJ to sigh that “Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies.”

Anyway, I bet that my doctor did not describe Vioxx for my backache 10 years ago because he read “The Australasian Journal of Bone and Joint Medicine”. Rather he must directly or indirectly have learned from the results of the VIGOR trial published in the New England Journal of Medicine.

With respect to the citation I began with, it is not from Merck, but from Pfizer as an answer to the question: “What is the purpose of publications?” on the header on a Pfizer sales document (2000)

References

1. Sismondo, S. (2007). Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry? PLoS Medicine, 4 (9) DOI: 10.1371/journal.pmed.0040286
2. Moffatt, B., & Elliott, C. (2007). Ghost Marketing: Pharmaceutical Companies and Ghostwritten Journal Articles Perspectives in Biology and Medicine, 50 (1), 18-31 DOI: 10.1353/pbm.2007.0009
   The whole issue is dedicated to this topic: Perspectives_in_biology_and_medicine.
3. Rochon PA, Gurwitz JH, Simms RW, Fortin PR, Felson DT, et al. A study of manufacturer-supported trials of nonsteroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med. 1994;154:157–163. [PubMed]
4. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality. BMJ. 2003;326:1167–1170. [PubMed]
5. Smith R. Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. PLoS Med. 2005 May; 2(5): e138. Published online 2005 May 17. doi: 10.1371/journal.pmed.0020138.
6. Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation JAMA. 2008;299(15):1800-1812.
7. http://www.medscape.com/viewarticle/492877

Photo Credits

Margaret Shear, Public Library of Science, see [6]

*Merck has never admitted that Vioxx could cause a cardiovascular risk, but the general idea is they just covered it up.

Blog Spam and Spam Blogs (2)

In a previous post I gave two examples of Health Blogs that are really pills-selling-sites. In this post I will show two examples of real Spam Blogs.

Spam blogs or splogs are usely fake weblogs where content is often either inauthentic text or merely stolen (scraped) from other websites. All spam artificially increases the site’s search engine ranking, increasing the number of potential visitors.

Database-management blog: no longer exists

Original post at this blog above and comment below.

One Spam blog that I wanted to show you, is no longer available. It is called Database Management.

Technorati-profile (authority=51)

This blog had no own content, but scraped it from blogposts having the (WordPress?) tag “database”. Although the post does link to the original site, it doesn’t refer to the author’s proper name, but some automatically generated fake name. For instance Shamisos instead of Laikaspoetnik (see Fig).

When I tried to place a comment on their site I had to login into the WordPress-account (although I was already logged in into mine). That’s when I began to really distrust it.

It’s technorati profile still exists (see Fig.). It is clear that the blog has rapidly increased it’s “authority” in the few months it existed. From zero to 51.
Many blogs linking to this blog are also gone or peculiar. Other blogs might have just linked to the spam blog because they assumed that this was the original post, not the copy. Presumably by having so much content on ‘database management’ the splog gets more traffic (of the preferred kind). This might be an example of a splog that backlinks to a portfolio of affiliate websites, to artificially inflate paid ad impressions from visitors, and/or as a link outlet to get new sites indexed (Wikipedia).

The second example of a spamblog is a very interesting site for Medical Librarians: Generic Pub, with the webadress: http://genericpubmed.com/pub/ with posts about PubMed. Really high quality information. Why? Because the posts derive from elsewhere. All of my posts about PubMed are in there, as are those of my colleagues, and perhaps your posts as well. There is no clue as to where the post really came from. You don’t get any pingbacks, unless the (original) post linked to you. That’s how I found out. As with the other spamblogs you cannot comment. Comments are always closed.

one of my posts on Generic Pub

Blogroll of Generic Pub

Generic PubMed homepage

The site does not hide its real intentions. To the left is a huge pill “cialis” and the blogroll consists of only pills, as well as PubMed tag feeds of Technorati and WordPress.

If you strip of the web adress to: http://genericpubmed.com you arive at the homepage, which is unmistakingly a pharmaceutical e-commerce website. Why is this done? Perhaps the sites looks more reliable whith all those PubMed posts or perhaps the site might be easier to find.

One way or another, these two sites steal posts from other sites. Tags used by Technorati or by WordPress, that can be easily transformed into a feed make it very easy for these spambloggers to automatically import blogposts with a certain tag.
By the way, did you find your post in there?

Previous post, see here.

————————————————————————–

Database-management blog: no longer exists

In een eerder post heb ik 2 voorbeelden gegeven van blogs die eigenlijk tot doel hebben pillen te verkopen.

Nu 2 voorbeelden van echte Spam Blogs.

Volgens Wikipedia: Spam blogs of splogs zijn doorgaans nep-weblogs, waarvan de inhoud vaak min of meer gestolen wordt (“scraped”) van andere websites. Dit verhoogt de ranking door zoekmachines en zorgt ervoor dat het aantal bezoekers toeneemt.

Een Spam blog dat ik jullie wilde laten zien, is niet langer beschikbaar, tw. Database Management.

Dit blog had alle inhoud gepikt van posts met de (WordPress?) tag “database”. Er wordt wel gelinkt naar de originele site, maar de naam van de auteur wordt vervangen door een of andere automatisch gegenereerde naam, bijv. Shamisos in plaats van Laikaspoetnik (see Fig in engelstalig gedeelte).

Toen ik een commentaar wilde plaatsen op deze site, werd ik gedwongen in te loggen in WordPress, terwijl ik nota bene al ingelogd was. Vanaf dat moment vertrouwde ik het echt niet meer.

Het technorati profiel van deze site bestaat nog steeds (zie fig in engelstalig gedeelte). Het blog is in enkele maanden tijd van 0,0 tot 51 gestegen in “authoriteit”.
Veel blogs die naar dit blog linken zijn ook opgeheven of zijn verdacht. Andere blogs hebben misschien slechts per ongeluk naar deze splog gelinked, omdat men dacht met de originele post van doen te hebben, niet de kopie. Waarschijnlijk krijgt de splog zo meer verkeer van mensen die juist in database management geinteresseerd zijn. Mogelijk is dit een splog die teruglinkt naar een aantal klonen en vice versa. (Wikipedia).

Het 2e voorbeeld van een splog is een erg interessante site voor medisch informatiespecialisten, nl Generic Pub met het webadres: genericpubmed.com/pub. Allemaal kwalitatief zeer goede posts over PubMed. Maar ze zijn wel gejat. Al mijn berichten met de tag PubMed zijn er te vinden, evenals die van mijn collega’s en misschien uw berichten ook wel.
Nergens is de ware herkomst van de berichten te herleiden. De echte auteurs krijgen normaal geen pingback, alleen als de oorspronkelijke post een link naar hen bevat. Zo kwam ik er eigenlijk achter. Evenals de andere splogs, kun je geen commentaar plaatsen.

De website verhult zijn werkelijke bedoelingen niet. Links staat een reuzachtige pil “cialis” en de blogroll bevat alleen namen van pillen alsmede de feeds van de PubMed tags van Technorati en WordPress.
Als je het webadres stript tot: genericpubmed.com kom je op de homepage, onmiskenbaar een e-commerce site. Waarom verschuilt men zich achter zo’n blog? Lijkt de site er betrouwbaarder door of vinden potentiele klanten de site makkelijker?

Hoe dan ook deze 2 sites stelen van andere websites. Een feed nemen op Technorati- of WordPress-tags is een eitje, en dit maakt het deze spambloggers erg makkelijk om automatisch blogposts met een bepaalde tag te importeren.
Tussen 2 haakjes, heeft u uw post al getraceerd?

Vorig bericht in deze serie, zie hier.

Blog Spam and Spam Blogs (1)

Flickr.com cursedthing (CC)

We all get our spam once in a while. Most of the time spamfilters block them. Askismet works well at this blog. Often you recognize spam by the hyperlinks or the words, i.e. “viagra”.

But sometimes spam is not so obvious. In 2 separate post I would like to give some examples of less obvious blog spam, spamblogs and something in between.

Acccording to wikipedia:

Blog spam is done by automatically posting random comments or promoting commercial services to blogs. Any web application that accepts and displays hyperlinks submitted by visitors may be a target.

Conversely, spam blogs are usely fake weblogs where content is often either inauthentic text or merely stolen (scraped) from other websites.

All spam artificially increases the site’s search engine ranking, which often results in the spammer’s commercial site being listed ahead of other sites for certain searches, increasing the number of potential visitors and paying customers.

Blogs & Spam: “Spam” by request?

David Rothman describes at his blog how he is often mailed by people asking him to post about their site, which often is “just a lousy site solely meant for pharma marketing”. He refuses if the site isn’t really useful, but apparently many of his fellow health bloggers aren’t that fussy, since those particular sites often manage to get mentioned on other health blogs anyway. David hopes that the blog-reader will read through this, but is that really the case? The blogger may be considered an expert in the field (that’s why he receives an email) and people may be inclined to take his word for granted. Striktly taken this may not be spam, but it sure works the same way.

Spam Blog (1). “Spam” hidden behind “Breaking Health News”

About a week ago, I had a look at WordPress.com and saw an interesting featured post with the (WordPress) tag “Health”.
At WordPress “Featured Posts” are at the top of a tag list -in this case “Health”-, which increases traffic to such posts). The subject captured my attention, because it was about Addison’s disease (which I have). I read it.

Somebody with primary Addison (Primary Adrenal failure, which leads to inability to make the hormones cortisol, aldosterone and dehydroepiandrosterone (DHEA)) asked whether the menstrual irregularity she developed a year ago could be caused by the replacement therapy with Hydrocortisone and Fludrocortisone and if this could lower her fertility.

The answer (see here) was rather lengthy, it discussed the causes of menstrual irregularity, primary Addison’s disease, replacement therapy, that (the often not replaced) DHEA might improve general well-being, and finally comes to possible explanations:

• changes in menstrual cycle could be related to too much or too little of the replacement hormones
• recurrence of menstrual cycles was reported in one patient treated with DHEA (also considered as a supplement, by the way).
• advice: consultation of an endocrinologist.

Nothing really wrong with this. However a more plausible explanation wasn’t mentioned, i.e. that the reduced cycling might be due to the disease itself. Nowadays the main cause for primary Addison is auto-immunity, and auto-immunity often doesn’t come alone. Gonadal failure can occur in approximately 5% of the woman with auto-immune Addison’s (Williams Textbook of Endocrinology, E-medicine).
For instance in 100 Dutch patients the distibution was as follows

… In 47% of the patients with autoimmune Addison’s disease at least one other autoimmune disorder was present. Primary hypothyroidism had the highest prevalence (20.5%), followed by vitiligo (9.6%), non-toxic goiter (8.4%), premature menopause (7.3% of the women) (….).
From: P.M.J. Zelissen et al, J Autoimmun. 1995 Feb;8(1):121-30.

I tried to place a comment. However, comments were closed (at the date of posting). Odd. I must say that I already found it weird for a patient to start with “I actually have an interesting question.” No one says that, but rather:

“Help, I’ve Addison and my menses become irregular, I want to have children, so I’m afraid that I’m becoming less fertile. Can this have anything to do with the corticosteroids I take?”

An even closer look points out that:

• both the Q & the A are written by the same person.
• The automatically generated “Possibly Related Posts” only link to posts at the same blog
• as do all “so called comments” (so a kind of self-ping).
• There is no info whatsoever about who is behind this site.
• The tab “About” is really the tab Pharmacy Store, where a bunch of “high quality medications” are offered.
• If I click on fosamax (which a lot of ex-Cushing (panhypopituitary) Addisonpatients need), I ‘m linked to a really (recognizable) commercial site: see here
  

Is this so bad? Well at least as bad as a lot of commercial-pills-selling-sites that don’t look like commercial-pills-selling-sites. It is quite misleading to use a blog on “breaking Health news” as a cover-up for real intentions: selling. Readers cannot respond, only trackback. Furthermore, in this particular case, the information was not really adequate for patients either (although “partially prepared” by pharmD candidates). One may also wonder why such a post becomes the featured Health blog at WordPress. Well, it will have suited them (and their tag “health” is well-thought-out).

But there are better (or really worse) examples of real spam blogs. Two examples will be given in the next post (see here).

Flickr.com cursedthing

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We hebben allemaal wel eens last van spam. Meestal wordt spam wel door spamfilters geblokkeerd. Askismet houdt in ieder geval het nodige tegen op dit blog (700 spam). Vaak herken je spam wel aan de (vele) hyperlinks of termen als “Viagra”.

Soms is echter niet zo duidelijk dat het om spam gaat. In tenminste 2 berichten wil ik voorbeelden geven van minder evidente blogspam, spamblogs en wat daar tussenin zit. Het zijn dingen waar ik toevallig tegenaan gelopen ben.

Eerst wat definities. Volgens Wikipedia :

Blog spam is done by automatically posting random comments or promoting commercial services to blogs. Any web application that accepts and displays hyperlinks submitted by visitors may be a target.

Conversely, spam blogs are usely fake weblogs where content is often either inauthentic text or merely stolen (scraped) from other websites.

All spam artificially increases the site’s search engine ranking, which often results in the spammer’s commercial site being listed ahead of other sites for certain searches, increasing the number of potential visitors and paying customers.

Blogs & Spam: “Spam” op verzoek?

David Rothman vertelt op zijn blog dat hij vaak een verzoek per mail krijgt om een post te plaatsen over een bepaalde site, terwijl het gewoon om een belabberde farmaceutisch e-commerce site gaat. David weigert dit als de site slecht is/zijn lezers niets biedt, maar kennelijk zijn z’n collega bloggers niet zo kieskeurig: vaak worden dergelijke sites binnen no time wel op andere gezondheidsblogs besproken. David hoopt dat de lezers van dergelijke blogs hier doorheen kijken, maar ik vraag me af of dat werkelijk zo is. Degene die erover schrijft op zijn blog wordt al gauw als expert gezien (daarom kreeg hij ook dat verzoek) en lezers zullen al gauw geneigd zijn wat hij bespreekt voor waar aan te nemen. Strikt genomen is dit wellicht geen spam, maar het resultaat is hetzelfde.

Spam Blog (1). “Spam” verborgen achter “Breaking Health News”

Ruim een week geleden zag ik een interessante post bij de “featured posts on Health” bij WordPress.com.
Bij WordPress komen “Featured Posts” bovenaan de posts met een bepaalde tag, in dit geval “Health” te staan. Ze worden daarmee extra in het zonnetje gezet en krijgen extra veel bezoek. Maar in dit geval trok ook het onderwerp mijn aandacht, omdat ik het zelf heb: de ziekte van Addison.

Iemand met primaire Addison (uitval van de bijnieren waarbij de oorzaak in de bijnieren zelf ligt, niet in de aansturing. Hierdoor worden de hormonen cortisol, aldosteron en dehydroepiandrosterone (DHEA) niet meer gemaakt) stelde een vraag over haar sinds een jaar vaak uitblijvende menstruatie. Ze wilde weten of dit iets te maken kon hebben met de substitutietherapie met Hydrocortison and Fludrocortison.

Het antwoord (zie hier) was nogal weinig to the point. Het volgende werd breeduit besproken: de oorzaken van onregelmatige menstruatie i.h.a., primaire Addison, substitutietherapie, dat het vaak niet gesubstitueerde DHEA (eigenlijk ook vaak gebruikt als voedingssupplement) de kwaliteit van leven kan verbeteren, om tot slot met enkele mogelijke verklaringen te komen:

• veranderingen in de menstruatiecyclus kunnen samenhangen met te weinig of te veel vervangende hormonen (maar niet door fysiologische doses, hetgeen het streven is bij vervanging).
• één patient kreeg weer een normale cyclus na gebruik van DHEA (overigens werden ook de andere hormonen beter ingesteld)
• tot slot een algemeen advies; ga naar je endocrinoloog.

Hier is niet echt wat mis mee (vooral met het laatste advies). Zij het dat een voor de hand liggende verklaring niet genoemd wordt, namelijk dat een onregelmatige cyclus en verlaagde vruchtbaarheid ook kunnen samenhangen met de ziekte zelf. Tegenwoordig is de belangrijkste oorzaak voor primaire Addison autoimmuniteit (afweerreactie tegen eigen weefsels/organen) en autoimmuniteit komt vaak niet alleen. Uitval van de geslachtsorganen kan in zo’n 5% van de patienten met primaire Addison voorkomen (Williams Textbook of Endocrinology, E-medicine).
Bij 100 Nederlandse patienten was de verdeling bijvoorbeeld als volgt:

… In 47% of the patients with autoimmune Addison’s disease at least one other autoimmune disorder was present. Primary hypothyroidism had the highest prevalence (20.5%), followed by vitiligo (9.6%), non-toxic goiter (8.4%), premature menopause (7.3% of the women) (….).
From: P.M.J. Zelissen et al, J Autoimmun. 1995 Feb;8(1):121-30.

Ik probeerde een reactie te plaatsen op de blogpost, maar dat was niet meer mogelijk. Nou ja niet meer: het was de dag dat het bericht geplaatst was. Raar. Ik moet zeggen dat ik al mijn wenkbrauwen fronsde bij het zien van de aanhef “I actually have an interesting question.” geen patient begint zo, maar zegt eerder:

“Help, Ik heb Addison. Mijn cycli worden onregelmatig en ik wil nog graag kinderen hebben, dus ik ben bang dat ik minder vruchtbaar wordt. Kan dit komen door de corticosteroiden die ik ter vervanging inneem?”

Geintrigeerd ging ik verder op zoek.

• De Q & de A bleken door dezelfde persoon geschreven.
• De automatisch gegenereerde “Possibly Related Posts” linken alleen naar berichten op het blog zelf.
• Dat geldt ook voor alle commentaren (een soort zelf-ping).
• Er is nergens info over wie er achter de site zit.
• De tab “About”/”Over” is eigenlijk de link naar de “Pharmacy Store“, waar een reeks “high quality medications” wordt aangeboden.
• Als je bijvoorbeeld op fosamax (vaak gebruikt door ex-Cushing Addisonpatienten) klikt kom je op een duidelijk herkenbare commerciele site terecht: zie hier
  

Is dit zo erg? Nou dit blog is net zo erg als die pillen-verkopende websites die er niet uitzien als pillenverkopende websites. Het is nogal misleidend om je blog te presenteren als een blog over “breaking Health news” om je werkelijke bedoelingen te verbloemen: pillenverkoop. Lezers kunnen niet reageren, alleen trackbacken. Verder was de informatie ook voor patienten niet helemaal volledig. Je kunt je ook afvragen hoe zo’n blog nou een featured Health blog bij WordPress wordt. Nou, het was wel lekker meegenomen (en ze kennen niet voor niets de tag “Health” toe).

Maar er zijn betere (or eigenlijk slechtere) voorbeelden van echte spam blogs. In de volgende post (zie hier) zal ik er twee bespreken.

The Best Study Design… For Dummies.

When I had those tired looks again, my mother in law recommended coenzyme Q, which research had proven to have wondrous effects on tiredness. Indeed many sites and magazines advocate this natural energy producing nutrient which mobilizes your mitochondria for cellular energy! Another time she asked me if I thought komkommerslank (cucumber pills for slimming) would work to loose some extra weight. She took my NO for granted.

It is often difficult to explain people that not all research is equally good, and that outcomes are not always equally “significant” (both statistically and clinically). It is even more difficult to understand “levels of evidence” and why we should even care. Pharmaceutical Industries (especially the supplement-selling ones) take advantage of this ignorance and are very successful in selling their stories and pills.

If properly conducted, the Randomized Controlled Trial (RCT) is the best study-design to examine the clinical efficacy of health interventions. An RCT is an experimental study where individuals who are similar at the beginning are randomly allocated to two or more treatment groups and the outcomes of the groups are compared after sufficient follow-up time. However an RCT may not always be feasible, because it may not be ethical or desirable to randomize people or to expose them to certain interventions.

Observational studies provide weaker empirical evidence, because the allocation of factors is not under control of the investigator, but “just happen” or are choosen (e.g. smoking). Of the observational studies, cohort studies provide stronger evidence than case control studies, because in cohort studies factors are measured before the outcome, whereas in case controls studies factors are measured after the outcome.

Most people find such a description of study types and levels of evidence too theoretical and not appealing.

Last year I was challenged to tell about how doctors search medical information (central theme = Google) for and here it comes…. “the Society of History and ICT”.

To explain the audience why it is important for clinicians to find ‘the best evidence’ and how methodological filters can be used to sift through the overwhelming amount of information in for instance PubMed, I had to introduce RCT’s and the levels of evidence. To explain it to them I used an example that stroke me when I first read about it.

I showed them the following slide :

And clarified: Beta-carotene is a vitamine in carrots and many other vegetables, but you can also buy it in pure form as pills. There is reason to believe that beta-carotene might help to prevent lung cancer in cigarette smokers. How do you think you can find out whether beta-carotene will have this effect?

• Suppose you have two neighbors, both heavy smokers of the same age, both males. The neighbor who doesn’t eat much vegetables gets lung cancer, but the neighbor who eats a lot of vegetables and is fond of carrots doesn’t. Do you think this provides good evidence that beta-carotene prevents lung cancer?
  There is a laughter in the room, so they don’t believe in n=1 experiments/case reports. (still how many people don’t think smoking does not necessarily do any harm because “their chainsmoking father reached his nineties in good health”).
  I show them the following slide with the lowest box only.
• O.k. What about this study? I’ve a group of lung cancer patients, who smoke(d) heavily. I ask them to fill in a questionnaire about their eating habits in the past and take a blood sample, and I do the same with a simlar group of smokers without cancer (controls). Analysis shows that smokers developing lung cancer eat much less beta-carotene containing vegetables and have lower bloodlevels of beta-carotene than the smokers not developing cancer. Does this mean that beta-carotene is preventing lung cancer?
  Humming in the audience, till one man says: “perhaps some people don’t remember exactly what they eat” and then several people object “that it is just an association” and “you do not yet know whether beta-carotene really causes this”. Right! I show the box patient-control studies.
• Than consider this study design. I follow a large cohort of ‘healthy’ heavy smokers and look at their eating habits (including use of supplements) and take regular blood samples. After a long follow-up some heavy smokers develop lung cancer whereas others don’t. Now it turns out that the group that did not develop lung cancer had significantly more beta-carotene in their blood and eat larger amount of beta-carotene containing food. What do you think about that then?
  Now the room is a bit quiet, there is some hesitation. Then someone says: “well it is more convincing” and finally the chair says: “but it may still not be the carrots, but something else in their food or they may just have other healthy living habits (including eating carrots). Cohort-study appears on the slide (What a perfect audience!)
• O.k. you’re not convinced that these study designs give conclusive evidence. How could we then establish that beta-carotene lowers the risk of lung cancer in heavy smokers? Suppose you really wanted to know, how do you set up such a study?
  Grinning. Someone says “by giving half of the smokers beta-carotene and the other half nothing”. “Or a placebo”, someone else says. Right! Randomized Controlled Trial is on top of the slide. And there is not much room left for another box, so we are there. I only add that the best way to do it is to do it double blinded.

Than I reveal that all this research has really been done. There have been numerous observational studies (case-control as well cohorts studies) showing a consistent negative correlation between the intake of beta-carotene and the development of lung cancer in heavy smokers. The same has been shown for vitamin E.

“Knowing that”, I asked the public: “Would you as a heavy smoker participate in a trial where you are randomly assigned to one of the following groups: 1. beta-carotene, 2. vitamin E, 3. both or 4. neither vitamin (placebo)?”

The recruitment fails. Some people say they don’t believe in supplements, others say that it would be far more effective if smokers quit smoking (laughter). Just 2 individuals said they would at least consider it. But they thought there was a snag in it and they were right. Such studies have been done, and did not give the expected positive results.
In the first large RCT (appr. 30,000 male smokers!), the ATBC Cancer Prevention Study, beta-carotene rather increased the incidence of lung cancer with 18 percent and overall mortality with 8 percent (although harmful effects faded after men stopped taking the pills). Similar results were obtained in the CARET-study, but not in a 3rd RCT, the Physician’s Health Trial, the only difference being that the latter trial was performed both with smokers ànd non-smokers.
It is now generally thought that cigarette smoke causes beta-carotene to breakdown in detrimental products, a process that can be halted by other anti-oxidants (normally present in food). Whether vitamins act positively (anti-oxidant) or negatively (pro-oxidant) depends very much on the dose and the situation and on whether there is a shortage of such supplements or not.

I found that this way of explaining study designs to well-educated layman was very effective and fun!
The take-home message is that no matter how reproducible the observational studies seem to indicate a certain effect, better evidence is obtained by randomized control trials. It also shows that scientists should be very prudent to translate observational findings directly in a particular lifestyle advice.

On the other hand, I wonder whether all hypotheses have to be tested in a costly RCT (the costs for the ATCB trial were $46 million). Shouldn’t there be very very solid grounds to start a prevention study with dietary supplements in healthy individuals ? Aren’t their any dangers? Personally I think we should be very restrictive about these chemopreventive studies. Till now most chemopreventive studies have not met the high expectations, anyway.
And what about coenzyme-Q and komkommerslank? Besides that I do not expect the evidence to be convincing, tiredness can obviously be best combated by rest and I already eat enough cucumbers…. 😉
To be continued…

SOURCES:
Clinical Studies and designs: several paper books; online e.g. GlossClinStudy on a vetenarian site
The ATCB study: The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35. See free full text here
Overview of ATBC and CARET study 2 overwiews at www.cancer.gov, one about the ATBCfollowup and one about the CARET-trial
Overview of other RCT’s with surprising outcomes: on wikipedia

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Toen ik er weer eens donkere kringen onder mijn ogen had, raadde mijn schoonmoeder me coenzym Q aan, waarvan ze net gelezen had dat het een wetenschappelijk bewezen effectieve vermindering van vermoeidheid geeft. Inderdaad bevelen veel webpagina’s en huis-aan-huis bladen deze “natuurlijke en energie-mobiliserende voedingstof die je mitochondrien aanzet tot cellulaire energie” aan. Een andere keer vroeg ze me of ik dacht dat je wat pondjes zou kunnen kwijtraken door komkommerslank. Ze nam met een stellig NEE genoegen.

Het is vaak heel moeilijk duidelijk te maken dat niet alle research even goed is en niet alle uitkomsten even significant (zowel statistisch als klinisch). Nog moeilijker is het om de “bewijsniveau’s (levels of evidence)” uit de doeken te doen of om uit te leggen waarom je uberhaupt zoiets zou willen weten. De pharmacie en zeker de supplement verkopende bedrijfjes varen wel bij de goedgelovigheid van de gemiddelde consument. Hun verhalen en pillen vinden gretig aftrek.

Een gerandomiseerde gecontroleerde trial (RCT) is, indien goed uitgevoerd, het ‘beste’ studietype om aan te tonen of een behandeling werkzaam of nuttig is. Een RCT is een experimentele studie waarbij de deelnemers, die bij start van de studie vergelijkbaar zijn, door het lot worden toegewezen aan een (bepaalde) interventie- of controlegroep en waarbij na een bepaalde tijd de uitkomsten in beide groepen worden vergeleken. Een RCT is echter niet altijd haalbaar of wenselijk, bijvoorbeeld omdat het niet ethisch is om mensen te randomiseren of om hen bloot te stellen aan bepaalde interventies.

Observationele studies zijn zwakker in bewijskracht, omdat de toewijzing van de factoren niet in handen liggen van de onderzoeker, maar van het lot (natuur, werkomstandigheden, eigen keuzes). Van de observationele studies hebben cohort studies een hogere bewijskracht dan case control studies, omdat de te onderzoeken factoren bij cohort studies worden bepaald vòòrdat de uitkomst bekend is, terwijl dit bij case control studies juist gebeurt nadat de uitkomst bekend is.

De meeste mensen vinden zo’n beschrijving van studietypes the theoretisch en nietszeggend. Het spreekt ze niet aan, omdat ze zich er niets bij voor kunnen stellen.

Afgelopen jaar werd ik uitgedaagd om te vertellen “hoe artsen medische informatie zoeken” (het centrale thema was Google en informatie) voor …en nou komt-ie.. “De Vereniging voor Geschiedenis en Informatica”.

Om het publiek uit te leggen waarom het belangrijk is dat klinici de beste evidence vinden en hoe zij met behulp van methodologische filters het kaf van het koren kunnen scheiden, moest ik hen eerst uitleggen wat RCT’s en bewijsniveau’s zijn. Ik legde hen dit uit aan de hand van een onderwerp dat mij na aan het hart ligt.

Ik toonde hen een dia met daarop de vraag: Voorkomt bètacaroteen longkanker?
En ik legde hen uit dat bètacaroteen een vitamine is die veel in worteltjes en bepaalde andere groente voorkomt, maar die je ook als pillen kan slikken. Er zijn aanwijzingen dat bètacaroteen longkanker bij rokers zou helpen voorkomen. Hoe denkt u dat u dit het best kunt aantonen?

• Stel u heeft 2 buren, beiden kettingroker, man, en even oud. De buurman die weinig groente eet krijgt longkanker, maar de buurman die heel veel groente eet en gek is op worteltjes krijgt het niet. Kunnen we nu concluderen, dat bètacaroteen longkanker bij rokers voorkomt?
  Er wordt hartelijk gelachen, dus men gelooft hier niet in n=1 experimenten/case reports. (maar je moet ze maar de kost geven die denken dat roken geen kwaad kan omdat hun shaggies verslindende vader een taaie kerel was die nog tot op hoge leeftijd volop van het leven genoot).
  Ik toon hen een nieuwe slide met daarop het woord “casus”.
• O.k. Wat vind u hiervan? Er is een groep longkankerpatienten, die veel gerookt heeft. Ik vraag of de patienten een vragenlijst willen invullen en neem wat bloed af. Datzelfde doe ik met een vergelijkbare groep rokers die géén kanker ontwikkeld heeft. Ik analyseer alles en wat blijkt? In de groep met longkanker zitten vooral rokers met een minder caroteenrijk voedingspatroon en minder caroteen in hun bloed. Betekent dit dat bètacaroteen longkanker voorkomt?
  Geroezemoes. Iemand zegt: “misschien kunnen sommige mensen zich helemaal niet zo goed herinneren wat ze vroeger precies hebben gegeten”. Anderen werpen tegen “dat het alleen maar een associatie is” en “dat je niet zeker weet of het echt alleen de betacaroteen is die dit effect geeft.” Heel goed! Op het scherm verschijnt “patient-controle onderzoek”.
• Dan doe ik het anders. Ik volg een grote groep ‘gezonde’ zware rokers, ik volg hun eetgewoonten (inclusief het gebruik van supplementen) nauwgezet en neem regelmatig bloed af. Na lange tijd krijgen sommige rokers longkanker, maar andere niet. Nou blijkt wéér dat de groep die geen longkanker kreeg meer caroteenrijk voedsel at en meer betacaroteen in zijn bloed had. Wat denkt u hiervan?
  Het is een beetje stiller, je voelt de aarzeling, tot iemand zegt. “Nou, het overtuigt wel iets meer”. Een ander werpt tegen: “maar wie zegt dat het de worteltjes zijn, misschien is het wel iets anders in het eten of misschien is de levensstijl sowieso gezonder. Cohort-studie verschijnt op het scherm. Wat een perfect publiek, daar kan menig geneeskunde student nog een puntje aan zuigen.
• Ik begrijp dat u niet geheel overtuigd bent van de bewijskracht van deze studies. Maar hoe zou u dan vaststellen dat bètacaroteen de kans op longkanker verlaagt bij rokers? Stel dat u het echt zou willen weten, hoe zet u de studie dan op?
  Gegrinnik. Iemand zegt: “Geef de helft van de rokers beta-caroteen en de andere helft niets”. “Of een placebo”. zegt een ander. Prima! Er verschijnt “Randomized Controlled Trial” boven aan de slide. Er is geen ruimte meer over, dus we zijn er. Ik vertel alleen nog iets over het belang van dubbelblind onderzoek.

Dan onthul ik dat dergelijke onderzoeken ook werkelijk gedaan zijn. Uit tal van observationele (case-control en cohort) studies is gebleken dat er een omgekeerde relatie bestaat tussen inname van bètacaroteen en ontwikkelen van longkanker bij rokers. Hetzelfde geldt voor vitamine E.

“Nu u dat weet”, vraag ik het publiek “Zou u dan als kettingroker deelnemen aan een studie waar u random toegewezen wordt aan een van de volgende behandelingen:
1. bètacaroteen, 2. vitamine E, 3. beiden of 4. geen van beiden (placebo)?”

De inclusie faalt. Sommigen geloven niet in supplementen, anderen stellen dat het beter zou zijn als rokers stopten met roken (instemmend gelach). Twee mensen zeggen dat ze het in overweging zouden nemen. Maar men vermoed (gezien het voorafgaande) een addertje onder het gras en ze hebben gelijk. Dergelijke studies zijn gedaan en hebben niet het gewenste resultaat opgeleverd.
In de eerste grote RCT (ca. 30.000 mannelijke rokers!), de ATBC Cancer Prevention Study, verhoogde bètacaroteen juist het aantal longkankergevallen met 18% en de algehele sterfte met 8% (hoewel het effect langzaam uitdooft als mensen met de pillen stoppen). Vergelijkbare resultaten werden verkregen in de CARET-studie, maar niet in een 3e RCT, de Physician’s Health Trial, die ook niet-rokers had geincludeerd.
Aangenomen wordt nu dat sigaretterook bètacaroteen afbreekt tot gevaarlijke afvalproducten, een proces dat gekeerd kan worden door andere oxidanten (normaal aanwezig in het voedsel). Of vitaminen een positieve (anti-oxidant) of negatieve (pro-oxidant) werking hebben hangt erg af van de dosis, de vorm, en de situatie: vitamines in fysiologische concentraties zijn met name nuttig bij een tekort eraan.

Deze manier van studietypes uitleggen aan goed-ontwikkelde leken vond ik erg effectief en leuk om te doen bovendien.

De boodschap is dat hoezeer observationele studies ook op een bepaald effect wijzen, beter evidence verkregen kan worden met een RCT (hoewel dit niet altijd kan en mag). Het laat ook zien dat je als wetenschapper (en dokter) heel voorzichtig moet zijn met het direct vertalen van ‘waarnemingen’ naar adviezen richting een bepaalde therapie of levensstijl.

Aan de andere kant vraag ik me wel af, of alle hypothesen getest moeten worden in een overigens zeer kostbare RCT (kosten van de ATCB trial bedroegen $46 miljoen). Zou er niet een heel stevige basis moeten zijn vòòr je een preventieve studie doet met supplementen bij gezonde individuen? Zijn er geen risico’s ? Zelf denk ik dat we heel terughoudend moeten zijn met chemopreventie studies. Tot op heden hebben ze trouwens niet aan de hoge verachtingen voldaan.
Wat coenzym-Q en komkommerslank betreft? Behalve dat ik er gewoon niet in geloof (ik bedoel dat er evidence bestaat dat ze werken), denk ik dat vermoeidheid het best bestreden kan worden met rust en ik eet zat komkommers. 😉 Volgende keer meer…..

Farmaceutische industrie & wetenschap: je zou er depressief van worden.

Ook in de Psychiatrie een nauwe verstrengeling tussen farmaceutische industrie en wetenschap.

Beluister hier het interview met Trudy Dehue in het radioprogramma Argos (de Ochtenden) van de VPRO/VARA (vrijdag 6 juni 2008), over haar boek De Depressie Epidemie
[ISBN: 9789045700953] .

In dit interview komt vooral de invloed van de industrie op het (te vaak) voorschrijven van depressiva (prozac e.d.) en het verdoezelen van bijwerkingen aan de orde.

In deze audio-opname wordt er ook op gewezen dat editors van vooraanstaande engelstalige tijdschriften (Lancet, BMJ) regelmatig de verstrengeling van geneesmiddelenindustie en wetenschappelijk onderzoek stevig aan de kaak stellen.

Klik hier voor zo’n editorial van Fiona Godlee BMJ 2008;336: “Editor’s Choice – Doctors and the drug industry” en hier voor een editorial van RE Ferner – BMJ 2005; 330: 855-856: “The influence of big pharma”.

Toevallig speelt nu ook de kwestie van het ADHD-medicijn Strattera, dat volgens het Nederlands Comité voor de Rechten van de Mens (NCRM) het risico op suïcidaal gedrag, hartaandoeningen en leverbeschadigingen zou verhogen. De NCRM beschikt over een gedeelte van het evaluatierapport over dit medicijn ‘Strattera Risk Benefit Assessment’ (2006). In de 67 beschikbare pagina’s zijn o.a. de volgende gegevens te vinden:

• 130 meldingen van suicidaal gedrag in één maand
• 766 spontane meldingen van hartaandoeningen
• 172 meldingen van leverbeschadigingen
• 20 geslaagde zelfmoorden

Morgen [9 juni 2008] is er een zitting van de Bestuursrechtbank in Amsterdam aangaande de openbaarmaking van het hele rapport in het kader van de Wet Openbaarheid Bestuur. Het Nederlands College ter Beoordeling van Geneesmiddelen (CBG) wilde het rapport namelijk niet vrijgeven.

Bronnen:

• Spits vrijdag 6 juni (papieren versie) , 5 juni e-versie: klik hier
• http://ncrm.nl/nieuws.htm