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Posted: Wed Sep 7th, 2005 05:04 |
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"Epidemiology is not 'science'. Its findings are not irrefutable."
http://www.jpands.org/vol10no3/miller.pdf
August 31, 2005
"On Evidence, Medical and Legal"
A new study by US Professor Donald W. Miller MD and British lawyer Clifford G. Miller
As sent on UK Press Association Newswire service Aug 31, 8:45 GMT: EMBARGO 1/SEPT/2005 - As released on PA wire service
London, England & Seattle USA 31 August: A new study by US Professor Donald W Miller MD and British lawyer Clifford G. Miller in the Journal of American Physicians and Surgeons Fall issue shows that valid legal claims of victims injured by medications can, unlike the Vioxx case in Texas USA, be blocked or systematically rejected by expert evidence based on flawed but accepted medical thinking. Courts depend on experts when deciding what causes injuries.
Medicine adverse reactions affect 40% of patients; kill 1:1000 inpatients; 1:10,000 surgical patients; cause 5% of annual UK hospital admissions. Claims blocked include child vaccine and pharmaceutical mercury victims.
The study shows experts can:
- dismiss evidence that could prove the victim’s case;
- rely on biased government and drug company funded research;
- refer to official statements and reports which make the same mistakes.
Dr D Miller, Professor of Surgery University of Washington School of Medicine said:
- "We demonstrate current 'evidence-based medicine' practice is flawed and over-reliant on epidemiology. It discards or downgrades important evidence, including eye witness testimony so fundamental in legal cases. Epidemiology is not 'science'. Its findings are not irrefutable.
Investigators can manipulate epidemiologic statistics to produce results favouring the view officials paying for a study want. In medicine there are other kinds of evidence that, placed in a 'factual matrix', have probative value. A recent University of Washington study, for example, shows parents are reliable witnesses when reporting their children developed normally before regressing and becoming autistic. Medicine has a lot of catching up to do in how it treats evidence.
Co-author, Clifford Miller, British commercial lawyer, former university law lecturer, and graduate physicist, London, England said: "Whilst medicine can be sophisticated, it is not science but tries too hard to be. Aspects of its evidential practices are stone age compared to other fields. Some UK and US judges and lawyers are knowledgeable about medicine, but must rely on expert testimony when deciding cases. Expert opinions based on flawed practices can cause injustices.”
Please Note that this study can be viewed online by September 3, 2005. "On Evidence, Medical and Legal" - http://www.jpands.org, 1 Sept 2005, Volume 10 Number 3 - Fall 2005
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This Pubmed search will let you see there are two schools of research - Clinical Science and Biological Science
http://tinyurl.com/2cbzha
You need to make up your own mind whether you want to know about the way the body actually works (its Biology), or how the body is thought to work (its Epidemiology).
..Trevor..
July08...This recent article by Steve Strauss, at the CBC deals directly with misreading epidemiological studies so that they prove what you expect them to prove:
http://www.cbc.ca/technology/story/2008/07/07/strauss-vitamind.html
See also:
The vast majority of studies fail to account for the long term effects of vitamin D.
What can medical research learn from the open source software movement?
Last edited on Tue Jul 22nd, 2008 18:20 by Foundation Staff
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Posted: Wed Sep 7th, 2005 23:28 |
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(filelink)
FDA trials
Q- I have fluid on my lungs and my doctor suspects Benicar because there were 3 cases of this in the FDA studies.
A- There is a failure in the medical community to recognize how serious the Th1 diseases really are. Even when a patient is close to suicide, Doc often cannot understand why the patient is complaining, a tragic lack of understanding.
Even after diagnosis, there is no recognition of the systemic nature of these diseases, nor is the FDA certification process set up to find things like we discovered with the MP. Those 3 patients out of several thousand who had fluid on their lungs during the Benicar trials may have seemed quite healthy to the Doctors, yet in actuality may have been severely ill with Th1 disease. There is just no way to tell, as no such record-keeping is required by the FDA yet. They don't track the health of folks subsequent to their having taken part in safety-trials. Those three folks may all have died from pulmonary insuffiency within a year, there is no requirement to report such things.
I hope this helps you understand thay way FDA trials are conducted. believe me, it takes a lot of knowledge just to navigate your way around an "adverse reactions" list these days 
Max Planck said ""Science progresses funeral by funeral"
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Posted: Sat Sep 10th, 2005 03:21 |
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(filelink)
Scientific evidence is not fact
Q- How do lay people disprove these flawed studies?
A- Problem is that if I explained it to you precisely, you would not understand one word. OK, maybe one or two words  Unfortunately there are charlatans who will take advantage of that, and provide simplistic explanations which sound sensible to you.
The problem with scientific evidence is that it is just that. Evidence. Not fact. And the more obvious something sounds the less likely that it will ultimately prove to be factual.
Sorry to have to speak this way, but all of us have to understand our limitations. I try not to get into fields I don't understand. But I was taught study-design 30+ years ago, and you will find our papers in Pubmed from the early '80s. It has taken me quite a while to assimilate all this stuff, and beat some sense out of it.
I read just this morning a pseudo-science description from a very well respected expert physician. I realized two things:
1. The science was faulty
2. His patients were not getting any better
But I think a lot of the readers would have just 'oohed' and 'aahed' at the big words. It is sad, really. I try not to use big words and so I get criticized for not knowing what I am talking about. Folks think that MP stands for 'Marshall Protocol whereas the important MP is the 'Marshall Pathogenesis.'"
..Trevor..
..........................................................................................
The limitations of published research
Solomon Snyder, senior editor at the Proceedings of the National Academy of Sciences, and a neuroscientist at Johns Hopkins Medical School in Baltimore, US, says most working scientists understand the limitations of published research.
"When I read the literature, I'm not reading it to find proof like a textbook. I'm reading to get ideas. So even if something is wrong with the paper, if they have the kernel of a novel idea, that's something to think about."
=====================================
I don’t understand the science behind the Marshall Protocol. Where can I get answers?
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Posted: Thu Sep 22nd, 2005 06:09 |
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(filelink)
"Clinical Studies 101"
http://www.nih.gov/news/WordonHealth/aug2004/story03.htm
================================
In a multi-factorial study, a drug is evaluated by testing it in combination with other drugs rather than by itself. For example, one group of patients might test therapy A, another test therapy B, a third group test A and B combined, and a control group test neither A nor B.
Randomized means people are assigned at random either to receive the new drug, the standard treatment for that disease, or a nonfunctional substitute (such as a sugar pill). This last group is often called the control group, or the placebo group.
Blinded studies can be double-blind in which neither the patient nor the physician knows who is getting which drug or single-blind in which the doctor knows but the patient does not.
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There is a detailed explanation of the process of peer review online at Wikipedia at http://en.wikipedia.org/wiki/Peer_review
Peer review is a process of sharing work and ideas with others who have expertise in the same field so they can provide suggestions for improvement and/or point out weaknesses.
If you read the Wikipedia articles, you will see that there are some limitations in the publishing peer review process and the peer review process does not keep fraudulent works from being published, distributed and accepted. In other words - the fact that a work is published doesn't make it factual. Once a work is published, that is when the open discussion of its validity and applicability begins.
All of Dr. Marshall's papers have been peer-reviewed. Some have been quite widely distributed via the internet, so there has been plenty of opportunity for feedback from experts in the field.
Belinda
PS Take a peek at Wikipedia's section about papers that were not peer reviewed. It's pretty interesting!
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Posted: Thu Dec 8th, 2005 22:20 |
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Correlation Studies
(filelink)
The problem with most correlation studies is that almost everyone makes the error of believing that correlation implies causality. Common sense tells us that if A is correlated with B, and it is obvious that B cannot possibly cause A, therefore A must cause B. For example, if increased weight is correlated with increased incidence of heart attacks, and it is obvious that the heart attack did not cause the history of higher weight, therefore the increased weight must cause the heart attack. This is just wrong logic even though nearly everyone makes this error, and no individuals reporting these results to the public ever provide the proper cautions. We hear of these kinds of studies almost daily in the popular press, especially as it relates to medicine.
The reason this logic is wrong is that there is always a possibility that some variable that was not included in the correlation study was present that caused both. That third variable was not included either because the people conducting the study knew about it but did not consdier it worth including, or because they didn't know such a variable existed.
Those of us who are aware of TH1 inflamation, its cause, and the wide number of symptoms it probably causes, should be very aware that nearly all medical studies of the type your described in your recent post and I generalized above, whether done recently or in the past, are totally worthless because they did not control for the presence of or level of TH1 disease.
For example in the study you quoted, if TH1 had been included as a variable, we would expect to see a negative correlation between presence or level of TH1 and the amount/quality of sleep. We might also find a positive correlation between TH1 and weight. Of course the correlation between sleep and weight actually found in the study you referenced would still be there. Results of this nature should then lead to further study to determine which is the root cause. Determining this often requires deeper understanding of the science than simple correlations. Determining the root cause might then lead to studies for a cure.
Fortunately for us Trevor didn't follow this all too common practice of conducting correlation studies, but instead tried to understand the science of what was really going on.
Why such a long post? I guess my point is that those of us who know about TH1 should question all medical correlation studies that do not control for TH1 inflamation. Maybe its a way to start a conversation with friends who need to be educated about medical issues of interest to them. Maybe its a way to counter arguments by medical professionals who are uninformed about TH1 who use such studies to make a point with which we disagree. We should not pass these fatally flawed studies along.
Gary
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Posted: Sat Dec 10th, 2005 16:45 |
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Lack of interdisciplinary cooperation
(filelink)
The explosive development of knowledge in the late nineteenth century was promoted by exchanges among scientists coming from many and varied horizons (chemistry, zoology, and medicine). In the twentieth century, the sciences split into diversified and specialized branches, giving rise to many skillful but narrow-minded scientists.
Fundamental ("pure") research has been considered nobler, more intellectually rewarding, and more challenging than "applied" research. In the coming years, I hope we will see greater interdisciplinary cooperation and closer exchanges between basic and clinical scientists. As put by Pasteur himself, "No category of science exists to which one can give the name of applied Science. Science and the application of science are linked together as a fruit is to the tree that has borne it."
http://cmr.asm.org/cgi/content/full/13/4/615
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Posted: Thu Dec 15th, 2005 07:59 |
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Statistics
(filelink)
"He uses statistics as a drunken man uses lamp posts--for support rather than illumination."
Andrew Lang
=====================================
Statistics alone never prove causality
Gerard E. Dallal, Ph.D. at Tufts University provides a good overview of the pitfalls of logical fallacies in determining "cause and effect" on his webpage. Click on "Cause and Effect". Dr. Dallal provides easy-to-understand explanations as to why statistics alone never prove causality. A mechanism of action must exist to explain causal relationship.
=====================================
"There are lies, damn lies, and statistics".
~Disraeli
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Posted: Fri Dec 16th, 2005 05:52 |
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Article touting vitamin D is ghostwritten by drug company rep
(filelink)
Ghost Story
At Medical Journals, Writers Paid by Industry Play Big Role...Articles Appear Under Name Of Academic Researchers, But They Often Get Help
J&J Receives a Positive 'Spin'
By ANNA WILDE MATHEWS
Staff Reporter of THE WALL STREET JOURNAL
December 13, 2005; Page A1
In 2001, the American Journal of Kidney Diseases published an article that touted the use of synthetic vitamin D. Its author was listed as Alex J. Brown, an associate professor at Washington University in St. Louis.
But recently, that same article was featured as a work sample by a different person: Michael Anello, a free-lance medical writer, who posted a summary of it on his Web site. Mr. Anello says he was hired to write the article by a communications firm working for Abbott Laboratories, which makes a version of the vitamin D product. Dr. Brown agrees he got help in writing but says he redid part of the draft.
It's an example of an open secret in medicine: Many of the articles that appear in scientific journals under the bylines of prominent academics are actually written by ghostwriters in the pay of drug companies. These seemingly objective articles, which doctors around the world use to guide their care of patients, are often part of a marketing campaign by companies to promote a product or play up the condition it treats.
A HIDDEN ROLE?
Now questions about the practice are mounting as medical journals face unprecedented scrutiny of their role as gatekeeper for scientific information. Last week, the New England Journal of Medicine admitted that a 2000 article it published highlighting the advantages of Merck & Co.'s Vioxx painkiller omitted information about heart attacks among patients taking the drug. The journal has said the deletions were made by someone working from a Merck computer. Merck says the heart attacks happened after the study's cutoff date and it did nothing wrong.
The Annals of Internal Medicine tightened its policies on writer disclosure this year after a University of Arizona professor listed as the lead author of a Vioxx article in 2003 said he had little to do with the research in it.
The practice of letting ghostwriters hired by communications firms draft journal articles -- sometimes with acknowledgment, often without -- has served many parties well. Academic scientists can more easily pile up high-profile publications, the main currency of advancement. Journal editors get clearly written articles that look authoritative because of their well-credentialed authors.
Increasingly, though, editors and some academics are stepping forward to criticize the practice, saying it could hurt patients by giving doctors biased information. "Scientific research is not public relations," says Robert Califf, vice chancellor of clinical research at Duke University Medical Center. "If you're a firm hired by a ! company trying to sell a product, it's an entirely different thing than having an open mind for scientific inquiry. ...What would happen to a PR firm that wrote a paper that said this product stinks? Do you think their contract would be renewed?"
Drug companies say they're providing a service to busy academic researchers, some of whom may not be skilled writers. The companies say they don't intend for their ghostwriters to bias the tone of articles that appear under the researchers' names.
Authors "have to sign off on everything," says Mark Horn, a Pfizer Inc. medical director. "This is properly viewed as a way to more efficiently make the transition from raw data to finished manuscript." Professors who get writin! g help generally say they give the writers input and check the work carefully.
The criticism of ghostwriting is one of several issues that have put scientific journals on the defensive. Even journal editors acknowledge they have sometimes done a poor job of detecting when articles cherry-pick favorable data to promote a particular drug or treatment. Some health insurers have stopped taking what they read in the journals on faith and are employing analysts to scrutinize articles for negative data that are buried.
It's hard to say how widespread ghostwriting is. An analysis presented at a medical-journal conference in September found that just 10% of articles on studies sponsored by the drug industry that appeared in top medical journals disclosed help from a medical writer. Often the help isn't disclosed. An informal poll of 71 free-lance medical writers by the American Medical Writers Association found that 80% had written at least one manuscript that didn't mention their contributions.
In the case of the vitamin D article, Dr. Brown says Abbott asked him to write it but he didn't have time. He had written an earlier article on the subject. "They said they would have one of their people write it, update my old review article and I would check it," he recalls. Mr. Anello, a Milwaukee writer who studied biochemistry at the University of Wisconsin, says he wrote the new article. "I've done a lot of ghostwriting jobs," he says, adding that sometimes he works closely with the named authors.
Dr. Brown says he had to rewrite "at least 30% to 40%" of Mr. Anello's draft. In retrospect, he says, he probably should have asked Abbott who Mr. Anello was and "if that person should be acknowledged." Abbott said the article's content was "under the complete discretion" of Dr. Brown and didn't discuss details. The journal's managing editor declined to comment because the journal is under new management.
Following questions from The Wall Street Journal, Mr. Anello removed the article summary from his Web site. Until recently, his online bibliography listed other scientific publications he has written under others' bylines that have yet to be published. The byline on one was "author to be named."
Medical writers frequently have scientific backgrounds. Some work for universities, drug companies or medical-communications firms, while others are free-lancers who typically get $90 to $120 an hour. A communications firm may charge $30,000 or more to have a team of writers, editors and graphic designers put together an article. Some of these firms are part of larger companies in publishing and advertising such as Thomson Corp. and Reed Elsevier PLC.
Elsevier's Excerpta Medica unit helps clients craft publications for prestigious scientific journals. Elsevier itself publishes many such journals, most notably The Lancet. Excerpta Medica says on its Web site that its relationship with its corporate parent's journals "allows us access to editors and editorial boards."
But Sabine Kleinert, an executive editor at The Lancet, says she has never worked with Excerpta Medica and rejects articles that have a marketing spin. "Promotion has a different goal than publishing a legitimate research study," says Dr. Kleinert. She suspects companies sometimes influence medical writers "to write it up in a certain way to make a product sound more efficacious than it is."
A 1999 document that turned up in a lawsuit describes Pfizer's publications strategy for its antidepressant Zoloft. The document, prepared by a unit of ad giant WPP Group, includes 81 different articles proposed for journals. They would promote the drug's use in conditions from panic disorder to pedophilia.
Author 'to Be Determined'
For some articles, the name of the author was listed as "TBD," or "to be determined," even though the art! icle or a draft was listed as already completed. Several of the listed articles ultimately ran in scientific publications -- including one in JAMA, the Journal of the American Medical Association -- without disclosing the role of outside writers.
In a statement responding to questions from The Wall Street Journal, Pfizer said agencies sometimes "pull together first draft manuscripts" based on information provided by researchers who will serve as authors. It says the academics who were later given credit as lead authors of the "TBD" articles were instrumental in designing the studies that the articles described. The lead authors said they had input into the drafts and approved the final papers.
In recent years, more journal editors have begun demanding that academic authors of studies explain their exact roles and disclose any work by medical writers. The editors say the writers can perform a valuable role so long as it's disclosed to readers.
Writers agree -- and the American Medical Writers Association is pressing for greater acknowledgment of its members' work. But some medical writers say they fear articles with full disclosure are likely to get bounced. Editors "say they want disclosure, but if you do it, they scream, 'ghostwriter' " says Art Gertel, who oversees medical writing at Beardsworth Consulting Group in Flemington, N.J. "Despite the cries for transparency, the journal editors still feel that there's an element of corruption if a medical writer is paid by a drug company."
Catherine DeAngelis, JAMA's editor in chief, says even a conscientious journal can only go so far in policing academics. "I don't give lie-detector tests to people," Dr. DeAngelis says.
BMJ, a British medical journal, has one of the toughest disclosure policies, but it can get misled. Last year, a note at the end of a BMJ article on painkillers and asthma said the article was "conceived and initiated" by its three academic authors. Lead author Christine Jenkins "performed the analysis and drafted the paper," the note said, adding that the work wasn't funded by a drug company. Dr. Jenkins is a senior researcher at Australia's Woolcock Institute of Medical Research, which has ties to the University of Sydney.
In fact, a medical writer paid by GlaxoSmithKline PLC helped draft the manuscript, the drug company confirms. The analysis was almost identical to an earlier, unpublished one that the company says was "initiated" by that writer. Both analyses concluded that acetaminophen or Tylenol (sold under a different name by GlaxoSmithKline in Britain) was safer for asthma patients than aspirin or other painkillers.
Dr. Jenkins says the structure of her work was "suggested" by the company version but she and the other authors did their own analy! sis. Dr. Jenkins says she personally "wrote a very large chunk" of the BMJ article and worked closely with the writer. Dr. Jenkins and GlaxoSmithKline declined to give the writer's name.
Dr. Jenkins says she didn't know that the company paid the writer. GlaxoSmithKline didn't pay Dr. Jenkins for the BMJ article, but the company previously paid her to speak at a conference and has given a major grant to the Woolcock Institute.
In a statement, GlaxoSmithKline says the paper "should have disclosed the involvement of a medical writer compensated by GSK." The company says it "regards the omission as a lapse on the part of GSK."
Fiona Godlee, BMJ's editor, says Dr. Jenkins "should have declared the involvement of the medical writer." Dr. Godlee says the journal will print papers that involve a medical writer, but she believes "the actual authors have to be incredibly closely involved."
When articles are ghostwritten by someone paid by a company, the big question is whether the article gets slanted. That's what one former free-lance medical writer alleges she was told to do by a company hired by Johnson & Johnson.
Instruction Sheet
Susanna Dodgson, who holds a doctorate in physiology, says she was hired in 2002 by Excerpta Medica, the Elsevier medical-communications firm, to write an article about J&J's anemia drug Eprex. A J&J unit had sponsored a study measuring whether Eprex patients could do well taking the drug only once a week. The company was facing competition from a rival drug sold by Amgen Inc. that could be given once a week or less.
Dr. Dodgson says she was given an instruction sheet directing her to emphasize the "main message of the study" -- that 79.3% of people with anemia had done well on a once-a-week Eprex dose. In fact, only 63.2% of patients responded well as defined by the original study protocol, according to a report she was provided. That report said the study's goal "could not be reached." Both the instruction sheet and the report were viewed by The Wall Street Journal. The higher figure Dr. Dodgson was asked to highlight used a broader definition of success and excluded patients who dropped out of the trial or didn't adhere to all its rules.
The instructions noted that some patients on large doses didn't seem to do well with the once-weekly administration but warned that this point "has not been discussed with marketing and is not definitive"
The Eprex study appeared last year in the journal Clinical Nephrology, highlighting the 79.3% figure without mentioning the lower one. The article didn't acknowledge Dr. Dodgson or Excerpta Medica. Dr. Dodgson, who now teaches medical writing at the University of the Sciences in Philadelphia, says she didn't like the Eprex assignment "but I had to earn a living."
The listed lead author, Paul Barré of McGill University in Montreal, says Excerpta Medica did "a lot of the scutwork" but he had "complete freedom" to change its drafts. Dr. Barré says he helped design the study and enroll patients in it. In statements, J&J and Excerpta Medica offered similar explanations of the process. J&J says it regularly uses outside firms "to expedite the development of independent, peer-reviewed publications."
A J&J spokesman said he wasn't familiar with the details of the instruction sheet and referred questions about the highlighted data to Dr. Barré, who said he never interacted with J&J's marketing department and doesn't believe the article was biased. He said the higher figure was "more representative" because those patients followed the study's rules. "Without wanting to distort data, you always want to put the spin that's more positive for the article," Dr. Barré says. "You're more likely to get it published."
Hartmut Malluche, an editor of Clinical Nephrology, declined to comment on details of the article. The journal doesn't require authors to disclose the role of medical writers. But after hearing Dr. Dodgson's story, Dr. Malluche said he would suggest changing the policy. "It's not good if the company has control over the article," he says.
Some academics are protesting ghostwriting. Adriane Fugh-Berman, an associate professor at the Georgetown University School of Medicine, says she received an email last year from a company hired by drug maker AstraZeneca PLC. The email offered her the chance to get credit for writing an article. "... [W]e will forward you a draft for your input so that you would need only to review and then advise us of any changes required," it said.
She says she was shown a draft but declined the offer. Then the Journal of General Internal Medicine asked her to peer-review a version of the same article, submitted by a different researcher. She decided to go public, and wrote about her experience in the journal.
AstraZeneca and the communications firm say it was all a mistake. Dr. Fugh-Berman should have been shown a different article from the one she was later asked to peer-review, they say. The article for peer review was in fact written by the author who submitted it to the journal, they say. AstraZeneca says it "does not support the practice of ghostwriting" and always discloses any support it gives to academic authors.
John Farrar, a pain expert at the University of Pennsylvania, says he once turned down a company's offer to give him a ghostwritten draft about a study on which he had worked. "They said, 'That's unusual,' " Dr. Farrar recalls. He wanted to write the manuscript himself because "you can put your spin on it. ...The way it is written -- the way it's structured -- is yours."
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Posted: Tue Apr 11th, 2006 02:38 |
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"Typical" heart patients not represented in trials
(filelink)
By Martha Kerr
NEW YORK (Reuters Health) - Patients enrolled in randomized clinical trials of coronary interventions are younger and have better cardiac risk profiles than the average patient in clinical practice, European heart doctors report. As such, they say, treatment "can only be partially evidence-based."
Dr. Eric Boersma from Erasmus Medical Center in Rotterdam, The Netherlands, and colleagues looked at the characteristics of 4713 heart patients in the Euro Heart Survey compared with those of 8,647 patients in 14 randomized heart treatment trials.
The investigators found that 64 percent of patients in their survey would not have met the strict enrollment criteria of the randomized clinical trials.
Compared with clinical trial patients, patients seen in everyday clinical practice are typically older, have more co-morbid illnesses, more likely to have single vessel disease, and more often have blockage of the left main coronary artery, Boersma and colleagues report.
"In the case in which the patient that is being treated is not represented in clinical trials, then his/her treatment can only be partly 'evidence based'," Boersma noted in comments to Reuters Health.
"In my view, treatment should then be based on a) observational studies; b) expert opinion; c) personal experience with certain treatment."
Once randomized clinical trials of strictly selected patients have been completed, it is time to conduct studies of more typical patients, Boersma asserted.
SOURCE: European Heart Journal March 2006.
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Posted: Sun Sep 17th, 2006 03:18 |
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Why Most Published Research Findings Are False
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"Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias."
John P. A. Ioannidis
Fulltext at: http://tinyurl.com/ceq33
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Posted: Sun Sep 17th, 2006 03:51 |
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We need an unbiased, efficient system to get the word out to practitioners on what works best.
(filelink)
(Many treatment choices are driven by habit, old information or glitzy promotional campaigns.)
The Sting of Ignorance
By JERRY AVORN
Published: September 16, 2006
Boston
LATE on a summer afternoon not long ago, the water at Lucy Vincent Beach on Martha’s Vineyard was warm, and the toxic jellyfish that had plagued bathers weeks earlier had floated out to sea. Body-surfing in on my last wave, I suddenly felt as if someone had whacked my leg with a lead pipe studded with nails. On the 1-to-10 pain scale we use with patients, I would have called it a 14. When I rubbed the area with my hand, my whole palm stung. Apparently those toxic jellyfish hadn’t all left.
A crowd of passers-by gathered to offer tips from the tainted well of conventional wisdom. “Use ammonia.” “Rub in some meat tenderizer.” “Apply vinegar.”
Soon a small army of bronzed youths in official-looking tank tops arrived carrying enormous medical kits. One poured sterile water on the sting area; another rubbed it with an ice pack. A third worked an alcohol-based anesthetic into the wound. Each treatment made the pain worse.
Eventually our group attracted the attention of a nurse strolling down the beach. A year-round Vineyard resident, she had seen her share of vacation-related medical emergencies. “You’ve removed the tentacle, haven’t you?” she asked matter-of-factly. No one, including the medical-professor patient, had thought of this. She took a piece of gauze and pulled off a slimy, transparent string laced with neurotoxins. It had continued to send those toxins into my leg for the first 20 minutes of my care. They are particularly activated, I would later learn, by distilled water, by mechanical pressure (as from an ice pack), and by alcohol-based topical medicines all the treatments I had so earnestly been given.
Now the pain began to abate. I drove home and reached for three of the most useful medicines I know: aspirin, acetaminophen (Tylenol) and the Internet. As the first two began to take effect, the third revealed a study published in February in The Medical Journal of Australia.
The clever Aussies (whose beaches are also infested by toxic jellyfish) had conducted a clinical trial that randomly assigned sting victims to application of hot water (to deactivate the poison) or icepacks. The trial was stopped halfway through because the hot-water group did so much better that it would have been unethical to continue. I didn’t discover this through any proprietary medical search engines. I used Google and Wikipedia, and it took about two minutes.
Coincidentally, much of my work is about defining which medications work best for which conditions, and how to close the gap between that knowledge and the care patients typically receive. My research group constantly comes across effective treatments that are underused, and poor-choice drugs that are widely prescribed. Even when good clinical trial data on a regimen or medicine exist, no coherent system ensures that the message gets out to doctors and patients. As a result, many treatment choices are driven by habit, old information or glitzy promotional campaigns.
My aquatic encounter was a small example of what millions of patients confront daily, in much more serious circumstances. The nation faces two yawning medical information gaps. First, we need more studies comparing treatments to each other, as that simple Australian trial did. Drug companies don’t usually do such tests, preferring to evaluate their new products by comparing them to placebos. (The drugs usually win.)
The National Institutes of Health, facing its first real-dollar budget cut in generations, isn’t likely to expand its mandate in this direction. But what about the insurers, private and governmental, who pay such a large share of the nation’s $220 billion annual drug bill? They could support such studies with the rounding error of their annual budgets and then save billions if the findings were put into practice.
The second problem is that much of the knowledge we do have is not communicated to the people who need it. Drug companies are adept at barraging doctors and patients with slick messages touting their most expensive products even if they are no better than older, more affordable standbys. Maybe if Merck held the patent on hot water, my well-intentioned beach squad would have known all about the Australian study. But that’s a poor way to ensure that patients receive the right care.
We need an unbiased, efficient system to get the word out to practitioners on what works best. My colleagues and I have done pro bono research aimed at developing such an approach. Because the drug industry is so adept at changing beliefs and practices, we’ve taken a few leaves from its book.
In a program financed by the Commonwealth of Pennsylvania, called the Independent Drug Information Service, we scan the medical literature for the best evidence on how to treat a given medical problem (like high cholesterol or arthritis), boil it down into user-friendly packets of information, and then send nurses and pharmacists out to doctors’ offices to recommend optimal treatments. The information we provide is unbiased and noncommercial, and we don’t offer free trips to golf resorts. The resulting savings from more cost-effective prescribing could more than cover the costs of programs like this.
The approach has been adopted in several Canadian provinces, and Australia runs a continent-sized program to update its primary care doctors (though I don’t know if it addresses jellyfish injuries). The government covers expenses, but scientific content is determined by nonprofit professional organizations. Their recommendations are transmitted in person by “outreach educators,” in concise newsletters, and electronically to doctors, health workers and patients.
If the Vineyard beach first responders had known of the latest research results, they wouldn’t have done everything they could to transfer toxin from the jellyfish tentacle to my leg. All of us need access to current, noncommercial medical information. Besides helping to contain our runaway medication expenditures, programs of this kind could prevent a lot of needless suffering by patients and doctors alike.
Jerry Avorn, a professor at Harvard Medical School, is the author of “Powerful Medicines: The Benefits, Risks and Costs of Prescription Drugs.”
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Posted: Sun Sep 17th, 2006 06:41 |
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"...in scientific journals, no less than in supermarket tabloids, you can't believe everything you read -- or shouldn't."
(filelink)
New Journals Bet 'Negative Results' Save Time, Money
September 15, 2006; Page B1 The Wall Street Journal
In ancient Greece, sailors who survived shipwrecks had their portraits displayed in a temple on Samothrace as a testament to the power of Neptune. When Diagoras of Melos was told that this proved that the gods insert themselves into the lives of men, he answered, "but where are they painted that are drowned?"
Today, showing only the rescued sailors would be called publication bias, the tendency of scientists to report findings that support some point (Neptune rescues sailors) but to bury examples (drowned sailors) that undercut it. It has existed for years, most seriously in the failure to publish studies that cast doubt on the safety or efficacy of new drugs.
Now, guardians of scientific probity are fighting back. A handful of journals that publish only negative results are gaining traction, and new ones are on the drawing boards.
"You hear stories about negative studies getting stuck in a file drawer, but rigorous analyses also support the suspicion that journals are biased in favor of positive studies," says David Lehrer of the University of Helsinki, who is spearheading the new Journal of Spurious Correlations.
"Positive" means those showing that some intervention had an effect, that some gene is linked to a disease -- or, more broadly, that one thing is connected to another in a way that can't be explained by random chance. A 1999 analysis found that the percentage of positive studies in some fields routinely tops 90%. That is statistically implausible, suggesting that negative results are being deep-sixed. As a result, "what we read in the journals may bear only the slightest resemblance" to reality, concluded Lee Sigelman of George Washington University.
Example: In the 1990s, publication bias gave the impression of a link between oral contraceptives and cervical cancer. In fact, a 2000 analysis concluded, studies finding no link were seldom published, with the result that a survey of the literature led to "a spurious statistical connection."
Keeping a lid on negative results wastes time and money. In the 1980s, experiments claimed that an antibody called Rap-5 latches onto a cancer-related protein called Ras, exclusively. Scientists using Rap-5 then reported the presence of Ras in all sorts of human tumors, notes Scott Kern of Johns Hopkins University. That suggested that Ras is behind many cancers.
Oops. The antibody actually grabs other molecules, too. What scientists thought was Ras alone was a stew of compounds. In part because the glitch was published in obscure journals, researchers continued to use Rap-5 and reach erroneous conclusions, says Dr. Kern.
"If the negative results had been published earlier, scientists would have saved a lot of time and money," adds Bjorn Olsen of Harvard Medical School, a founding editor, with Christian Pfeffer, of the Journal of Negative Results in Biomedicine.
After a slow start in 2002, that journal is receiving more and better papers, says Dr. Olsen. One found that, contrary to other reports, the relative length of the bones of a woman's index finger and ring finger may not be related to her exposure to testosterone in utero. Another found that a molecule called PYY doesn't have a big influence on body weight; another, that variations in a gene that earlier studies had associated with obesity in mice and in American and Spanish women isn't linked to obesity in French men or women.
That may sound like the set-up for a joke, but studies that dispute connections between a gene and a disease are among the most important negative results in biomedicine. They undercut the simplistic idea that genes inevitably cause some condition, and show instead that how a gene acts depends on the so-called genetic background -- all of your DNA -- which affects how individual genes are activated and quieted. But you seldom see such negative results in top journals.
Hence, Dr. Olsen's journal, which is full of studies disputing reported links between gene variations and disease. The Sod1 gene and inherited forms of Lou Gehrig's disease? Probably not. MTHFR and the age at which Huntington disease strikes? Uh-uh. PINK-1 and late-onset Parkinson's disease? No.
Hopefully, each of these reports kept researchers, including those at drug companies, from wasting time looking for ways to repair the consequences of the supposed genetic association. But it isn't clear that any would have been published without the new journal.
Questionable correlations between a gene and cancer are the bread-and-butter of NOGO, the Journal of Negative Observations in Genetic Oncology, which Dr. Kern edits.
"Fully half [of discoveries] of novel mutations in tumors, we found, were not confirmed in the subsequent literature," he says. "You expect to see follow-ups if the claims held up, so the fact that we didn't casts doubt on the original claim. But that wasn't explicitly reported."
Why are scientists coy about publishing negative data? In some cases, says Dr. Kern, withholding them keeps rivals doing studies that rest on an erroneous premise, thus clearing the field for the team that knows that, say, gene A doesn't really cause disease B.
Which goes to show that in scientific journals, no less than in supermarket tabloids, you can't believe everything you read -- or shouldn't.
• Email me at sciencejournal@wsj.com.
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Posted: Mon Sep 18th, 2006 03:18 |
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Scientists studying vitamin D do not consider the fact they are studying a steroid
(filelink)
Cause and Effect
Gerard E. Dallal, Ph.D. at Tufts University provides a good overview of the pitfalls of logical fallacies in determining "cause and effect" on his webpage. Click on "Cause and Effect". Dr. Dallal provides easy-to-understand explanations as to why statistics alone never prove causality. A mechanism of action must exist to explain causal relationship.
The first few pitfalls in reasoning about vitamin D are:
1. Vitamin D is a vitamin.
2. If a little vitamin is good, more must be better.
VITAMIN D TUTORIAL explains why these are misconceptions.
In many studies, the research statistics may be OK, but the methodology is wanting. They are observing variables and assuming causality, without evidence of causality.
This is pretty common in most of today's Vitamin D research - everybody assumes they are researching a vitamin - and that the body needs an exogenous source of the substance - and the study's methodology fails with that assumption.
I think the realization that the basic molecular science has now described a steroid, and not a vitamin, will gradually dawn on these clinical folk, but it will take a long time, maybe a generation.
The only way to deal with folk who want to argue this is to show them my Karolinska paper and the science in it.
http://AutoimmunityResearch.org/karolinska-handout.pdf
Molecular Science is inherently testable. Any expert in the field can test the molecular images and data I presented to Team Nobel, and I am sure that some of them already have (there are also lots of top-notch researchers who would like to think I might have been incorrect).
But until somebody can point out an error in the molecular science I have propounded, then there can be no realistic argument - Vitamin D is a sterol/steroid, and the body can manufacture all it needs to maintain good health. That is the primary difference between molecular science and clinical science - total, and rapid, testability.
Briefly, the mistakes are
1. The failure to notice that 'autoimmune' disease is due to a failure of innate immunity, even when the focus on adaptive immunity was leading nowhere
2. The failure to understand that the hormone we call "Vitamin D" is a secosteroid transcriptional activator, expressing over a thousand genes
3. The failure to note that the body closely controls the level of this hormone, and that exogenous ingestion of the Vitamin D metabolites unbalances this homeostasis
4. The failure to note that the active metabolite, 1,25-D is over-expressed in 'autoimmune' disease (see, eg, see the paper you cited)
5. The failure to note that the precursor metabolite, 25-D is being under-expressed in 'autoimmune' disease
Trevor Marshall, Ph.D
Most researchers fail to consider the alternate hypothesis about vitamin D.
When it comes to vitamin D, the current medical climate of consensus is hostile to new ideas.
Research touting vitamin D's benefits is often biased, methodically weak, and ultimately misleading.
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Posted: Wed Nov 22nd, 2006 05:46 |
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Scientific revolutions require a pardigm shift
(filelink)
Dougs wrote:
When the efforts to convert the NIH were publicized here last summer I remembered a book that I read at college 35 years ago. It is entitled “The Structure of Scientific Revolutions” by Thomas Kuhn. In this book Kuhn popularized the concept of science operating within a paradigm (i.e., a world view). Scientific revolutions according to Kuhn require a paradigm shift. Unfortunately for us these shifts take place a brain at a time.
The following excerpts are from chapter 12 which discusses how scientific revolutions occur.
“What is the process by which a new candidate for paradigm replaces its predecessor? Any new interpretation of nature, whether a discovery or a theory, emerges first in the mind of one or a few individuals. It is they who first learn to see science and the world differently, and their ability to make the transition is facilitated by two circumstances that are not common to most other members of their profession. Invariably their attention has been intensely concentrated upon the crisis-provoking problems; usually, in addition, they are men so young or so new to the crisis-ridden field that practice has committed them less deeply than most of their contemporaries to the world view and rules determined by the old paradigm. How are they able, what must they do, to convert the entire profession or the relevant professional subgroup to their way of seeing science and the world? What causes the group to abandon one tradition of normal science in favor of another? …………
“At the start a new candidate for paradigm may have few supporters, and on occasions the supporters’ motives may be suspect. Nevertheless, if they are competent, they will improve it, explore its possibilities, and show what it would be like to belong to the community guided by it. And as that goes on, if the paradigm is one destined to win its fight, the number and strength of the persuasive arguments in its favor will increase. More scientists will then be converted, and the exploration of the new paradigm will go on. Gradually the number of experiments, instruments, articles, and books based upon the new paradigm will multiply. Still more men, convinced of the new view’s fruitfulness, will adopt the new mode of practicing normal science, until at last only a few elderly hold-outs remain.” (The Structure of Scientific Revolutions - Thomas Kuhn)
I think Kuhn’s work is relevant to our efforts. If the NIH really wanted significant results they would seek people like Trevor. We should understand that grants will be given out to people operating within the accepted paradigm (i.e., autoimmunity is misplaced-immunity which needs to be suppressed). People not operating within this paradigm are threatening and at best will be ignored. We must remember that they are not bad or evil. They merely see the world differently. They react to us much as we react to people that come around here talking about adrenal crisis. To paraphrase the Godfather: It’s not personal it’s just science.
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Posted: Mon Dec 4th, 2006 15:26 |
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(filelink)
Consensus
Author Michael Crichton, (Harvard MD degree), said:
"I regard consensus science as an extremely pernicious development that ought to be stopped cold in its tracks. Historically, the claim of consensus has been the first refuge of scoundrels; it is a way to avoid debate by claiming that the matter is already settled. Whenever you hear the consensus of scientists agrees on something or other, reach for your wallet, because you're being had. Let's be clear: the work of science has nothing whatever to do with consensus. Consensus is the business of politics...In addition, let me remind you that the track record of the consensus is nothing to be proud of."
See Why won’t my doctor consider the Marshall Protocol?
...........................................................................................................................................
October 9, 2007
New York Times
Diet and Fat: A Severe Case of Mistaken Consensus
In 1988, the surgeon general, C. Everett Koop, proclaimed ice cream to a be public-health menace right up there with cigarettes. Alluding to his office’s famous 1964 report on the perils of smoking, Dr. Koop announced that the American diet was a problem of “comparable” magnitude, chiefly because of the high-fat foods that were causing coronary heart disease and other deadly ailments.
He introduced his report with these words: “The depth of the science base underlying its findings is even more impressive than that for tobacco and health in 1964.”
That was a ludicrous statement, as Gary Taubes demonstrates in his new book meticulously debunking diet myths, “Good Calories, Bad Calories” (Knopf, 2007). The notion that fatty foods shorten your life began as a hypothesis based on dubious assumptions and data; when scientists tried to confirm it they failed repeatedly. The evidence against Häagen-Dazs was nothing like the evidence against Marlboros.
It may seem bizarre that a surgeon general could go so wrong. After all, wasn’t it his job to express the scientific consensus? But that was the problem. Dr. Koop was expressing the consensus. He, like the architects of the federal “food pyramid” telling Americans what to eat, went wrong by listening to everyone else. He was caught in what social scientists call a cascade.
We like to think that people improve their judgment by putting their minds together, and sometimes they do. The studio audience at “Who Wants to Be a Millionaire” usually votes for the right answer. But suppose, instead of the audience members voting silently in unison, they voted out loud one after another. And suppose the first person gets it wrong.
If the second person isn’t sure of the answer, he’s liable to go along with the first person’s guess. By then, even if the third person suspects another answer is right, she’s more liable to go along just because she assumes the first two together know more than she does. Thus begins an “informational cascade” as one person after another assumes that the rest can’t all be wrong.
Because of this effect, groups are surprisingly prone to reach mistaken conclusions even when most of the people started out knowing better, according to the economists Sushil Bikhchandani, David Hirshleifer and Ivo Welch. If, say, 60 percent of a group’s members have been given information pointing them to the right answer (while the rest have information pointing to the wrong answer), there is still about a one-in-three chance that the group will cascade to a mistaken consensus.
Cascades are especially common in medicine as doctors take their cues from others, leading them to overdiagnose some faddish ailments (called bandwagon diseases) and overprescribe certain treatments (like the tonsillectomies once popular for children). Unable to keep up with the volume of research, doctors look for guidance from an expert — or at least someone who sounds confident.
In the case of fatty foods, that confident voice belonged to Ancel Keys, a prominent diet researcher a half-century ago (the K-rations in World War II were said to be named after him). He became convinced in the 1950s that Americans were suffering from a new epidemic of heart disease because they were eating more fat than their ancestors.
There were two glaring problems with this theory, as Mr. Taubes, a correspondent for Science magazine, explains in his book. First, it wasn’t clear that traditional diets were especially lean. Nineteenth-century Americans consumed huge amounts of meat; the percentage of fat in the diet of ancient hunter-gatherers, according to the best estimate today, was as high or higher than the ratio in the modern Western diet.
Second, there wasn’t really a new epidemic of heart disease. Yes, more cases were being reported, but not because people were in worse health. It was mainly because they were living longer and were more likely to see a doctor who diagnosed the symptoms.
To bolster his theory, Dr. Keys in 1953 compared diets and heart disease rates in the United States, Japan and four other countries. Sure enough, more fat correlated with more disease (America topped the list). But critics at the time noted that if Dr. Keys had analyzed all 22 countries for which data were available, he would not have found a correlation. (And, as Mr. Taubes notes, no one would have puzzled over the so-called French Paradox of foie-gras connoisseurs with healthy hearts.)
The evidence that dietary fat correlates with heart disease “does not stand up to critical examination,” the American Heart Association concluded in 1957. But three years later the association changed position — not because of new data, Mr. Taubes writes, but because Dr. Keys and an ally were on the committee issuing the new report. It asserted that “the best scientific evidence of the time” warranted a lower-fat diet for people at high risk of heart disease.
The association’s report was big news and put Dr. Keys, who died in 2004, on the cover of Time magazine. The magazine devoted four pages to the topic — and just one paragraph noting that Dr. Keys’s diet advice was “still questioned by some researchers.” That set the tone for decades of news media coverage. Journalists and their audiences were looking for clear guidance, not scientific ambiguity.
After the fat-is-bad theory became popular wisdom, the cascade accelerated in the 1970s when a committee led by Senator George McGovern issued a report advising Americans to lower their risk of heart disease by eating less fat. “McGovern’s staff were virtually unaware of the existence of any scientific controversy,” Mr. Taubes writes, and the committee’s report was written by a nonscientist “relying almost exclusively on a single Harvard nutritionist, Mark Hegsted.”
That report impressed another nonscientist, Carol Tucker Foreman, an assistant agriculture secretary, who hired Dr. Hegsted to draw up a set of national dietary guidelines. The Department of Agriculture’s advice against eating too much fat was issued in 1980 and would later be incorporated in its “food pyramid.”
Meanwhile, there still wasn’t good evidence to warrant recommending a low-fat diet for all Americans, as the National Academy of Sciences noted in a report shortly after the U.S.D.A. guidelines were issued. But the report’s authors were promptly excoriated on Capitol Hill and in the news media for denying a danger that had already been proclaimed by the American Heart Association, the McGovern committee and the U.S.D.A.
The scientists, despite their impressive credentials, were accused of bias because some of them had done research financed by the food industry. And so the informational cascade morphed into what the economist Timur Kuran calls a reputational cascade, in which it becomes a career risk for dissidents to question the popular wisdom.
With skeptical scientists ostracized, the public debate and research agenda became dominated by the fat-is-bad school. Later the National Institutes of Health would hold a “consensus conference” that concluded there was “no doubt” that low-fat diets “will afford significant protection against coronary heart disease” for every American over the age of 2. The American Cancer Society and the surgeon general recommended a low-fat diet to prevent cancer.
But when the theories were tested in clinical trials, the evidence kept turning up negative. As Mr. Taubes notes, the most rigorous meta-analysis of the clinical trials of low-fat diets, published in 2001 by the Cochrane Collaboration, concluded that they had no significant effect on mortality.
Mr. Taubes argues that the low-fat recommendations, besides being unjustified, may well have harmed Americans by encouraging them to switch to carbohydrates, which he believes cause obesity and disease. He acknowledges that that hypothesis is unproved, and that the low-carb diet fad could turn out to be another mistaken cascade. The problem, he says, is that the low-carb hypothesis hasn’t been seriously studied because it couldn’t be reconciled with the low-fat dogma.
Mr. Taubes told me he especially admired the iconoclasm of Dr. Edward H. Ahrens Jr., a lipids researcher who spoke out against the McGovern committee’s report. Mr. McGovern subsequently asked him at a hearing to reconcile his skepticism with a survey showing that the low-fat recommendations were endorsed by 92 percent of “the world’s leading doctors.”
“Senator McGovern, I recognize the disadvantage of being in the minority,” Dr. Ahrens replied. Then he pointed out that most of the doctors in the survey were relying on secondhand knowledge because they didn’t work in this field themselves.
“This is a matter,” he continued, “of such enormous social, economic and medical importance that it must be evaluated with our eyes completely open. Thus I would hate to see this issue settled by anything that smacks of a Gallup poll.” Or a cascade.
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Posted: Sun Jan 14th, 2007 17:00 |
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(filelink)
In-vitro studies
There is also the issue of in-vitro vs in-vivo errors. The functions of 1,25-D are so profound, its concentration so miniscule (30 picograms per milliliter) that in-vitro experiments tend to be not useful.
..Trevor..
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Posted: Wed Jan 17th, 2007 02:11 |
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(filelink)
Human and murine macrophages are different
From the text: Immunology by Roitt, Brostoff & Male, 6th Edition, Mosby Publication: pg: 252
'This is important because much experimental work is based on murine macrophages. Mycobacteria illustrate the complexity of the topic. IFNy (sic) can activate murine macrophages to destroy mycobacteria completely. This appears to be due to the nitric oxide pathway.
However, IFNy acting on human macrophages causes, at best, feeble inhibition of M. Tuberculosis or, at worst, significantly increased growth. This may relate to species differences in NO production.
On the other hand, human cells do something which has not been reported in murine cells. IFNy causes human macrophages to express a 1-hydroxylase enzyme that converts the circulating inactive form of
25-hydroxycholecalciferol into an active metabolite,
1,25-dihydroxycholecalciferol. This metabolite activates antimycobacterial mechanisms in the macrophages rather more efficiently than IFNy itself, though the mechanism of the enhanced antimicrobial effect is not known.'
Comparison of treatment effects between animal experiments and clinical trials: systematic review.
http://tinyurl.com/3a4psa
"Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately "
Mice do not have an innate immune system driven by Vitamin D
Mice, being night-dwelling rodents, do not have an innate immune system driven primarily by Vitamin D, but by NO (nitric oxide). That is why mice have failed to be useful models of autoimmune disease, or infections, in man.
Rats, also
Biologists (at tleast the ones at the Salk conference) know this, but argue that there is no better model than Murine models (Wrong!)
..Trevor..
Mice have totally different innate immune systems from homo sapiens.
It is crazy to extrapolate any studies, such as the one you cite, to the human CFS disease state.
Biologists know that human innate immunity is dependent on the VDR, and that murine (rodent)innate immunity is not. Rodent innate immunity is, in a manner still to be fully determined, dependent on a nitric-oxide cascade.
The rodent VDR is different from the human VDR. In fact, Benicar does not even bind into the rodent VDR in the same way it does in humans. The genomes are different, and the importance of those differences is only now starting to become clearer.
Due to the way that academics are given grant money, there is a pressure to ignore important failings in the experimental method, in order to make it look as though they were successful, so they will get more grant money , and further their careers.
I have just written a (short) paper on the differences between murine and human VDR, esepcially as they relate to rodents being useless in studies of cancers and immune disease. You see, the VDR is reponsible for expression of about 913 genes. Many of them are cancer genes (like the breast-cancer-gene BRCA2), but they also include anti-microbial peptides and a host of other immune mediators. Differences in the species mean that experimental results cannot be extrapolated between rodents and man. That is why you are all still ill... A fundamental flaw in scientific method...
My study of rodent and human VDRs now forms part of our submissions to the FDA, the applications for designation of the MP in Sarcoidosis and PTLDS.
Rolf Zinkernagel's mice were injected with a virus before their adaptive immune system was up and running. A big difference there. Yes, there are difficulties extrapolating his results directly, but I don't think I have done that - I have adopted the concept of protection in the neo-natal period- the thought process - which is fully portable to man, where adaptive immunity is delayed weeks after birth. Recent work at Stanford shows it only takes days for human infants to pick up all the bugs floating around the family...
..Trevor..
Three papers published on-line in Nature Immunology on Aug. 5 highlight differennces between murine and human differentiation of Th-17 (T helper cells important in inflammation and innate immunity).
Interleukins 1 and 6 but not transforming growth factor- are essential for the differentiation of interleukin 17–producing human T helper cells
Eva V Acosta-Rodriguez, Giorgio Napolitani, Antonio Lanzavecchia & Federica Sallusto
Published online: 05 August 2007; | Abstract| Full Text | PDF (690 KB) | Supplementary information
The development of inflammatory TH-17 cells requires interferon-regulatory factor 4
Anne Brüstle, Sylvia Heink, Magdalena Huber, Christine Rosenplänter, Christine Stadelmann, Philipp Yu, Enrico Arpaia, Tak W Mak, Thomas Kamradt & Michael Lohoff
Published online: 05 August 2007; | Abstract | Full Text | PDF (683 KB) | Supplementary information
Development, cytokine profile and function of human interleukin 17–producing helper T cells
Nicholas J Wilson, Katia Boniface, Jason R Chan, Brent S McKenzie, Wendy M Blumenschein, Jeanine D Mattson, Beth Basham, Kathleen Smith, Taiying Chen, Franck Morel, Jean-Claude Lecron, Robert A Kastelein, Daniel J Cua, Terrill K McClanahan, Edward P Bowman & Rene de Waal Malefyt
Published online: 05 August 2007; | Abstract | Full Text | PDF (377 KB)| Supplementary information
Of mice and men: Are the scientific studies you read accurate?
July 08 "The science now explains why mice can never emulate Human Chronic disease, including Cancers. There have been no major breathroughs from murine work, and I now know why there will be none.
Reason 1: The Mouse VDR does not transcribe either the Cathelicidin or the beta-Defensin anti-microbials. The human VDR does. When a microbe knocks out the mouse VDR it does not knock out these antimicrobial defenses, as it does in man.
Reason 2: The VDR binding pocket homology between mice/rats and humans is poor. Drugs will act differently in the two VDR."
..Trevor..
Last edited on Thu Jul 17th, 2008 20:35 by Foundation Staff
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Posted: Sun Feb 4th, 2007 05:34 |
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It is not possible to understand the immune system without many years of study
First, I would note that the modulation of the TLR by VDR was mentioned by me in my Karolinska abstract at URL
http://autoimmunityresearch.org/karolinska-abstract.pdf
I am not necessarily trying to discourage you posting Pubmed abstracts, but you would have gained this insight some time ago with more focused research, taking into account what is already written in my previous publications.
Olmesartan is a partial agonist and antagonist of many, many receptors. Basically, almost anything that 1,25-D targets is also a potential target for Olmesartan. Those receptors range from Rhodopsin GPCR (in the eyes) through to the Type 1 nuclear receptors (all of them, but particularly VDR, GCR, MCR, Progesterone and Thyroid), all the way to the Angiotensin GPCR.
Most drugs have a wide spectrum of effect, but in those cases we know very little about their effects until the FDA reports "adverse events" like heart attacks, or whatever.
By contrast, I have explored the effects of Olmesartan on a wide variety of body systems using the most advanced modeling technology available to science. I also watch the literature for signs of clinical studies whih would send me scurrying back to my lab, or alternatively, give me a "Eureka" moment.
I am continually fed study results by my professional colleagues, from all around the world, and we carry on a vigorous discussion, out of the public spotlight, and at conferences.
I cannot promise that there is nothing we have missed, but anytime that just one of the thousands of patients on the MP, or their physicians, report a problem, we look at it as a matter of priority. The FDA is not so zealous.
Finally, it is just not possible to try and understand TLR signalling in the immune system, or DNA transcription by the nuclear recptors, without many years of study, and thorough understanding of research methodology. PubMed is a wonderful resource, but what you read there has to be read with the skeptical eye of a university professor. Unless you know where the mistakes are likely to have been made, you will not be able to extend knowledge from the data published by others. Everybody makes mistakes, even me. You will note that our Dec 2005 paper says that Benicar is an atagonist for the VDR. 99% of ligands act as antagonists, so this is always the initial assumption. However, my later work showed the path for its agonistic effects, and my views had to change in accord with the advancing science.
..Trevor..
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Posted: Sat Sep 15th, 2007 07:07 |
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Most Science Studies Appear to Be Tainted By Sloppy Analysis
September 14, 2007; Page B1 The Wall Street Journal
We all make mistakes and, if you believe medical scholar John Ioannidis, scientists make more than their fair share. By his calculations, most published research findings are wrong.
Dr. Ioannidis is an epidemiologist who studies research methods at the University of Ioannina School of Medicine in Greece and Tufts University in Medford, Mass. In a series of influential analytical reports, he has documented how, in thousands of peer-reviewed research papers published every year, there may be so much less than meets the eye.
These flawed findings, for the most part, stem not from fraud or formal misconduct, but from more mundane misbehavior: miscalculation, poor study design or self-serving data analysis. "There is an increasing concern that in modern research, false findings may be the majority or even the vast majority of published research claims," Dr. Ioannidis said. "A new claim about a research finding is more likely to be false than true."
The hotter the field of research the more likely its published findings should be viewed skeptically, he determined.
Take the discovery that the risk of disease may vary between men and women, depending on their genes. Studies have prominently reported such sex differences for hypertension, schizophrenia and multiple sclerosis, as well as lung cancer and heart attacks. In research published last month in the Journal of the American Medical Association, Dr. Ioannidis and his colleagues analyzed 432 published research claims concerning gender and genes.
Upon closer scrutiny, almost none of them held up. Only one was replicated.
Statistically speaking, science suffers from an excess of significance. Overeager researchers often tinker too much with the statistical variables of their analysis to coax any meaningful insight from their data sets. "People are messing around with the data to find anything that seems significant, to show they have found something that is new and unusual," Dr. Ioannidis said.
In the U. S., research is a $55-billion-a-year enterprise that stakes its credibility on the reliability of evidence and the work of Dr. Ioannidis strikes a raw nerve. In fact, his 2005 essay "Why Most Published Research Findings Are False" remains the most downloaded technical paper that the journal PLoS Medicine has ever published.
"He has done systematic looks at the published literature and empirically shown us what we know deep inside our hearts," said Muin Khoury, director of the National Office of Public Health Genomics at the U.S. Centers for Disease Control and Prevention. "We need to pay more attention to the replication of published scientific results."
Every new fact discovered through experiment represents a foothold in the unknown. In a wilderness of knowledge, it can be difficult to distinguish error from fraud, sloppiness from deception, eagerness from greed or, increasingly, scientific conviction from partisan passion. As scientific findings become fodder for political policy wars over matters from stem-cell research to global warming, even trivial errors and corrections can have larger consequences.
Still, other researchers warn not to fear all mistakes. Error is as much a part of science as discovery. It is the inevitable byproduct of a search for truth that must proceed by trial and error. "Where you have new areas of knowledge developing, then the science is going to be disputed, subject to errors arising from inadequate data or the failure to recognize new matters," said Yale University science historian Daniel Kevles. Conflicting data and differences of interpretation are common.
To root out mistakes, scientists rely on each other to be vigilant. Even so, findings too rarely are checked by others or independently replicated. Retractions, while more common, are still relatively infrequent. Findings that have been refuted can linger in the scientific literature for years to be cited unwittingly by other researchers, compounding the errors.
Stung by frauds in physics, biology and medicine, research journals recently adopted more stringent safeguards to protect at least against deliberate fabrication of data. But it is hard to admit even honest error. Last month, the Chinese government proposed a new law to allow its scientists to admit failures without penalty. Next week, the first world conference on research integrity convenes in Lisbon.
Overall, technical reviewers are hard-pressed to detect every anomaly. On average, researchers submit about 12,000 papers annually just to the weekly peer-reviewed journal Science. Last year, four papers in Science were retracted. A dozen others were corrected.
No one actually knows how many incorrect research reports remain unchallenged.
Earlier this year, informatics expert Murat Cokol and his colleagues at Columbia University sorted through 9.4 million research papers at the U.S. National Library of Medicine published from 1950 through 2004 in 4,000 journals. By raw count, just 596 had been formally retracted, Dr. Cokol reported.
"The correction isn't the ultimate truth either," Prof. Kevles said.
URL for this article:
http://online.wsj.com/article/SB118972683557627104.html
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Posted: Mon Oct 20th, 2008 20:27 |
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Publish and be wrong (Oct. 9, 2008 The Economist)
Why Current Publication Practices May Distort Science (PLoS Medicine)
Neal S. Young*, John P. A. Ioannidis, Omar Al-Ubaydli
Published: October 7, 2008
This essay makes the underlying assumption that scientific information is an economic commodity, and that scientific journals are a medium for its dissemination and exchange. While this exchange system differs from a conventional market in many senses, including the nature of payments, it shares the goal of transferring the commodity (knowledge) from its producers (scientists) to its consumers (other scientists, administrators, physicians, patients, and funding agencies). The function of this system has major consequences. Idealists may be offended that research be compared to widgets, but realists will acknowledge that journals generate revenue; publications are critical in drug development and marketing and to attract venture capital; and publishing defines successful scientific careers. Economic modelling of science may yield important insights.
The Winner's Curse
In auction theory, under certain conditions, the bidder who wins tends to have overpaid. Consider oil firms bidding for drilling rights; companies estimate the size of the reserves, and estimates differ across firms. The average of all the firms' estimates would usually approximate the true reserve size. Since the firm with the highest estimate bids the most, the auction winner systematically overestimates, sometimes so substantially as to lose money in net terms [1]. When bidders are cognizant of the statistical processes of estimates and bids, they correct for the winner's curse by shading their bids down. This is why experienced bidders sometimes avoid the curse, as opposed to inexperienced ones [1–4]. Yet in numerous studies, bidder behaviour appears consistent with the winner's curse [5–8]. Indeed, the winner's curse was first proposed by oil operations researchers after they had recognised aberrant results in their own market.
Summary
The current system of publication in biomedical research provides a distorted view of the reality of scientific data that are generated in the laboratory and clinic. This system can be studied by applying principles from the field of economics. The “winner's curse,” a more general statement of publication bias, suggests that the small proportion of results chosen for publication are unrepresentative of scientists' repeated samplings of the real world. The self-correcting mechanism in science is retarded by the extreme imbalance between the abundance of supply (the output of basic science laboratories and clinical investigations) and the increasingly limited venues for publication (journals with sufficiently high impact). This system would be expected intrinsically to lead to the misallocation of resources. The scarcity of available outlets is artificial, based on the costs of printing in an electronic age and a belief that selectivity is equivalent to quality. Science is subject to great uncertainty: we cannot be confident now which efforts will ultimately yield worthwhile achievements. However, the current system abdicates to a small number of intermediates an authoritative prescience to anticipate a highly unpredictable future. In considering society's expectations and our own goals as scientists, we believe that there is a moral imperative to reconsider how scientific data are judged and disseminated.
(Click on above links for the full articles)
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