|Year : 2000 | Volume
| Issue : 2 | Page : 93-9
Scientific literature and gospel truth.
Department of Ophthalmology & Visual Sciences, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
S S Hayreh
Department of Ophthalmology & Visual Sciences, College of Medicine, University of Iowa, Iowa City, Iowa 52242
Source of Support: None, Conflict of Interest: None
We live in an age of science, an age in which science impacts practically every phase of our life. In the field of medicine, our entire understanding of diseases and their management depends on scientific knowledge. To obtain that knowledge, we rely on the published scientific literature. Therefore, the sanctity of science must be fiercely guarded. In medicine, true science leads to valid treatment--and preservation of the life, health and (for ophthalmologists) eyesight of our patients. A corrupted science results in corrupted scientific knowledge which in turn, in medicine, leads to wrong treatment and harm to the patients.
Keywords: Ethics, Medical, Humans, Ophthalmology, standards, Philosophy, Publishing, standards, Research, standards, Research Support, Non-U.S. Gov′t, Sc
|How to cite this article:|
Hayreh S S. Scientific literature and gospel truth. Indian J Ophthalmol 2000;48:93
People in general assume that what is written in textbooks and scientific journals is gospel truth, particularly when it is published in refereed and prestigious journals. But is it always true? No doubt most of the published information is valid; but not all of it. We have plenty of examples in the medical literature of ill-founded science leading to not only useless but at times even dangerous treatments. I would like to give you a brief insight into the problems with some of the published literature.
One of the essential prerequisites of any study is to review critically the available literature on the subject. According to the Chambers Twentieth Century Dictionary research is "Re-search" - "to search again". One has to first search the relevant scientific literature to find out what is already known. Bernal rightly stated that "In science, more than in any other human institution, it is necessary to search out the past in order to understand the present and to control the future."
Reviewing the scientific literature can be highly confusing and frustrating. Langley, back in 1899, succinctly stated that "Those who have occasion to enter into the depths of what is oddly, if generously, called the literature of a scientific subject, alone know the difficulty of emerging with an unsoured disposition.... Much that he is forced to read consists of a record of defective experiments, confused statements of results, wearisome description of detail, and unnecessary protracted discussion of unnecessary hypotheses."
| Hypotheses|| |
The scientific literature is full of hypotheses. So, first of all, how valid are hypotheses? As Hughlings Jackson, in 1881, wrote: "An hypothesis is not a conclusion; it is only a provisional conclusion, something to be proved or disproved." However, that is not always how people look at hypotheses. Goethe, the famous German writer and scientist, pointed out that "Hypotheses are cradle songs by which the teacher lulls his pupils to sleep." A hypothesis has to be supported by solid facts; without these, it is simply a fiction. Thomas Henry Huxley (1825-1895) said: "The great tragedy of Science- the slaying of a beautiful hypothesis by an ugly fact." But the facts are what we need, even if they are ugly and unwelcome.
Hypotheses fall into different categories. There are hypotheses which simply reflect a dreamed up notion, impressively presented but without a shred of scientific evidence. [5,6] It is also not unusual in the literature to find the mutating hypothesis which Fermor neatly described; " 'Let us assume' turns in a few pages into 'We may assume', which in a few more, is 'As we have shown'; and, after a few more pages yet, the shy initial hypothesis has hardened into a brazen established landmark, all the time with not an atom of new evidence being adduced." The other distortion of hypotheses occurs when the original author may state conscientiously that his statements are speculative, but the hypothesis, once in print, curiously assumes a life of its own. After a few repetitions and citations, it tends to become accepted as an established fact, and is then extremely difficult to "weed out". Such purely speculative hypotheses without a scientific basis can do great disservice to science in the long run. This reminds me of what the famous American author Mark Twain once said "A lie can be half way around the world before truth has time to put its shoes on." A more honest way to present an hypothesis is, as Sir Stewart Duke-Elder, my mentor very nicely stated: "It is to be accepted in the light of a working hypothesis which may, or may not, aid after the manner of temporary scaffolding in the erection of a building of whose very design we are ignorant. And as such it is to be treated. For the whole progress of knowledge is strewn with wrecks of such systems."
| Folklore|| |
Our knowledge often is based on the ingrained folklore which we inherit. That folklore often originates in the pronouncements of academic "stars" who are well-known and politically powerful but, unfortunately, scientifically mediocre. These academic "stars" or senior clinicians, to justify what they believe or advocate, often fall back on what they call "Clinical Experience". O'Donnell defined clinical experience as "Making the same mistake with increasing confidence over an impressive number of years." At other times we hear about "Evidence-based Medicine" which O'Donnell defined as "Perpetuating other people's mistakes instead of your own".
| Misleading information in scientific literature|| |
Invalid information finds its way into the literature, including the so-called prestigious scientific journals, for a number of reasons. Let me give you a few personal examples from ophthalmology about such misleading studies.
1. Studies and results designed to prove someone's dearly cherished notion. In 1954 to 1956 three papers were published in the British Journal of Ophthalmology by a well-known Belgian group, Francois and colleagues,[10-12] claiming that they had discovered a new artery called the "Central artery of the optic nerve" which, according to them, supplied the optic nerve. This was meant to explain their hypothesis of how anterior ischaemic optic neuropathy develops. Historically, these papers assume special significance for me, because I started my research in 1955 intending to confirm the presence of this artery, while I was working in the Medical College, Patiala, India. I studied 100 human eyes and optic nerves and to my surprise never found this artery. I published my results in the British Journal of Ophthalmology in 1960. [13,14] That landed me in the center of a major controversy because Professor Jules Francois was one of the most famous and powerful ophthalmologists in the ophthalmic world at that time - he was the secretary general of the International Council of Ophthalmology. I was a young, unknown researcher from Patiala, India. It was like a fight between David and Goliath.
After years of controversial publications between me and Professor Francois, ultimately in 1966 he came to see me at the Institute of Ophthalmology of the University of London where I was working at that time, and told me that we should try to resolve our ongoing controversy. I told him that as a researcher it was hard for me to agree to the presence of something that I could not find, in spite of meticulously looking for it. He told me he would ask another research fellow working with him to re-investigate the entire subject afresh, to clear up the controversy. In 1977 they finally confirmed, absolutely, what I had published in 1960. The so-called "central artery of the optic nerve" was simply a product of wishful thinking by a research fellow of Professor Francois. This non-discovery had tremendous scientific implications, because we know now that poor circulation in the optic nerve head plays a vital role in the development of anterior ischaemic optic neuropathy and also glaucoma, and those two conditions are the most common causes of blindness. Had I not stood up for what I found - or rather did not find - we might still be blaming blindness in anterior ischaemic optic neuropathy and glaucoma on an artery which never existed.
How did this happen? What was known about the blood supply of the optic nerve head could not explain the mechanism for development of anterior ischaemic optic neuropathy. It seems that Professor Francois concluded that it must be due a special artery supplying only the optic nerve head, and his research fellow, who actually did the study, somehow found just what the research guide wanted. This is an example where the entire study and its results were designed to find proof of someone's dearly cherished notion. I have come across a number of similar studies; often the persons responsible are politically powerful and well-known. Fools have rushed in - in large numbers where angels fear to tread. Under these circumstances, it is sometimes practically impossible to distinguish fact from fantasy.
2. Advocated treatment without scientific rationale.
From the scientific point of view, to evaluate any therapy for a disease, it is first essential to determine whether the therapy has a scientific basis. Treatments without a logical foundation prove not only useless but also sometimes harmful, as in the case of a treatment, published in a prestigious American ophthalmic journal.
Anterior ischaemic optic neuropathy is one of the most common causes of serious visual loss in the middle-aged and elderly, with no effective treatment. In 1989 a group of neuro-ophthalmologists from one of the famous eye hospitals in the USA, published an expedited publication in the Archives of Ophthalmology claiming that if the sheath around the optic nerve was decompressed by making a window in the sheath, that "improved visual loss" in "a disorder without any previous effective therapy". I had done decades of research on all the basic issues involved with this subject, and I felt that the claim made in that paper had no scientific basis. I wrote a letter to the editor of the Archives of Ophthalmology stating my scientific objections to the claims made in that study and warned that the advocated surgical procedure could be harmful. Once again I became internationally very unpopular, because the procedure quickly became highly popular all over the world, since patients with anterior ischaemic optic neuropathy were desperate to have better vision and no other treatment was available. Also, there was a financial incentive for ophthalmologists to offer this procedure. This was a dynamite combination: desperate patients, and a lucrative new surgical procedure. Finally, the United States' National Institutes of Health conducted a clinical trial which was very soon stopped, and an urgent warning was sent to all ophthalmologists in North America that the procedure was "not effective and may be harmful", because patients who underwent this procedure lost more vision than those who were left alone - 24% versus 12%. Here is an example of a treatment of a common blinding condition, published on an expedited basis in a prestigious ophthalmic journal, which ultimately proved to be harmful because it had no scientific rationale.
3. Wrongly interpreting the natural history of a disease as beneficial effect of a treatment. Before trying experimental treatments, it is vital to know the natural history of a disease - that is, the course it naturally takes if the patient is not given any kind of treatment. There are examples where the natural course of a disease has wrongly been attributed as beneficial effect of an advocated treatment. For instance, central retinal artery occlusion is a stroke of the retina, where an eye suddenly goes blind. There is no treatment available to recover or improve the lost vision. In April 1999 a German group published a paper in the journal Ophthalmology claiming that they found 66% of the eyes had improvement of vision following fibrinolytic therapy. I have done a natural history study of central retinal artery occlusion during the past 26 years, and on going through my data I found that the incidence of final vision seen by these authors was exactly identical to what I had seen without any treatment whatsoever, as shown in [Table:1]. I also pointed out that there was little scientific rationale for this therapy in the vast majority of the patients. Moreover, fibrinolytic therapy is a dangerous therapy and over the past 3-4 years a number of papers based on large clinical studies have shown a high incidence of mortality and morbidity from this treatment.[21-24] In fact one paper reported 2 patients who were treated with fibrinolytic therapy for central retinal artery occlusion - one of them died and the second was left severely disabled from brain haemorrhage.
4. Exaggerated and unconfirmed claims for a method of treatment. Central retinal vein occlusion is another common blinding disease, seen most often in the elderly, with no known cure. In 1982, a group, from the same famous eye hospital in the USA, reported that prophylactic laser treatment in 100 consecutive patients had prevented development of the most dreaded and blinding complication of glaucoma in 100% of them - a most unusual claim. We subsequently did a prospective study of the same treatment in central retinal vein occlusion which showed that, statistically, the treatment had no benefit - in fact, on the contrary, laser treatment resulted in severe visual loss. Similarly the study by the multicenter Central Vein Occlusion Study Group showed that prophylactic panretinal photocoagulation in ischaemic central vein occlusion does not totally prevent iris or angle neovascularization and neovascular glaucoma.
5. Flawed study design. The design of any study must be most carefully reviewed because that determines its outcome. If the design is wrong, its conclusions will not be worth the paper they are written on. The United States' National Institutes of Health spent millions of dollars conducting a multicentre study on laser treatment in eyes with central retinal vein occlusion, as mentioned, a seriously blinding and common condition, with no definite treatment. The results of that study were published in the Archives of Ophthalmology and Ophthalmology. I have researched various aspects of this topic for almost 3 decades and I found serious flaws in the design of that study, which invalidated its conclusions. In a letter to the editor of Ophthalmology commenting on the problems with the study and conclusions, I wrote: "A multicenter, multimillion dollar study conducted under the aegis of the National Institutes of Health carries tremendous prestige and its conclusions become a weighty verdict. We must remember that the study design determines the outcome. A study with such flaws in its basic design has the potential to provide serious misinformation that may retard rather than advance knowledge."
6. Financial interests. We live in an age of rapidly evolving technology and medical advances, particularly in the field of therapeutics. When evaluating published studies advocating a new instrument or drug, one has to examine them very carefully for signs of vested interest by the authors or those who funded the study, because that can skew the results. For example, practically none of the studies funded by tobacco companies found any harmful effects of smoking while all others did. When a paper lauds a product, the reader should always ascertain if the study was funded by a drug company or industry, and whether the authors have any ownership interests consultancies, etc, in that company. The New England Journal of Medicine, one of the most prestigious American medical journals, has published 36 "Drug Therapy" reviews since 1997 - in 8 articles the author(s) had links to drug companies that marketed treatments evaluated in the articles. That has recently resulted in a good deal of justified criticism from the press and public about the policy of the journal publishing those kinds of reviews.
In this connection, I was involved in another controversy about a machine. As I mentioned earlier on, poor circulation in the optic nerve head is responsible for the development of optic nerve damage and associated loss of vision in anterior ischaemic optic neuropathy and glaucoma. Therefore, at present there is a tremendous interest in methods to measure the blood flow in the optic nerve head for prevention and management of loss of vision under these common conditions. Riva and colleagues invented the Laser Doppler Flowmeter machine and claimed that it measured the blood flow in the optic nerve head, and they published a series of papers in a number of prestigious ophthalmic journals making that claim. Based on my studies on the subject of optic nerve head circulation, I doubted their claims. I finally convinced them to collaborate with me to find out if their claims were justified. We spent a couple of years jointly conducting an experimental study. When we analyzed the data, it clearly showed that their claims were not valid. They were extremely reluctant to publish the results, naturally, because that would have invalidated their previous studies and proved that the Laser Doppler Flowmeter is not a reliable means of measuring the blood flow in the optic nerve head. It was only after long and unpleasant arguments that I finally got them to publish the results in April 1999.
These are a few examples of how research can be distorted. In addition there are other factors which can introduce misleading information in scientific literature, as discussed below.
[TAG:2]"The bandwagon jumping phenomenon" in research[/TAG:2]
If someone proposes a theory or a mode of treatment, suddenly a number of publications start to appear in support of that, even though later on the original study and its conclusions may be found to be totally flawed. For example, in the case of optic nerve sheath decompression in anterior ischaemic optic neuropathy, discussed earlier, soon after the initial report a number of papers[32-34] appeared allegedly confirming the original observation of its beneficial effects, although it was finally shown that the procedure was actually harmful. Contrary to the usual belief, this shows that confirmation of findings of a study by other studies is not always a proof of its scientific validity.
| Association mistaken as a cause-and-effect relationship|| |
In clinical studies, it is not unusual to find an association between two or more factors, and that association is often mistaken for a cause-and-effect relationship. But association does not necessarily translate in to cause-and-effect. For example, President Jimmy Carter of the United States once gave a radio talk to the nation and about 10 persons died of heart attacks while listening to that talk; but the President's talk was not the cause of their death. This kind of misunderstanding has often caused a great deal of confusion among the medical as well as the lay public in interpreting results of biomedical research studies.
| Misinterpretation of statistics|| |
Benjamin Disraeli (1804-81), the British statesman, famously said: "There are three kind of lies - lies, damned lies, and statistics." It has also been said that figures can lie and liars can figure. Giving statistical data analyses and p-values has become an essential part of almost all scientific publications. If a paper gives a lot of statistics and statistically significant p-values (p-values of ≤ 0.05), the readers and audience automatically take it for granted that the findings are scientifically valid and important. Although most of the time that information is essential and very helpful for evaluation of the scientific merit of the study, unfortunately, that is not always true. A statistically significant p-value may be totally misleading; the validity of a p-value depends upon the sample size, the number of variables for which tests are performed, the correct use of Bonferroni or other similar corrections for multiple tests, and other factors in the data. Statistical data analysis may be manipulated to prove what the author wants to prove. Some authors simply use statistics to boost the merit of weak studies. Lang rightly stated: "He used statistics as a drunken man uses lampposts; for support rather than illumination".
| Bias toward publishing positive results|| |
As Lancet recently reported, research publications also have other problems. Researchers are strongly motivated to complete and publish positive rather than negative results, and editors also are more likely to publish them. Abstracts usually emphasize positive results. Also there are a number of factors which can produce positive biases, and these include methodological errors, such as flawed randomization, or relative-risk data. It is extremely rare to find a study reporting entirely negative findings - though negative findings can be just as important and informative as positive ones.
| Similar studies are not necessarily parallel|| |
Yet another problem is that sometimes authors conducting research on the same topic state in the literature that they have done similar studies and that their results can be compared; but a careful review of the studies' designs and data analyses often reveals that those were not parallel studies at all, and their results are not comparable.[38-40] Such a comparison can result in a good deal of controversy and confusion.
In 1962, Sir Stewart Duke-Elder remarked to me, "In scientific literature, if everything which has appeared in print was valid, we would not need to do any more research on those topics." How true that is!
Thus, I find that the field of medicine is littered with myths, originally drawn from simple clinical impressions, anecdotal reports, personal biases, defective experiments, erroneous interpretations, and temporary lapses of famous physicians. These myths come to be regarded as 'established facts'. Any attempt to weed out myths is met with severe resistance and even ridicule. I know that well, because I have spent the past 40 years trying to weed out misinformation, which is not at all a pleasant job and does not make you popular. But then one has to remember that if you witness a crime and do not do anything to prevent that from happening, you are a party to the crime. As Edmund Burke (1729-1797), the great British statesman, said: "All that is necessary for the triumph of evil is for good men to do nothing."
The most important thing to remember in research is that scientific research is like collecting innumerable pieces of a complex jig-saw puzzle, in the hope that one day we or someone in the future will have all the pieces and will be able to fit them together to form a clear picture of problem we are trying to solve. The tragedy of scientific research often is that researchers try to build the whole picture from only a few incongruous pieces of the jigsaw puzzle. Baron Justus von Liebig in 1846 rightly stated that "History teaches that the commencement of every branch of science is nothing more than a series of observations and experiments which had no obvious connection with one another." There is a great temptation to put forward theories based on inadequate information.
Those who are or want to get into the business of scientific research must remember the words of Harvey Cushing: "To accept the opportunity of advancing knowledge is not light responsibility." At the same time, please do not adopt the policy of not doing research for fear of making mistakes. Take courage from words of Albert Szent-Gy φrgyi, the Nobel Laureate of 1937, who stated "There is but one safe way to avoid mistakes - to do nothing, or at least, to avoid doing something new. This, however, in itself, may be the greatest mistake of all."
In conclusion, I would like to stress strongly, that most of the information in the scientific literature is valid and trustworthy; it is only a small part of it that is corrupted, and even, prestigious journals are not immune from publishing that. Therefore, it is important to be aware of such misinformation, which can prove harmful if left unchallenged.
So how should a scientist or a physician read the reports in the literature? First and last, he/she should always be skeptical, particularly of claims of dramatic breakthroughs which get widely advertised in the news media by interested parties. Unfortunately, like any other field, the field of research also has its fair share of chauvinistic persons. Also, there are many pseudo-scientists. Ideally, the reader should examine critically the assumptions behind the hypothesis; the bona fides of the persons doing the research and their possible biases and vested interests; the natural history of the disease or conditions being treated; the study design and data analyses used; the scientific rationale for the claimed benefits of a treatment; and the possibility of optimistic over-interpretation of results and trends. This is a tall order! Perhaps the best advice is: be skeptical and be cautious, most of all when the drug or instrument or procedure purports to cure or alleviate a condition for which there is at present no cure. As they say, if it sounds too good to be true, it probably is not true. I am reminded of a saying of Aristotle (384-322 B.C.), the ancient Greek philosopher: "Unlike the young, the old have lived long, they have often been deceived, they have made many mistakes of their own, they have seen the pain caused by positive men, and so they are positive about nothing. And when they err, they err in all things by extreme moderation."
| Humanity of patients break in the business of medicine|| |
Finally, medicine is becoming more and more dependent on scientific advances in drugs, tests and technology. At the same time, it is progressively becoming more and more a business. However, in medicine we deal with sick human beings and not machines. Each patient is a unique individual. Recent studies on the effectiveness of placebos have shown that a physician helps his patients heal as much by giving them his undivided attention, sympathy and reassurance as he does by prescribing a treatment. Patients put their trust in us and seek our help; we must respect their trust and treat each patient not as a "case" or a scientific problem or an opportunity for income, but as a person whose well-being is our primary concern. Thus, in the business of medicine, we must never forget the humanity of our patients.
| Acknowledgement|| |
I am grateful to my wife Shelagh for her help in the preparation of this manuscript; to Ms. Patricia Duffel, our librarian; and Ms. Georgiane Parkes-Perret, my secretary, for their help with bibliography. This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, USA. Dr. Hayreh is a Research to Prevent Blindness Senior Scientific Investigator.
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