From Facts to Artifacts in Medicine and Science

By Dr. Philippe Tellier, CMNA Clinique Sainte Catherine, Arras, France


According to Webster’s dictionary on-line artifacts can be defined in six ways: i) any object  made by human beings, especially with a view to subsequent use; ii) a handmade object, as a tool, or the remains of one, as a shard of pottery, characteristic of an earlier time or cultural stage, such as an object found at an archaeological excavation; iii) any mass-produced, usually inexpensive object reflecting contemporary society or popular culture, such as artifacts of the pop rock generation; iv) a substance or structure not naturally present in the matter being observed but formed by artificial means, as during preparation of a microscopic slide; v) a spurious observation or result arising from preparatory or investigative procedures; vi) any feature that is not naturally present but is a product of an extrinsic agent, method, or the like, such as statistical artifacts that make the inflation rate seem greater than it is. The two last definitions are most interesting in Science in Medicine, particularly in clinical research, as they introduce to an epistemological approach of the subtle interactions between facts and artifacts (1).

Methodological artifacts: a new concept?

From a more general point of view, methodological artifacts is a term to be used in order to describe those spurious observations which result from all the techniques and methods used in order to shape the reality according to the scientific or politic beliefs characterizing an historical period, i.e. its paradigm. An over-trust in these sophisticated tools is therefore characteristic of the past century, but this tendency will continue for the following centuries, if those techniques are used without critical sense and precaution (1).

Artifacts are obviously the most serious concurrent of facts and, more and more often, it becomes difficult to distinguish those brothers and enemies, as they are perfectly interrelated.  The interpretation of the results of a study or an experiment is sometimes too fast to allow any critical approach and this results in a dramatic amplification of artifacts; through the overgrowing Internet.  Moreover, when artifacts conceptually belong to the current paradigm, they may be transformed by experts, media, politics and lawyers into facts in order to support their personal convictions or interests. Things are going faster when there is a whiff of scandal... Artifacts when amplified by a higher and higher throughput of information without any retroactive feed-back, such as critical sense contribute to the commercialization of science and medicine and in fine to the destruction of scientific knowledge.

As wrote Thomas Fuller (1608-1661) “A lie has no leg but a scandal has wings”. Some Artifacts are in some way genuine lies, according to the level of consciousness of the liar or the “artifacter” which depends not only of the observer but also of his environment. The best arguments are from the best data, which are not so easy to obtain since observation is nowadays indirect and more and more dependent on sophisticated techniques and methods whose limits are unknown, ignored or worse neglected. In many cases, data are in fact largely insufficient to result in a reliable approach of reality or scientific knowledge which remains one of the main objectives of research and la raison d’être of human kind.

Let us remember that artifact can be «a spurious observation or result arising from preparatory or investigative procedures or any feature that is not naturally present but is a product of an extrinsic agent, method, or the like». Let us also remember that methods which are used in clinical research and science are far from perfect and that their validation is often missing or incomplete, because “gold standards” which are necessary to this process are rather difficult to obtain and easy to forget. Moreover interpretation of results could be another mechanism of artifacts, due to conceptual approach where are interrelated the limits of every scientific and every science, at the light or... in the darkness of the dominating paradigm.

Methodological and conceptual artifacts appear to be closely related, as the choice of methods depends of concepts that underlie the scientific approach of a specific problem. For example, an epidemiologist will choose a case-control study in order to avoid a fastidious longitudinal study, because, conceptually, the first approach is easier to perform, cheaper, and commonly used to “publish or perish”, although it is polluted by many biases that should not be ignored in the interpretation of its results.

Finally, another problem is the detection of rare or very rare phenomena in time or space with very imperfect tools that are not adapted to such an aim. The famous ratio signal/noise which is well-known in electronics and physics is never taken into account in other scientific domains, such as epidemiology or pharmaco-epidemioly. Some side-effects of drugs or some very rare diseases, both real and virtual, belong to this class of very rare phenomena which introduce to a new “phenomenology”.

When a phenomenon occurs too rarely, it cannot be extracted from the natural background: the signal is too weak and the noise dampens it, in such a way that it becomes not detectable. How can you distinguish between a spontaneous fact whose annual incidence is 10-3 and what is supposed to be a new fact which has the nearly the same incidence? You may use other techniques to produce artifacts.

Recent “affairs” might recall us the major role of artifacts not only in Biology and Medicine, but also in the shaping of reality and society, through amplification processes that are modulated or activated by the media tom-tom.

From the mind of water to the hepatitis B vaccination and the hormonal treatment of menopause

In 1988, Nature published a famous paper about high dilution experiments (2) which resulted in the controversy on «the mind of water». Secondly, in 1997, the British Medical Journal published a case-control study which established « convincing evidence in childhood leukemia of a causal role for environmental radiation exposure from recreational activities on beaches » (3). The imperfections of our methodological approach of more and more complex problems have been clearly underlined by the conclusions of both affairs. Without critical sense and validation of some data by other researchers, one might now consider that water has some mind (4) and that living near a nuclear plant significantly increases the risk of leukemia in childhood. «La Hague controversy» which ended by the refutation of its conclusions by other more plausible epidemiological data clearly underlines the limitations of a simplistic approach of complex problems

Reports of multiple sclerosis developing after hepatitis B vaccination have led to the concern that this vaccine might be a cause of multiple sclerosis in previously healthy subjects or lead to relapses of this disease. The results of two negative large case-controlled studies recently published in the New England Journal of Medicine (5, 6) provide some good evidence that: firstly, there was no relation between the receipt of hepatitis B vaccine and the development of multiple sclerosis; secondly, that the administration of vaccines against hepatitis B, influenza, and tetanus did not exacerbate the clinical course of multiple sclerosis in patients in whom the disease had already been diagnosed (1). Those results confirm that hypotheses can become “facts’’ long before the critical data are in our possession.  Nevertheless, in France, the problem is not solved and there are still juridical debates and affairs about the role of hepatitis B vaccination in some cases of multiple sclerosis or even other neurological disorders.

Another affair concerns the hormonal treatment of menopause. For years, it was told to women that this treatment was the best way to alleviate the functional and physical consequences of menopause while preventing its complications. Recently, the contrary was claimed. Why? Because of both methodological and conceptual artifacts which answered to the confusing paradigm of everlasting youth and financial interests where medicine is in one’s element.

Observational cohort  or case-control studies which represented 95 % of the available epidemiological information  before the introduction of hormone replacement therapy were... the cornerstone of the medical attitudes of beliefs on this matter (7), instead of controlled studies which were published thereafter and demonstrated that the ratio benefit/risk of hormonotherapy in the treatment of menopause was unfavorable. “A more rigorous evaluation of side-effects of hormone replacement therapy in the framework of long-term controlled trials was therefore clearly required. The indications of such a treatment should only rely on objective data... “(7).

In fact, contrary to some allegations, risk of breast cancer and cardiovascular disease was significantly increased by such a treatment, whereas efficacy in terms of prevention was really modest (8), and throughout the world, hormonal replacement therapy in menopause was considered as undesirable, except in some selected indications (8).

The next example is chosen among another famous affair which might be called: the saga of fenfluramines (1).

The saga of fenfluramines 

Fenfluramines have been commonly prescribed in Europe as appetite suppressants in the short-term treatment of obesity since 1963.  Their benefit/risk ratio in the long term treatment of obesity has never been established, because of the very restrictive recommendations of regulatory agencies throughout the world. Potential neurotoxicity which was never confirmed was the main fear of the regulators in reference to amphetamines: nevertheless, although fenfluramines have some chemical parity with amphetamines, their pharmacological profile is quite different.

On April 29, 1996, FDA approved dexfenfluramine (Redux) for long term treatment of obese patients, as obesity was already a major health problem in USA. In September 1997, fenfluramines were withdrawn from the market because of an «epidemic» of carcinoid-like valvulopathies which were imputed to combined fenfluramine-phentermine (fen-phen) (9).

In this case, inconsistent features were considered as firmly established facts by neglecting some possible artifacts and subscribing to two fallacious hypothesis (1) : i) a single case-control study is necessary and sufficient to demonstrate a causality relationship; ii) echocardiography-Doppler is a perfectly objective and reproducible technique, just like a laboratory test.

Fenfluramines and primary pulmonary hypertension

Fenfluramine was launched in France in 1963. A few cases of pulmonary hypertension associated to fenfluramine were reported in the European literature... only in 1981, whereas the drug had been prescribed to more than 500 000 patients. Between 1963 and 1996, fenfluramines (fenfluramine and dexfenfluramine) were used mainly in Europe in about 50 millions of patients (10, 11) and the prevalence of “well-defined PPH” associated but not imputed to these drugs could be estimated to about 2-3 cases for 1 million of treated patients. Let us remember that PPH is a very rare disease whose annual incidence is about 1-2 cases for 1 million in the French general population. The ratio signal/noise, i.e. PPH associated to fenfluramine /spontaneous PPH is near unit and the signal is not detectable from a methodological point of view.

Those estimations rely on cases of «well-defined PPH» but do not take into account cases of «uncertain primary» or secondary pulmonary hypertension that are not PPH stricto sensu. It also includes cases of pulmonary hypertension which were recruited for the International Primary Pulmonary Hypertension Study (IPPHS) (12) designed in 1992 to document an association between appetite-suppressants and PPH. The diagnosis of PPH relied mainly on hemodynamic parameters (12) and exclusion criteria which are both non specific but agree with its most recent definitions (13, 14). There was obviously no allusion to histopathologic abnormalities which are considered as the “gold standard” for diagnosis of PPH by many authors (14).

PPH or idiopathic pulmonary hypertension appears as a rather vague entity in search of a specific cause as many idiopathic diseases or syndromes in the past (14). As a case-control study, IPPHS could only establish a significant association, not a causality relationship between a very uncommon and mysterious disease and a frequent exposition to fenfluramines. So it could not be written that IPPHS «indicted anorexigens, particularly fenfluramine or its congener, dexfenfluramine as etiological agents of pulmonary hypertension» (10, 15).

The limitations of case-control studies

Case-control studies are more and more used in clinical research. Their advantages are well-known, but their limitations are readily omitted. For many physicians, only the results of a study are taken into account, particularly when they are quantitative and the methods appear to be less important, a fortiori when results are published in some prestigious journals and amplified by the media circus. Such an attitude is the contrary of scientific rules. The vocabulary of epidemiology is somewhat confusing and confusion is often made between prospective and retrospective approaches. Biased data in analytical research are so numerous and common that shaping of the reality cannot result from a single published case-control study (16). This is not «scientifically correct», although perhaps “medically correct”, but medicine is not only an art, it is also a science according to the Hippocratic tradition (1).

A single case-control study is clearly insufficient to establish facts and causality; this is contrary to the rules of all sciences, where confirmation of results by other studies or experiments is the cornerstone of their validity as scientifically established facts.

Why the results of IPPHS were ratified by FDA comes under the article of politics more than of Science (1).The hypothetical results of IPPHS were largely in accordance with beliefs and needs of experts who considered the scientific value of the study as necessary and sufficient to conclude, all the more this was published in the New England Journal of Medicine (1) which is like a gold standard in medical literature.

Fenfluramines and cardiac valve disorders

On the other side of the Atlantic Ocean, about 2 months before the publication of IPPHS in the New England Journal of Medicine, dexfenfluramine was approved by FDA for use in the United States, on April 29, 1996. Sixteen months later, a series of case-reports (9) gave the illusion of an epidemic of valvular abnormalities which were imputed to the combination fen-phen, but only one case of pulmonary hypertension in a young patient treated by fen-phen for 23 days was published in the same time (17). According to the quantitative results of IPPHS and the use of prescription weight loss pills among U.S. adults in 1996-1998, at least 100 to 200 cases of primary pulmonary hypertension were awaited  (1,18). Instead of them, there were 5 cases of carcinoid-like valvular abnormalities documented at surgery, with specific macroscopic and/or microscopic lesions (1)  which concerned only (n=4) or mainly (n=1) mitral valves. The other cases of “cardiac valve disorders’’- 19 in Connolly’s paper and 34 in other initial reports- were mainly documented by echocardiographic techniques as non specific valvular regurgitations, most often mild and less often moderate, with a prevalence which astonishingly varied between 7% and 32%, (19-22).They were attributed to long term treatment by a combination of fenfluramine (or dexfenfluramine) and phentermine.

These initial facts which constitute the «epidemic» of anorexigen induced “valvular heart disease” in the United States resulted in a worldwide scandal and a prompt withdrawal of fenfluramines on September, 1997. The combined pressure of lawyers, media and class actions resulted in hundreds of abnormal echocardiographic studies in patients who were previously treated by fenfluramines.

Since this initial report, numerous conflicting data have been published. In 5 full papers , except one where clinical signs were used for the diagnosis of valvulopathy (23), cardiac valve disorders were characterized by non specific echo-Doppler findings, according to FDA seemingly objective but imprecise criteria: «aortic regurgitation of mild or greater severity or mitral regurgitation of moderate or greater severity, as determined by echocardiography» (20). All the published data, with one exception (22), were issued from retrospective case-control studies. Anatomopathological abnormalities which are necessary to establish the diagnosis of carcinoid or carcinoid-like valvulopathy as a gold standard were never mentioned. (21-25). Methodology and criteria of interpretation of echo-Doppler were, in general, poorly described (1).

More recently, prospective studies have investigated the natural history of “anorexogen-allied cardiac valve disorders”: in most of cases, valvular regurgitations, particularly aortic regurgitations, remained stable or improved after discontinuation of therapy (26-28): such an evolution is far to be sufficient to establish a causal relationship between mild aortic regurgitations and exposure to anorexigens. It might simply reflect the interoperator variability of measures, because between a light and moderate valvular regurgitation, particularly in an obese patients, the gap is not so vast (1). All these studies and others have been reviewed in detail in a previous paper (1).

That an American «epidemic» of cardiac valve disorders was foretold by an European «epidemic» of idiopathic pulmonary hypertension is really disturbing, although some authors consider this chronological  sequence of events as logical (10,15). Moreover, between the 5 cases of severe carcinoid-like valvulopathies associated to phen-fen (9) and the mild aortic regurgitations described in hundreds of patients treated by fenfluramines alone, there is a curious shift which might indicate the metamorphosis of facts into artifacts (1).

Echography-doppler is not a reproducible laboratory test

Echocardiography, with or without Doppler investigation is basically an operator-dependent technique. There is always a sonographer between the patient and the machine, whether he is a technician, as in the United States or a physician, in France. (1). The detection and a fortiori the quantitative evaluation of cardiac abnormalities are not automatic processes, but imply the acquisition and processing of data by an experienced observer who has to interact with the patient not only by putting a probe on a thorax, but also by talking over various matters, such as medical history or intake of some drugs (1). This is a major problem in epidemiology or pharmaco-epidemiology as the results of such a test should not be biased by any information which might influence the acquisition or interpretation of the data, through the setting of more and more sophisticated machines whose technical performances are not created equal (1).

Technician-to-technician reproducibility which has to be distinguished from interreader reproducibility is unknown not only in obese patients, but even in patients with normal body weight, at least for some variables such as the severity of valvular regurgitations. Variability of the acquisition process has been completely ignored in all the published studies: that seems incredible, but those are the facts resulting in methodological artifacts. Recent publications have underlined the poor reproducibility of this acquisition process particularly in obese patients and even with quantitative parameters which are in theory more reproducible (30, 31).

The a posteriori blinded reading of final data even by  independent observers is not at all sufficient to warrant the objectivity of the results, as the data gathered by the operator and the machine do not rely on universal constants, but on skills and subjectivity of the operator. In fact, there is no universal consensus between echocardiographists for the optimal detection and evaluation of valvular regurgitations. FDA criteria appeared to be subjective and too imprecise to guarantee technician to technician reproducibility.

Moreover, in the Framingham Heart Study (32) where placement of the transducer, gain settings and other details were not omitted in the chapter Methods, a substantial proportion of 3589 healthy men and women had detectable valvular regurgitation by color Doppler echocardiography. Mitral regurgitation of more than or equal to trace severity was seen in 19.0% of men and 14.8% of women and aortic regurgitation more than or equal to trace severity in 13.0 of men and 8.5% of women. «These data provide population-based estimates for comparison with patients taking anorectic drugs» (32).

For all these reasons, echo-Doppler should not be used without precaution as a laboratory test in the field of epidemiology or pharmaco-epidemiology with the aim to detect side effects of drugs Negligence of both human and technical factors might result in artifacts and severe errors of judgment, as foretold by a prophetic and forgotten editorial, published 16 years ago in Circulation (33).


According to the game of conjectures and refutations, as defined by Sir Karl Popper critical analysis of facts is to be applied to every problem submitted to the human understanding, particularly in the field of modern medicine. The aim is to detect artifacts and to understand how they are constructed, because of their deleterious effects on the shaping of human knowledge. This is more and more difficult, as the analytical methods used in biology and medicine are more and more sophisticated and sometimes poorly reproducible, a major limitation which is often neglected by hyperspecialized physicians. Over-trust in some techniques appears to be characteristic of the modern and the post-modern era, particularly in medicine, despite of many deceptions.

The fenfluramines saga is an intellectually well-orchestrated symphony where ultrasound imaging and epidemiological methods play the most important role, but where are the diagnostic standards that guarantee the validity of the whole partition? The analytical dissection of the partition shows numerous contradictions and pernicious artifacts which are not compatible with a scientific standpoint (1). This is also true for other affairs where the methodological imperfections of non controlled studies have been clearly shown: La Hague controversy, hepatitis B vaccination, hormonal replacement treatment, cellular phones and so on.

 In fact, we are really confronted with more en more seemingly universal explanations which cannot be refuted by first-rate data. Such dogmatic explanations are exactly the premises of a new kind of mythology where machines and bad methodology are deified under the pressure of media tom-tom which seem to dominate societal and political environment throughout the industrialized countries.

The contribution of media and some prestigious medical journals is also part of the problem, as their relative weight in the structure of medical thought appears to be disproportionate (1). A new paradigm in biology and medicine might emerge through tenebrous affairs with a whiff of mystery, where political, financial and juridical arguments are clearly superior to any other argument. Scientific knowledge in medicine and biology might become the privilege of a constellation of lawyers and financial trusts where science looks...  like the icing on a cake.

This might be the beginning of a conceptual revolution... Let us remember the words of Karl Popper: “Science, scientific knowledge is always conjectural knowledge and the method of science is the critical method... “and those of Goethe puts in the mouth of Devil:

“Reason and science you despite

The highest powers of the mind?

Hell’s willing slave! With others of your kind,

You are the profits of my enterprise”

Nevertheless, artifacts are not the creation of Devil, but the production of human being. The history of artifacts is the history of the humankind. let us remember that an artifact is a spurious observation or result arising from preparatory or investigative procedures or any feature that is not naturally present but is a product of an extrinsic agent, method, or the like...

Methodological and conceptual artifacts are emerging as a new entity requiring special attention in the field of science and medicine, as tomorrow, with the development the post-genomic and proteomic era, facts are becoming more and more virtual, more and more artifacts. This is only the beginning... A world of artifacts, both conceptually and methodologically constructed might be our bright future.



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28.Weissman NJ, Tighe JF, Gottdiener JS, Gwynne JT. Prevalence of valvular-regurgitation associated with dexfenfluramine three to five months after discontinuation of treatment. J Am Coll Cardiol 1999, 34: 2088-2095.

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32.Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL,Lehman B, Benjamin EJ. Prevalence and clinical determinants of mitral, tricuspid and aortic regurgitation (The Framingham Heart Study). Am J Cardiol 1999, 83: 897-902.

33. Sahn DJ, Maciel BC. Physiologic valvular regurgitation: Doppler echocardiography and the potential for iatrogenic heart disease. Circulation 1988, 78: 1075-1077.


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