From Facts to Artifacts in Medicine and Science
By Dr. Philippe Tellier, CMNA
Clinique Sainte Catherine, Introduction 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 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 On
April 29, 1996, FDA approved dexfenfluramine (Redux) for long term treatment of
obese patients, as obesity was already a major health problem in 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 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 These
initial facts which constitute the «epidemic» of anorexigen induced “valvular
heart disease” in the 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 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). Conclusion
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. References
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