More research is needed—but what type?
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4662 (Published 25 August 2010) Cite this as: BMJ 2010;341:c4662All rapid responses
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I write to support the case for a translational or inter-disciplinary
approach to research as set out by Geoff Watts (1), and discussed by Fiona
Godlee, editor BMJ (2), in her most timely editorial, in view of impending
spending cuts on research.
A concrete example of the use of this approach comes from a published
review I carried out integrating the epidemiological, laboratory and
clinical research findings of coronary heart disease (CHD) (3). This
found that all the epidemiological and risk factors were associated with
enhanced activity of the catecholamines or the sympathetic nervous system
(SNS), either stimulating such activity or resulting from it, and that the
SNS played a major role in all the basic mechanisms of CHD-vascular
endothelial damage, increased blood coagulability and myocardial ischaemia
and infarction.
This led to the hypothesis that CHD was caused by a number of
apparently unrelated factors, having a common pathway mediated through the
S.N.S.
There were many uses and implications of this approach -
understanding the causes and mechanisms of CHD, distinguishing between
causal and associated risk factors, the need to research factors other
than the traditional risk factors that stimulated the SNS - eg. psycho-
social stress, chronic inflammation eg in peri-odontal disease, thermal
stress from heat and cold, cadmium levels in soft water. There was also a
need to study variation in SNS tone and activity in individuals and
groups.
By clarifying the aetiology and pathogenesis of CHD, it should be
possible to distinguish between causal and associated risk factors. The
need for this arose recently after reports in the national press of a
conference of the American Sociological Association in the USA where Prof.
Donald Light, a sociologist and professor at the University of Medicine
and Dentistry in New Jersey, stated that two major trials of statins found
little evidence that they reduced the risk of heart attacks. He suggested
that drug companies had reduced complex relationships between heart
disease and saturated fats and cholesterol into the over-simplistic
message that "cholesterol kills". The inter-disciplinary review showed
that elevated cholesterol and low density lipoprotein levels were
associated risk factors of CHD but not necessarily independent causative
ones. Do we need to review the efficacy of statins?
I believe this example illustrates the need for translational
research which is defined by the Institute of Applied Health Sciences,
University of Aberdeen in the article by Geoff Watts(1)- where knowledge
obtained from the basic sciences is applied to clinical and community
settings and information obtained from human experimentation can be used
to refine our understanding of the biological principles underpinning the
heterogeneity of human disease.
References
1. Geoff Watts. Lost Without Translation, BMJ 2010; 341 : c 4363,
p428 - 429 (28 August)
2. Fiona Godlee, editor BMJ. Editors Chance, More research is needed
- but what type? BMJ. 2010; 341 : c 4662. (28 August)
3. Lee, J.A. The role of the sympathetic nervous system in ischaemic
heart disease: A review of epidemiological features and risk factors,
integration with clinical and experimental evidence and hypothesis.
Activ. nerv. sup. (Praha). 25, 1983, No. 2 p. 110-121.
Competing interests: No competing interests
Dear Colleague,
I agree with most of what you write, except with this phrase:
Diseases are only accidents. If one follows the correct rules of healthy
life style, accidents (diseases) will be rare indeed!
I was diagnosed with Hairy Cell Leukaemia in 1994.
It was the consequence of a 2-yearly blood check, when hairy cells were
found in a sub-population of my lymphocytes.
It took about 10 months before my neutrophils were low, before I
received a prescription for Interferon (subcutaneous injections I did
myself), which made me very sick, but brought me into a recovery.
Two years later, things going worse again, I had 5 successive days a
1 hour infusion of 1-Chloro-deoxyadenosin (a product of medical research
that never reached general medical papers)and after that, I had first
monthly, the 6-monthly, and now once a year haematology controls.
So, I remember that about my grandfather, who died in 1924, my
cousins discussed if it had been wise to take his spleen out. He died of
"Bouroncle's disease". He was 49 years of age.
I do not believe I could have escaped the hairy cell leukemia by
living a healthier life.
Best regards,
Competing interests: No competing interests
Healthcare is ostensibly based on objective scientific research. But
who conducts and/or sponsors this research? All too often, it's the very
companies whose products are being studied, and thus have obvious
conflicts of interest. As a result, this "research" becomes little more
than a euphemism for advertising and marketing. As the shield between life
and death, healthcare should be based on science and mercy, not business
and commerce.
Competing interests: No competing interests
Dear Fiona,
The caption comes from the 1854 book, Walden, by Henry David
Thoreau, which shows why we love our conventional research
so much even in 2010.
Science is making models, mostly mathematical constructs,
which with verbal explanations are supposed to work! That
was the opinion of one of the great brains in science, John
von Neumann. Western science is lost in this mess and is
searching for a better model for future research. A leading
western scientist, Douglas C Wallace, writing in the famous
Genetics Journal, has shown that the non-linear model of
Asian medical systems like Ayurveda is more useful to human
physiology and recommends those methods for future research!
The mathematical base of modern medical research is linear
while the human body is non-linear. All the research we have
been doing has come to grief. First, human diseases
affecting a wide range of organs could result from systemic
defects in energy metabolism and, second, hereditary human
diseases could result from mutations in the non-Mendelian
mtDNA. Consequently, mitochondrial biology and genetics
become excellent candidates for expanding the anatomical and
Mendelian paradigms to address the complexities of the age-
related diseases, ageing, and cancer, wrote Wallace.
(Genetics 2008; 179: 727)
It was in the year 127 AD that a great teacher of
medicine, Galen, wrote that the liver pumps blood around the
system. For the next 1500 years all teachers and students
everywhere wrote their research papers based on this
premise. It was only in the year 1628 AD a thinking family
physician in London, William Harvey, observing a fire
hydrant working, thought that the heart pumps blood.
Knowledge advanced after 1500 years. I ask the same question
today. Is the heart a simple muscular pump? The answer is
probably-NO. But who cares? If one reads my article in an
indexed journal entitled is the human heart a simple
muscular pump one would be shocked to know how far away from
the target are we hitting.
(medind.nic.in/jac/t10/i1/jact10i1p16.pdf) Many such wrong
ideas are being taught and followed.
All that I wish to convey through this response is that many
good THINKERS among students could do good research. No law
will make any one a thinker!! If doctors confined themselves
to curing the sick rarely, comforting them mostly, but to
consoling them always, they would be doing a great service
to the public. Good teachers and researchers are as
important to a medical school as are good bedside
clinicians. These two breeds, combined with a few thinkers
who could do genuine research to take knowledge forwards,
would be an ideal combination in medical schools to motivate
students with different skills and interests. It will be
foolhardy to expect all these three in one individual except
very, very rarely.
Modern medicine is becoming unpopular in the west. In the
year 1997 alone 629 million people took treatment from
alternative systems of medicine in the west paying from
their own pockets. This is more than the number of people
that saw their family doctors in the same year, according to
a survey done by Eisenberg and colleagues in 1998. (JAMA
1998; 280: 1569) India should take note of this as we have
one of the best systems of health care in Ayurveda,
especially for chronic illness syndromes. If this could be
judiciously clubbed with the emergency care methods of
modern hi-tech medicine, complementing each other, we could
bring down the costs of medical care to almost one tenth of
its present level with less ADRs as a bonus.
The future lies in emphasizing promotive health. We should
change the present teaching in medical schools from the
disease-centred education to that of patient-centred
community based education. We should use statistics
sparingly in medical research. One of the drawbacks of
applying disease statistics to the healthy population is
that the latter throws up a very high percentage of false
positives, resulting in epidemiologists predicting the
unpredictable, resulting in epidemics. The fear of an
illness could help the illness to take a strong footing in a
healthy person. Modern medicine has realized that the human
mind plays a vital role in disease causation as well as its
control. Hence there is a need for doctors to train
themselves in human psychology and behavioral sciences.
Health is our birth right. Diseases are only accidents. If
one follows the correct rules of healthy life style,
accidents (diseases) will be rare indeed!
If we are interested in getting better medical scientists in
the future we should see that every medical school has a
department of medical research with a decent budget, headed
by some one who has done real good refutative research work
published. S/he must be adequately compensated lest the
person should look elsewhere for succor. The departmental
work must be subjected to strict periodic auditing. Such
teachers alone could motivate brilliant young students to do
good research. Drug studies are NOT research in the true
sense. Even if such studies are needed they should NEVER be
funded by drug companies as is the case at the moment.
While good research is refutative, all kinds of repetitive
research must be shunned. Karl Popper once wrote that
knowledge advances not by repeating known facts but only by
refuting false dogmas, of which there are plenty in modern
medicine today. The medical school should be proud of such a
research department and should include that as a selling
point in the brochure for prospective students. If this is
genuinely pursued, a time will come when we will get a few
good researchers in the world. They would make us proud.
Outstanding research is only serendipitous. One can not plan
such work in advance. That said I must warn that serendipity
helps only those with prepared minds receptive to creative
thinking. Let us work to get more prepared minds in the
country and not legislate to have the usual IMRAD
(introduction, material methods, results, and discussion
type) research papers most of which are not even worth the
weight of the paper on which they are written.
Sadly even in 2010 we do not have a correct science of man.
Great minds in western science, from the time of Galileo,
were happy working on models for inanimate objects like in
Physics and chemistry. Even biology does not have a model of
its own. Human physiology is far, far away from reality with
its linear model of the inanimate sciences applied to a
dynamic human system with its all pervading consciousness.
Man is but his mind, says Indian Ayurveda which has human
beings classified into many gentico-constitutional types
which take into consideration human consciousness as well.
These classes could then be used for better RCTs; the latter
at the moment compares only a small fraction of the
phenotype of cohorts! One size fits all is foolishness in
our present research. Individualised medicine has gone out
of the window. Peer review is the enemy of progress as the
peers can only deal with the known and if a refutative
researcher wants to publish an out of the box thinking paper
that would promptly go to the waste paper basket.
Let us think out of the box rather than use more complicated
Latin words for new research with the same flawed science of
man. Intellectual integrity made it quite impossible for me
to accept the myths and dogmas of even very great
scientists, more particularly of the belligerent and so-
called advanced nations. Indeed, those intellectuals who
accepted them were abdicating their functions for the joy of
feeling themselves at one with the herd.(Bertrand Russell-
1872-1969)
Yours ever,
bmhegde
Competing interests:
None declared
Competing interests: No competing interests
Godlee highlights the importance of asking "what type of research is
needed?" when making research recommendations [1]. When budgets are finite
- which they are for research as well as healthcare - it also becomes
pertinent to ask "how much to spend on the research?" Indeed, the benefits
of reducing uncertainty through research need to justify the cost. As
most, if not all, clinical decisions have uncertain outcomes, there will
always be a chance that a wrong decision is made, and this has a cost, in
terms of health benefit and resources forgone. This cost can be quantified
in a value of information analysis, which places an upper limit on the
value of conducting research [2]. As an example, we calculated the value
of a future clinical trial of drug and lifestyle intervention in obese
adolescents. We considered plausible estimates of the following from
existing research: a mean 1-year treatment effect on BMI of -1.4kg/m2 (SD
2) [3]; mean costs of £1084.03 (SD £212.29) in the treatment group
and £276.12 (SD £297.15) in the control group [4,5]; an NHS
willingness to pay of £800 per unit reduction in BMI over 1-year [6]; a
period of 5-years until such time as a more effective treatment becomes
available (assumption) and, based on the 99th centile in BMI defining
treatment eligibility, an annual UK incidence of 37,180 12-16 yr olds [7].
Following standard methods [2], we calculated the value of information to
be £171m, indicating that research on the combined use of a drug and
lifestyle intervention for the management of obesity in adolescents has a
large societal impact, which would greatly exceed the costs of a clinical
trial.
1. Godlee F. More research is needed - but what type? BMJ 2010; 341:
c4662
2. Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S. A pilot study
on the use of decision theory and value of information analysis as part of
the NHS Health Technology Assessment programme. Health Technol Assess.
2004 Jul;8(31):1-103, iii.
3. Park MH, Kinra S, Ward KJ, White B, Viner RM. Metformin for obesity in
children and adolescents: a systematic review. Diabetes Care. 2009;
32(9):1743-5.
4. McConnon A, Kirk SF, Cockroft JE, Harvey EL, Greenwood DC, Thomas JD,
Ransley JK, Bojke L. The Internet for weight control in an obese sample:
results of a randomised controlled trial. BMC Health Services Research
2007, 7:206
5. Joint Formulary Committee of the British Medical Association and the
Royal Pharmaceutical Society of Great Britain. British National Formulary.
59th Edition, March 2010.
6. Moodie M, Haby M, Wake M, Gold L, Carter R. Cost-effectiveness of a
family-based GP-mediated intervention targeting overweight and moderately
obese children. Econ Hum Biol. 2008; 6(3):363-76
7. Office for National Statistics. Mid-year population estimates 2009.
Available at: http://www.statistics.gov.uk/statbase/Product.asp?vlnk=15106
(Accessed 27 August 2010)
Competing interests:
None declared
Competing interests: No competing interests
A Definition of Comparative Effectiveness Research
Despite all the attention to (and contention about) comparative
effectiveness research in the US, much of it very well summarized in the
recent paper by Tunis and Pearson [1], it is striking that most
publications and websites fail to provide a comprehensive yet boundary-
setting definition of comparative effectiveness research (including,
unfortunately, the Tunis and Pearson paper). Instead, one is likely to
find statements about the drivers, the methods, the intended results, and
beneficiary stakeholders. To paraphrase Godlee [2], this is baffling
indeed, not only because the need for comparative effectiveness research
is so obvious, but also because significant resources will be committed to
an enterprise (much needed) that will shape health care decision-making
from the patient to the policy levels.
For instance, the Federal Coordinating Council defines comparative
effectiveness research as "the conduct and synthesis of research comparing
the benefits and harms of various interventions and strategies for
preventing, diagnosing, treating, and monitoring health conditions in real
-world settings" [3]. The Agency for Health Care Research and Quality
refers to comparative effectiveness research as "a type of health care
research that compares the results of one approach for managing a disease
to the results of other approaches. Comparative effectiveness usually
compares two or more types of treatment, such as different drugs, for the
same disease. Comparative effectiveness also can compare types of surgery
or other kinds of medical procedures and tests. The results often are
summarized in a systematic review." [4] In its Congressionally-mandated
task to identify priorities for comparative effectiveness research, the
Institute of Medicine defined comparative effectiveness research as "the
generation and synthesis of evidence that compares the benefits and harms
of alternative methods to prevent, diagnose, treat and monitor a clinical
condition, or to improve the delivery of care. The purpose of [comparative
effectiveness research] is to assist consumers, clinicians, purchasers,
and policy makers to make informed decisions that will improve health care
at both the individual and population levels."[5]
We faced the challenge of defining comparative effectiveness research
in our efforts to develop an interprofessional postdoctoral fellowship
program in clinical outcomes and comparative effectiveness research in
rural primary care. This program will bring together doctorally prepared
practitioners from nursing, medicine, pharmacy, and public health for
advanced research (80%) and clinical (20%) training. Taking the best from
these definitions yet also aiming to provide more specificity in terms of
foci and methodologies and setting boundaries to both concept and
enterprise, we built on the Institute of Medicine definition but extended
it significantly. Hence we propose the following definition:
"Comparative effectiveness research is the generation and synthesis
of evidence generated through prospective and retrospective studies with
either primary or secondary data sources by:
- Comparing the benefits and harms of alternative methods to prevent,
diagnose, treat and monitor a clinical condition, or to improve the
delivery of care;
- Comparing the same method(s) between different patient groups;
- Comparing the same method(s) between different clinical
environments; or
- Comparing one or more methods across combinations of treatments,
patient groups, and/or environments.
At the clinical level, comparative effectiveness research
investigates methods, already shown to be efficacious in randomized
controlled trials, in real-world settings; i.e., under ordinary and
variable conditions, when prescribed by licensed clinicians with varying
degrees of expertise and practicing across the spectrum of health care
settings, to treat a heterogeneity of patients.
Comparative effectiveness research aims to discover the best methods
for personalizing care to individual patients by broadening the evidence
base, and by providing more, better, and detailed information with which
to craft a management strategy for each individual patient.
The ultimate purpose of comparative effectiveness research is to
assist consumers, clinicians, purchasers, and policy makers to make
informed decisions that will improve health care at both the individual
and population levels."
It is indeed important to adopt a broad but also well-delineated
definition of comparative effects. This, we believe, will facilitate the
mission of the Patient-Centered Outcomes Research Institute and enable it
to fulfill its scientific and public service mandates.
References
[1] Tunis SR, Pearson SD. US moves to improve health decisions. BMJ
2010;341:c4336.
[2] Godlee F. More research is needed - but what type? BMJ
2010;341:c4662.
[3] Conway PH, Clancy C. Comparative-effectiveness research -
implications of the Federal Coordinating Council's Report. N Engl J Med
2009;361:328-330.
[4] See http://effectivehealthcare.ahrq.gov/index.cfm/glossary-of-
terms/. Last accessed 9 September 2010.
[5] Institute of Medicine. Initial national priorities for
comparative effectiveness research. Washington, DC: National Academies
Press, 2009.
Corresponding author: Ivo Abraham, College of Pharmacy, The
University of Arizona, 1295 N. Martin Avenue, Room B-211G, Tucson, AZ
85716, USA. Email: abraham@pharmacy.arizona.edu.
Competing interests: No competing interests