Medical Research: A Prescriptive View

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82 PEDIATRICS Vol. 95 No. I January 1995

SPECIAL

ARTICLES

Medical

Research:

A Prescriptive

View

Michael S. Kramer, MD

Why should we do research? The word “should”

here indicates that I am being prescriptive, rather than descriptive. (To be perfectly honest, these views do

not even accurately describe my own research; I wish

I had done a better job of following my own

pre-scription.) If you are willing to play a collective

Dante to my Virgil, let me lead you up the five levels

of the Mount Purgatory of medical research, each

representing a goal or reason for doing research

(Fig 1).

The lowest goal for the medical researcher is Level

1, improving one’s curriculum vitae. Unfortunately,

all too many academics appear to be caught in

posi-tions where they are expected to do research in

which they have no interest and which is highly

unlikely to lead to one of the higher levels, and

where the sole aim is to improve their CVs in

prep-aration for promotion or tenure review. In my view,

people who are doing research because they have to

should be doing something else. Nor should

aca-demic departments expect all department members

to be researchers, but that is a topic for another day.

Next on our upward journey is Level 2, where the

goal is to derive personal satisfaction. Although it is

obviously easier to recruit potential clinicians and

others to a demanding activity like research when

that activity is personally satisfying, Level 2 is an

insufficient goal on its own to justify the time, effort,

and money involved. Besides, researchers who reach

one of the higher levels can gain additional

satisfac-tion above and beyond that gained by doing the

research itself.

Further up still is Level 3, increasing knowledge. Many scientists claim this level should be the highest

goal of research. That may be true for mathematics

and theoretical physics, but taxpayers who are

re-sponsible for the large expenditures for medical

re-search expect more than that. It seems logical that

increased knowledge can eventually lead to one of

the higher levels, but to the extent that increasing

knowledge becomes an end in and of itself, the links

From the Departments of Pediatrics and of Epidemiology and Biostatistics, McGill University Faculty of Medicine, Montreal, Quebec, Canada. Received for publication Jun 14, 1993; accepted Apr 28, 1994.

Dr. Kramer is a National Health Research Scientist of the National Health

Research and Development Program, Health Canada.

Based on a presentation in acceptance of the Research Award of the Am-bulatory Pediatric Association on May 5, 1993, in Washington, DC.

Reprint requests to (M.5.K.) 1020 Pine Avenue W, Montreal, Quebec H3A 1A2, Canada.

Acad-emy of Pediatrics.

to higher levels may remain hypothetical and

unre-alized.

A worthier goal for research is Level 4, changing

other researchers’ behavior. Research that improves

the way that other investigators conduct their

re-search may eventually lead to the highest level, and

we can claim at least some indirect credit.

Finally, we arrive at the summit, Level 5, the

Earthly Paradise, which I claim should be the

prin-cipal goal of medical research: to improve health.

Very few of us can point to direct links between our

own research and improved health, but one thing is

sure: if improving health is not our goal, we will

never get there.

After getting our goals straight and deciding why

we want to do research, the next question is what

kind of research should we do? In most discussions I

have heard, this usually comes down to the familiar

dichotomy of basic versus clinical research. At the

risk of appearing obtuse, I must admit having no idea

what people mean when they use the terms “basic”

and “clinical.” For me, these terms are almost as

fuzzy as “prospective” and “retrospective.” For

ex-ample, is clinical research restricted to the study of

intact human subjects, does it include human cells or

other body components, or does it refer to any

re-search that has some connection, however distant,

with human health and disease? As an example of

the fuzziness of this dichotomy, here are just a few of

the titles of articles published in the January 1993

issue of the Journal of Clinical Investigation: “Direct

Evidence for the Absence of Active Sodium

Reab-sorption in Hamster Ascending Thin Limb of Henle’s

Loop”; “Hyperoxic Sheep Pulmonary Microvascular

Endothelial Cells Generate Free Radicals Via

Mito-chondrial Electron Transport”; “Lovastatin Inhibits

Proliferation of Rat Mesangial Cells”; “Soluble

Corn-plex of Complement Increases Hydraulic

Conductiv-ity in Single Microvessels of Rat Lung.” Now, taking

the leap of faith that “clinical investigation” and

“clinical research” mean the same thing, I find very

little in these titles that I can relate to the health and health care of patients. If this is clinical research, then

what I do is not. Does that make me a basic

researcher?

What I particularly dislike about the basic versus

clinical research dichotomy, besides its fuzziness, is

that it carries implications of both quality

(method-ologic rigor) and importance. Research quality can

vary considerably at any “locus” of investigation,

from the molecule to the population. What is the

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

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5Improve Health

4 Change

3 Increase

Fig 1. The Mount Purgatory of medical research.

Useful Not Useful

r---

-Rigorous

a

Not Rigorous

C

b

d

Fig 2. A classification of medical research.

SPECIAL ARTICLE 83

evidence that sloppy epidemiology is any more

prevalent than sloppy molecular genetics?

As to importance, I have often heard reputable

scientists argue the case for so-called basic research

by recounting a number of important serendipitous

discoveries that have been made by basic researchers in medicine or elsewhere in science. Unfortunately,

the number of serendipitous discoveries is a

numer-ator without a denominator. The question isn’t

whether researchers with no higher goal than Level

3, that is, increasing knowledge, ever come up with

important discoveries that eventually change other

researchers’ behavior or even improve health. The

real question is whether research projects that strive

no higher than increasing knowledge are more likely

to lead to improvement in health than those that start

out with health improvement as their primary goal. I

admit there are no data on this question, but I have

difficulty believing that such would be the case.

One statement frequently encountered in journals

and at scientific meetings really makes me see red.

The statement goes something like this: “A

funda-mental understanding of the basic mechanisms

un-denying the pathophysiology of Disease X is

obvi-ously a prerequisite for improvements in treatment

and outcome.” To me, this statement sounds like the

Sermon on the Mount. I am not aware of any

evi-dence that such a fundamental understanding of

ba-sic mechanisms is a requirement for improvements

in health. In fact, many examples contradicting the

statement can be cited in the area of child health.

Epidemiologic studies demonstrating an

ex-tremely strong relationship between exposure to

as-pm and Reye’s syndrome have led to a dramatic

reduction in aspirin use in febrile children and the

consequent virtual disappearance of Reye’s

syn-drome.1’2 Meanwhile, our so-called basic science

col-leagues are still trying to figure out what it is about

aspirin that interacts with the mitochondrion in

pre-sumably genetically predisposed individuals that

causes the metabolic dysfunction leading to Reye’s

syndrome.

Infant mortality has been falling dramatically in

recent decades,3 but most of the fall can probably be

attributed to improvements in high-risk obstetric

and neonatal care stemming from better machinery,

trial and error, observational studies, and a few din-ical trials, rather than a fundamental understanding

of basic mechanisms. Clearly, advances in basic

research have had an important role in the

develop-ment of surfactant therapy,4 and some of the

additional reduction in infant mortality seen in

recent years might indeed be attributable to those

advances.5

Sickle cell disease is another good example. We

have known the molecular defect involved for over a

quarter century, but any reduction in morbidity and

mortality achieved has been the result of screening

programs and the use of prophylactic penicillin6 and

pneumococcal7 and Haemophilus influenzae vaccines8’9

to prevent overwhelming sepsis, that is, so-called

clinical research. Cystic fibrosis represents the other

side of the coin. Life expectancy and quality of life

have improved dramatically over the last 15 to 20

years despite complete ignorance of the genetic

defect until very recently.1#{176}

I do not for a moment wish to impugn the past

accomplishments and future potential of

fundamen-tal, laboratory-based research. One need only

con-template the contribution of virologists and

immu-nologists to the development of childhood vaccines

to appreciate its incalculable importance to child

health. In fact, I believe that much epidemiologic and “clinical” research could be improved by

incorporat-ing physiologic, biochemical, and molecular tools

and by active collaboration with bench scientists.

But, as discussed earlier, bench research is no

guar-antee of quality (rigor), and, as illustrated by the

above examples, it is often neither necessary nor

sufficient for improving health.

Well, if the basic versus clinical research

dichot-omy is not a helpful one, how can we classify

differ-ent types of medical research? I believe there are two,

and only two, helpful dichotomies: whether or not

research is potentially useful, again in the sense of

improving health, and whether or not it is

method-ologically rigorous. In my view, the best way of

ensuring that a research project will yield useful

results is to start at the end, that is at Level 5, by

deciding what aspect of health the researcher wishes

to improve and then choosing the project most likely

to achieve that goal. Inevitably, that means thinking hard about how the results of one’s research will lead to changes in clinical or public health decisions that

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84 MEDICAL RESEARCH: A PRESCRIPTIVE VIEW

can have a direct impact on health. The second

di-chotorny is whether or not the research is

method-ologically rigorous. The design and analysis of the

research should minimize systematic and random

error in the estimation of effects. It is probably no

mere chance occurrence that all four winners of the

Ambulatory Pediatric Association Research Award

to date have had formal training in epidemiology.

Assuming that only about 10% of the APA

member-ship has such training and that the Award recipients

were independently chosen, the P value associated

with four successive epidemiologist winners is about

10.

Based on these two dichotomies, one can come up

with a far more meaningful classification of medical

research than the usual one of basic versus clinical.

Figure 2 shows a 2-by-2 table, the columns of which

denote research that is either potentially useful or not

useful. The rows denote research that is either

rigor-ous or not rigorous. The 2-by-2 table contains the

familiar four cells: a, b, c, and d. Research in cell a is

both useful and rigorous, and therefore should be

designed, funded, published, and acted upon. Such

research can thrive at any “locus”: molecular,

cellu-lar, intact animal or human, or population. In cell b,

the research is rigorous but not very useful. An

ex-ample might be finding the 17th mutation of codon X

for some rare genetic disease or, perhaps somewhat

closer to home, investigating whether parents’

satis-faction with care decreases with increased waiting

time in the emergency room, with multiple linear

regression analysis used to control for potential

con-founding variables. Rigor in the service of trivial

questions is rigor mortis. Such research is a waste. It is a waste of talent, but this kind of waste is recyclable;

we can try to convince researchers to devote their

talents to more useful endeavors.

Cell c represents unrigorous methods applied to

potentially useful research questions. An example

might be yet another observational study of the

re-lationship between the number of prenatal care visits

and pregnancy outcome, instead of a much-needed

randomized trial in women at high risk for

made-quate care. Such research represents another kind of

waste: a waste of opportunity. The question is

im-portant, but the methods used will not answer it.

Theoretically, this kind of waste is also recyclable,

because researchers with sounder methodologies

could be encouraged to devote themselves to these

questions, or alternatively, researchers already

inter-ested in the questions could be encouraged to obtain

the additional training required to use more rigorous

methods.

Finally, cell d is the worst of both worlds:

unrig-orous methods applied to unuseful questions. This

type of research is a total waste of time, effort, and money, and the waste is probably unrecyclable.

Enough of my opinions. I certainly don’t delude

myself that my arguments are likely to change the

reasons why researchers do research, nor are they are

likely to change its focus or quality. In fact, I am not

even sure I will be successful in following my own

prescription. But I do aim to try, and I hope many

others will as well. Changing the world is an

exciting, if elusive, goal.

To be sure, medical research does have a “down

side.” I remember when I was in clinical training and

was attracted to research as a way of avoiding, to

some degree, the long, grueling hours of clinical

work and the inescapable telephone and bellboy. I

don’t know whether times have changed, or I am just

seeing the world from a different perspective, but I

now envy my clinical colleagues who can go home at

the end of the day and don’t have to spend most of

their evenings and weekends reviewing grant

appli-cations and manuscripts, correcting 11th versions of

students’ theses, and spending “quality time” with

their home PC. The fact that the long hours are

largely self-inflicted dulls the pain only slightly.

Learning to say “no” is a finely honed skill, and I

hope that some future APA Research Award winner

will enlighten us how to develop that skill.

But all in all, we researchers aren’t too badly off.

Let me close by quoting Shakespeare’s Henry the

Fifth, who, feeling at least equally overcommitted before the battle of Agincourt, referred to his troops

as “We few, we happy few, we band of brothers.”

We happy band of brothers and sisters in medical

research are actually quite a lucky lot, and today, at

least, you have made me feel like the luckiest of all.

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2. Arrowsmith JB, Kennedy DL, Kuntsky JN, Faich GA. National patterns of aspirin use and Reye Syndrone reporting, United States, 1980 to 1985.

Pediatrics. 1987;79:858-863

3. Kleinman JC. The slowdown in the infant mortality decline. Paediatr

Perinat Epidemiol. 1990;4:373-381

4. Jobe AH. Pulmonary surfactant therapy. N EnglJMed. 1993;328:861-868

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6. Gaston MM, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl IMed.

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1995;95;82

Pediatrics

Michael S. Kramer