Published by Oxford University Press on behalf of the International Epidemiological Association

The Author 2008; all rights reserved. Advance Access publication 17 December 2008

International Journal of Epidemiology 2009;38:393402

doi:10.1093/ije/dyn268

POINT-COUNTERPOINT

The triumph of the null hypothesis:

epidemiology in an age of change
Wasim Maziak

Accepted

8 May 2008

Summary

The recent confusion concerning the relation between hormone

replacement therapy and cardiovascular disease has stirred a new
wave of debate about the value and future of epidemiology.
Opponents of epidemiology suggest an ever-diminishing role in an
age of small risks and complex diseases, yet proponents are not in
consensus about how to adapt their discipline to the challenges
associated with ageing societies and changing disease patterns. While
epidemiology is likely to be increasingly called upon to make sense of
the risks involved with these changes, wading into this era with a
mindset and tools that were derived from epidemiologys golden era
of tackling major risk factors, has created more confusion than
understanding. Increasingly, we need to downsize epidemiology to
what is testable, measurable, and relevant, based on robust
methodology and public health rationale. Applying an evolutionary
perspective, that views health problems of modernity as a manifestation of the mismatch between our ancient genes and hi-tech
lifestyles, can provide guidance for a 21st century research agenda.

Keywords

Epidemiology, chronic disease, small risk, complex disease, evolutionary epidemiology

Introduction
The recent uncertainty surrounding the relation
between hormone replacement therapy and cardiovascular disease (HRT-CVD) has again ignited the
debate about the value and future of epidemiology.1,2
The issue this time is more serious than the optimal
amount of fruits and vegetables we need to eat daily,
as it involves the devastating irony that millions of
healthy women have been encouraged to take a
medication that may put them at risk of the same
ailment they were trying to ward off.3 Underlying this
dilemma is a credibility crisis brought about by
inconsistencies in the results of various epidemiological studies.46 Increasingly, voices within and
outside the discipline of epidemiology are calling for
University of Memphis, School of Public Health, Memphis, TN
38152, USA.
Corresponding author. University of Memphis, 633 Normal
Street, Memphis, TN 38152, USA.
E-mail: wmaziak@memphis.edu

a total re-evaluation of its tools and paradigms, some

going as far as to suggesting abandoning the field
entirely.1,711 One can argue whether epidemiology
is to blame for this state of affairs by adopting the
results of cohort studies to formulate treatment
guidelines,12 or has been the voice of reason via
arguing caution about the protective relation
between HRT-CVD,1315 or is an innocent bystander
or even pawn at the hands of mass media and corporate interests that manipulate public opinion about
medical treatments.1 Regardless, the unavoidable
issue is the legitimate concern about the role of epidemiology in an era of small effect, lifestyle-related
risks of chronic diseases. This concern has in recent
years stirred calls for major methodological and
conceptual reevaluation of observational studies
(e.g. case control and cohort),1,5,811 as their propensity for subtle forms of bias and confounding can
influence their value for the study of small risks of
chronic disease. Yet a more suitable starting point
would be to restore some of the fundamentals of
epidemiological practice based on strong theoretical

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guidance, proper assessment tools and clear public

health rationale. As these elements are usually within
researchers control, addressing them in the context of
new directions to improve the prospects of chronic
disease epidemiology is warranted.

A historical snapshot
For some time now, epidemiologists have been debating the future ability of their discipline to accommodate
emerging disease patterns resulting from the ageing
and lifestyle changes of modern societies.79,1622
Mervyn and Ezra Susser identified three main historical
stages of epidemiology reflecting the main health
threats of the times and the level of knowledge about
them. Starting from the sanitary era with its Miasma
paradigm, to the infectious disease era accompanying
the germ theory, to our chronic disease/risk factors era
with its so called black box paradigm, to quote Petr
Skrabaneks famous metaphor.7,23 Perhaps, it is black
box epidemiology, referring to the pursuit of exposureoutcome relations without much attention to biological
understanding or inference, that has been most
problematic.2224 The willingness of epidemiologists to
run ahead of biology to influence the societal burden of
disease is a longstanding tradition of the discipline with
some impressive successes.25,26 But while mechanistic
associations can lead to hypothesis formulation in the
area of major risk factors,26 they are unlikely to be as
successful with small risks, given the complexity of the
causal grid. This inadequacy has paved the way for a
new phase in epidemiology,9,27,28 called ecoepidemiology by the Sussers.27 The concept of ecoepidemiology is
based on a multilevel paradigm called the Chinese
boxes to reinforce the importance of distal (societal),
individual and microbiological interactions in disease
development.27 The ecoepidemiology concept also is an
attempt to reclaim the public health edge of epidemiology, thought by many to have been lost amidst an
overemphasis on individual-level risk factors.1821,29

Risk factor epidemiology and the

importance of guiding hypotheses
Observational studies have been instrumental for the
identification of major risk factors to health (e.g.
smoking, hypertension, hypercholesterolemia, malnutrition). Yet the HRT-CVD debate has drawn attention
to the potentially high price of making unwarranted
claims about small and interconnected associations.
Epidemiologys doubters argue that the success stories
of epidemiology were all easy hits; the magnitude of
the association between cigarette smoking and lung
cancer was so large that it could be reliably observed
even with flawed study designs.30 However, when we
move to the realm of complex diseases and smaller
effect sizes, bias and confounding start to creep into
cohort and case control studies in a variety of

unpredictable ways leading to their derailment in

any direction.8,22,30,31 But, if we could establish major
risk factors with crude tools, why cannot we be able
to assess small risks with better ones?
So far, the uncertainty about epidemiological evidence has led to the here-today-gone-tomorrow
nature of medical wisdom,30 and perhaps the confusion we ourselves have about how to lead a healthy
lifestyle.3032 Notwithstanding our position on the
ever-changing nature of scientific knowledge and the
processes involved, epidemiology has been hurt most
by ill conceived and conducted studies with rushed
conclusions. As we witnessed, an excess of such
studies, combined with vested interests in certain
results and media hunger for the newsworthy, has
become a formula for trouble.
Epidemiologists have always been vigilant about the
danger of claiming associations that do not exist in
reality by adopting the null/alternative hypothesis
approach, which emphasizes lower tolerance for such
error (i.e. type I error) than for missing a real link
(i.e. type II error).33 It is an approach similar to the
judicial system, which considers convicting an innocent
a greater mistake than letting a criminal go free. This
approach emphasizes as well the need for research to be
driven at the outset by a sound and fully articulated
hypothesis. The wisdom of this safeguard seems to
be lost on many researchers nowadays, who like to
formulate and interpret their studies by what comes out
of the logistic regression grinder. Given researchers
ingeniousness in explaining exotic associations, and the
ever-expanding volume of knowledge, it is not hard to
find biological explanations for contradictory findings.
For example, studies showing positive associations
between exposure to pets and childhood asthma
attribute this association to animal allergens (compatible with the allergy paradigm), while studies showing
negative associations attribute it to pet-related microbial products (compatible with the hygiene paradigm).34,35 There are ample examples of tailor-made
post hoc hypotheses, transforming epidemiology from a
rational to a ridiculous endeavour, and highlighting the
growing importance of epidemiological studies being
guided by well-grounded a priori hypotheses.

The asthma epidemic and the

importance of measurement
In the current age of small risk factors, the need for
epidemiology to be grounded in strong inference is
matched only by the need for sensitive tools to assess
exposures and outcomes. As an example, childhood
asthma is a recent global epidemic, whose secular
and spatial patterns favour environmental causes.36,37
Yet more than two decades of intensive research has
yet to yield a single target for intervention.8,38 To get
out of this deadlock, researchers have been calling for
large prospective studies, studies starting as early in

THE NULL HYPOTHESIS AND FUTURE OF EPIDEMIOLOGY

life as possible and to differentiate between different

asthma phenotypes.3941 Others have argued, invoking
Geoffrey Roses seminal work,42 that the etiological
factors involved in the asthma epidemic are likely to
be homogenously distributed within populations,
indicating the need for international comparisons.43
These attempts to shore up asthma research reflect
sound epidemiological reasoning, but have yet to
advance our understanding of the etiology of the
asthma epidemic, despite a big price tag.4446
So, is this impasse in asthma research due to an
inadequate conceptual framework or faulty study
designs and tools of epidemiology? Research into the
asthma epidemic was guided for the most part by the
hygiene hypothesis, which relied on early observations
of the protective effect of sibship size and birth order
to suggest that the asthma epidemic could be the side
effect of our increased hygiene and success in curbing
infectious diseases.47 Biological underpinnings of the
hygiene hypothesis were soon provided based on
the preferential development of immune-allergic
responses in the absence of infectious stimuli.48,49
Certainly, the hygiene hypothesis provided a timely
model for an environmentally driven epidemic incorporating changes in our lifestyles with a good dose of
evolutionary wisdom. While evidence for and against
the hygiene model are accumulating, it has become
apparent that it is an over-simplification of a more
complex picture.45,5052
Part of the reason why we still do not have a verdict
on the hygiene hypothesis despite countless studies,
lies in the uncertainty surrounding the measurement
tools we are applying in asthma research. For the most
part, this research relied on self-reported or parentalreported questionnaires to assess asthma symptoms
and exposures. As a result, asthma was transformed
gradually into wheeze, as the symptom and the
disease became synonymous in epidemiological
studies. Even in English, this substitution results in
crude assessment of a disease that has several
phenotypic and age-related manifestations53 but in
other languages, translations of wheeze can relate
poorly to asthma.54,55 Video questionnaires or objective
markers (e.g. bronchial hyperresponsiveness, BHR)
also have been used for outcome assessment, but none
has come close to being a gold standard for the
assessment of asthma in epidemiological studies.5664
Exposure assessment in asthma studies has not fared
better, as questionnaires again have been the main tool
to assess exposure to infection, animals and their
products, air pollutants, certain foods and medicines,
and secondhand smoke.65,66 For example, exposure to
air pollution in the International Study of Asthma and
Allergies in Children (ISAAC) was assessed based on
questions asking about (i) the frequency of trucks
passing on the residential street on weekdays; and
(ii) the severity of traffic noise that forced participants
to close the window.67 One cannot expect such
assessment to provide credible information about this

395

exposure, let alone study its relative contribution

among a variety of other exposures measured
with similarly crude instruments. In cases where
more objective markers of exposure were sought
(e.g. endotoxin, antibodies, skin tests) they were
either non-specific/sensitive, were poor markers of
chronic exposure relevant to the development of
asthma, or were perhaps offset by the crude measurement of the outcome.6873 The resultant confusion was
even greater than researchers ingenuity to explain it,
to the extent that it is not uncommon to see asthma
studies conclude that factor X was associated with past
year wheeze, but not ever-wheeze or asthma diagnosis,
or with sensitization but not asthma symptoms or
BHR, or for that matter any combination of a myriad
of outcomes that arguably represent the same clinical
entity.7486 Such inconsistencies have yet to invoke a
major re-examination of research paradigms and tools
used to study asthma, perhaps signifying black box
epidemiology at its darkest hour.

From static to dynamic and

relevant epidemiology
The transformation needed in small risk epidemiology involves not only applying better guiding models
and sensitive markers, but perhaps as importantly, a
departure from a static perception of the relation
between exposure and disease, reflecting the era of
questionnaires and categorical variables, to a more
dynamic, context-relevant and life-course approach.87,88 As such, snapshot exposure assessment
should be replaced with modelling of exposures based
on information from a variety of sources/levels (GIS,
mobility patterns, biosensors), the use of sensitive
markers of long-term exposure (e.g. hair/nail nicotine
for exposure to ETS, or glycosolated haemoglobin for
control of blood sugar), and the incorporation of macrolevel attributes (e.g. area level characteristics).8994 This
can potentially sharpen our ability to approximate the
dynamic nature of our interaction with our everchanging environments. Similar transformation is
needed in our perception of risk to reflect its dynamic
nature across peoples life roles, past experiences and
current behaviors and contexts. For example, many of
us will fall under some risk category for several chronic
diseases only by virtue of our age, which may lead us to
seek controversial treatments that can be themselves
risky (e.g. vitamin/mineral supplements).9597
This inner conceptual dynamism should be supplemented with an outer public health orientation.
Without that, epidemiology may dwell in the realm
of the ideal rather than deal with the constraints of
reality. For example, even if efficacy trials confirm the
benefits of a school-based programme or five portions/
day of fruits in obesity prevention, this can be useless
if such results are not translatable into society-wide
sustainable interventions.98 Another form of this
reductionist approach is for epidemiological studies

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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

to statistically control for socioeconomic deprivation,

zooming in on more proximal behavioral determinants, while relegating an apparently major determinant of chronic disease risk to the status of a
nuisance variable.20 Both approaches shift focus from
the society to the sufferers,17,20 who are arguably
blamed for failing to follow the health recommendations we have imparted to them for years, and, in the
process, stripping epidemiology of its public health
essence. This is not to say that public health cannot be
advanced by purely medical interventions (e.g. vaccination), or that we need to structure peoples lives
around some health ideals, but to desensitize epidemiology to a major determinant of chronic disease,
such as socioeconomic deprivation has perhaps
contributed to the widening of health inequalities,
particularly in the USA.99 Classifications such as
social epidemiology, clinical epidemiology, infectious
disease or cardiovascular epidemiology, may have
facilitated this selectiveness in how we treat different
variables, by creating a false perception of compartmentalization of different disease processes within
individuals and populations.
The opposite can be true as well, as some studies
of distal-level determinants lack clear public
health orientation. For example, what are the public
health implications of demonstrating that low
neighbourhood-level educational attainment is detrimental to cognitive functions of elderly residents,100
as one can argue that intervening on older residents
to improve their cognitive ability is more practical
than increasing the average education level of whole
geographic areas. Finally, many relations sought by
epidemiologists are fly-by-night endeavours embodying no foreseeable public health rationale or follow-up
plan, an example of which is the finding of a positive
association between husbands participation in housework and wives psychosocial health.101 One can
argue that such a study proves the obvious, can
neither be free of residual confounding (husbands
who help with housework are likely to be a different
breed from those who do not), nor has a clear public
health message (who should use this information and
how?). For epidemiology to stay relevant, associations
must not only be driven by statistical empiricism, but
must have a clear public health rationale.

Epidemiology in the age of

complex lifestyle-related diseases
It has been hard for epidemiologists to adapt to
changing patterns of diseases and their risks in
modern societies, partly because of the pace of such
changes. New epidemics, such as obesity, asthma and
depressive disorders are evolving rapidly and creating
pressure for evidence-based solutions. In response,
inspired by past successes with major risk factors,
epidemiologists rushed to the scene with their usual
tools. As it turned out, the task this time was more

difficult, casting some serious doubt on epidemiologys ability to respond to current and future threats
to health.8,9,30 While only time can tell the fate of
epidemiology, one major lesson to be learned from the
HRT-CVD story is that observational epidemiology
can never be free of residual confounding when
comparisons involve health-oriented behaviours.102,103
Yet, observational studies can be valuable for the
study of long-term side effects of drug treatments, as
these are mostly unintended and unpredictable,
therefore are not confounded by indication; meaning
that they are usually not associated with the treatment decision.104106 A similar valid scenario for
observational epidemiology is the study of potential
risk/protective factors that are unknown to the public,
as this reduces the probability of associative-selection
bias based on differential health awareness between
the comparison groups.107
In reality, as we continue to monitor the health of
populations, epidemiology will likely be called upon
increasingly to make sense of the risks involved in the
dramatic changes in our lifestyles and environments.
But to continue doing epidemiological studies using
the same tried and failed approaches is not an option;
the asthma example is a clear indicator of how
epidemiology can turn into an absurd exercise when
aims are put ahead of tools and concepts. Realizing
the current crisis of credibility, epidemiologists have
responded by calling for larger and longer studies,
coupling of epidemiology with molecular genetics
(e.g. genetic epidemiology and biobanks), strong
inference, incorporating multilevel attributes and for
greater attention to residual confounding.8,108114
They have also mobilized to improve the reporting
of observational studies (STROBE guidelines) to allow
editors, reviewers and consumers of epidemiological
data to make informed judgement on the quality of
reported studies.115 All these approaches can potentially improve epidemiologys ability to zoom in on
small risks, yet the defining feature of the small risk/
chronic disease era has so far been the triumph of the
null hypothesis (i.e. no effect).8,9,116
Such responses reflect healthy self-criticism on the
part of epidemiologists, but a clearer articulation of
priorities is needed in the face of mounting criticism.
Bigger samples and longer studies, for example, can
lead to the magnification of errors, loss to follow up,
and increase in costs, while applying multilevel
approaches without a sound theoretical framework
runs the risk of becoming another form of black box
epidemiology.117 Genetic epidemiology on the other
hand, is not free of the problems of observational
epidemiology,8 yet recent years have witnessed
some promising advances in this field, especially the
application of Mendelian randomization to control
for environmental confounders in observational
studies.118 Mendelian randomization utilizes the
random distribution of genetic alleles at the time of
gamete formation to identify genetic variants that

THE NULL HYPOTHESIS AND FUTURE OF EPIDEMIOLOGY

robustly predict environmentally modifiable exposures

and uses them as un-confounded proxies (instruments) for those exposures. While the promise of this
approach is still unfolding,119 there are currently not
many conditions that can be studied this way, i.e. in
which we have a clear understanding of the genetic
basis of suspected etiological exposures.
As epidemiologists relish the promise of ecoepidemiology,28,111 this concept can come with its own
caveats. Namely, a comprehensive hypothesis based
on this approach can involve many-to-many factors
to account for,8,120 as the range and possibilities
of geneenvironment interactions and pathways
involved in chronic disease form a vast causal
universe. As such, a vision that lies between black
box and Chinese boxes may be needed, whereby
certain causal pathways can be identified and worked
upon without the need to unravel the whole complexity of the relation between exposures, genes, and
chronic diseases. For example, if we can establish an
effective way to influence obesity in the society (e.g.
through policy that rewards/supports active transportation), we can potentially influence a good deal of
CVD, and perhaps a variety of other illnesses, without
needing to have all the information about the factors
and mechanisms involved. Ecological models of major
health risks are emerging, which can harness candidate pathways for study and intervention (Figure 1).
In parallel, methodological paradigms and analytical
tools are being developed to accommodate this new
direction (e.g. complexity theory, multilevel modelling, pathway analysis).98,115,121124 For example, the
use of multilevel analysis for the study of obesity and
CVD risk has helped to shift the focus from personal
behaviours to encompass wider environmental influences (e.g. neighbourhood adversities) that may
be more amenable to sustainable interventions
through policy.125129 The widening of health inequalities in the US, driven mainly by non-linear socioeconomic and political dynamics,99 underscores the
importance of these new trends in epidemiology.
Influences

An evolutionary perspective
for epidemiology
Given the methodological constraints imposed on
epidemiological research by the complex nature of
problems we are increasingly facing, epidemiology can
benefit from some guidance as to what risk factors
represent good targets for exploration, and how to
interpret inconsistent epidemiological data. An evolutionary perspective can help provide a guiding framework for the epidemiology of chronic diseases, being
viewed as a result of the immense adaptive pressures
brought about by the mismatch between our genes still
lingering at the hunter-gatherer era and our hi-tech
lifestyles.130 Accordingly, exposures relevant to our
health are those that either underwent a rapid change
within a short time, or represent an obvious diversion
from the environments that prevailed during most of
our evolution. In this sense, our eating, mobility,
recreation, socialization and communication patterns,
as well as our increasingly indoor existence should be
relevant to the development of chronic diseases such
as obesity, asthma, CVD and depression.131
As broad as this perspective can be, its application
can help to sift through the tides of confusing health
information we are bombarded with each day. For
example, examining the HRT-CVD relation under the
evolutionary lens would have raised a big red flag
about a potential for harm; women did not evolve to
have lifelong active ovaries, despite the clear reproductive advantage such a trait would have conferred.
The same would apply to the long-held protective
relation between low fat diet and CVD risk132136,
which was recently refuted in a randomized clinical
trial.137 As huntergatherers, humans until 500 generations ago consumed mainly wild and unprocessed
food foraged and hunted from their environment and
rich in fats, fibre, vitamins and minerals.138140 So,
the low-fat mania perhaps does not tell the whole
story about the dietCVD risk relation, especially
when corporate voices join the choir by promoting

Mediators

Behaviours

Outcomes

Area
Walkability, safety (crime-traffic), social
networks, deprivation, access to fast food or
quality foods, recreational facilities

- Increased time-indoors
- Increased access to food
- Decreased opportunity of PA
- Increased TV/screen time
- Increased exposure to food
advertisement

Increased sedentary
pastime; TV/PC/games

Over consumption of
junk food-soft drinks
Decreased
unstructured PA

Society
Food policies and regulations, urban
planning, energy policies

Figure 1 Simplified multilevel approach to the study of environmental influences on obesity98

Energy imbalance/at risk of

obesity/obesity

Indi vidual-Family
Structure (parenthood, siblings, pets), SES,
perceptions/attitudes (safety, healthy
nutrition & behaviour), time structure
School
Food/PA policy, PA equipment, food sales
and sponsorships

397

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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

low-fat options, potentially creating a complacency

that can even lead to increased consumption.98
Another benefit of the evolutionary perspective is to
help understand the difficulties facing genetic epidemiology, based on the fact that the direction of
evolution of traits is from phenotype to genotype and
not the opposite.141 This can underlie the existence of
multiple genetic pathways to each outcome complicating the genetic study of chronic diseases. To add
another layer of complexity is the fact that phenotype
fitness is not a simple measure, but represents a
complex fitness landscape involving the trade-off of
numerous traits, each of which is the result of even
greater genetic diversity.142 For complex traits therefore, considerable genetic variance can be maintained
within the population even in the face of strong
selection forces.143 Such complexity undermines the
hopes that genetic epidemiology will provide ready
answers to the puzzles of chronic diseases.
Finally, an evolutionary perspective can guide
intervention research. Specifically, rather than basing
nutritional and physical activity recommendations on
observational data that may well reflect a systematic
difference in the way we assemble our comparison
groups (e.g. those who eat healthy are likely to be
engaged in other less-measurable health behaviours),
we may need to inform such recommendations with
knowledge of our ancestral dietary and activity
patterns.144,145 In addition, the appreciation that we
have a genetically hard-wired taste for energy-dense
food can help us understand why most dietary-based
obesity interventions fail in the long run.98 So instead
of trying to work more forcefully against our instincts
by increasing the intensity and length of interventions, we may be better off trying to manipulate food
taste and energy content,146 to imitate the Paleolithic
diet but without the excess calories.

Concluding remarks
Apparently, the golden era of major risk factor epidemiology is giving way to a less glorious, but certainly more
complex and perhaps more important one of studying
small and interconnected risk factors related to our
ever-changing lifestyles and environments. We perhaps
have just scratched the surface of what epidemiology
can achieve and how it can help us understand how
unfavourable environments are shaping our behaviour
and health. Wading into this era with a major risk
factor mentality and instruments has created confusion. While endorsing new developments in epidemiological research, the era of chronic disease epidemiology
mandates more than ever the need to rely on sound
theoretical models as well as accurately measurable
outcomes and exposures. So in contrast to the calls for
larger, longer and wider-reach epidemiology, what is
advocated here is to downsize epidemiological research
to what is testable, measurable and relevant. An
evolutionary perspective of the dynamic interaction of
humans with their environments can help guide such a
research agenda. In the age of publish or perish, vested
interests, publication bias, scarce funding, medias
hunger for hit news and web publishing, epidemiology
can best navigate these rough waters by being anchored
in a clear sense of its inner methodological constraints
and outer public health thrust.

Funding
NIDA (R01DA024876-01 to W.M.).

Acknowledgements
Wasim Maziak thankfully acknowledges Dr Kenneth
Ward for critically reading and editing this article.
Conflict of interest: None declared.

KEY MESSAGES
 There is a crisis of credibility facing epidemiology today, brought about by the barrage of studies with
less than optimal methods and conflicting results.
 As epidemiology enters the era of chronic disease and small risk, it becomes more critical for
epidemiological studies to be guided at the inception by well-grounded hypotheses, a dynamic
perception of the relation between exposure-outcome and to utilize accurate assessment tools.
 Novelty or methodological precision should not substitute for public health relevance when evaluating
epidemiological studies.
 New conceptual (e.g. multilevel ecoepidemiology) and methodological (e.g. Mendelian randomization)
advances should be embraced in light of the need to downsize epidemiology to what is testable,
measurable and relevant.
 An evolutionary and dynamic understanding of our interactions with our changing environments can
provide a guiding context for epidemiological research.

THE NULL HYPOTHESIS AND FUTURE OF EPIDEMIOLOGY

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