Nutrition Research Methodology 319either an exposed or a nonexposed group, commonly
referred to as the treatment and the placebo group.
The placebo is a substance that is indistinguishable
from the treatment and enables both subjects and
investigators to be blinded to the treatment. Changes
in indicators of health or disease status are compared
between the two groups at the end of the experiment
to identify the effect of the exposure.
Crossover designs in epidemiology operate on the
same principles as the repeated-measures designs
common to basic science research. All study subjects
receive the treatment and the placebo for equal
periods, with a washout period in between, and the
order of treatment or placebo administration is
selected at random for each study subject. Crossover
designs are appropriate only for studies of treatments
that have no lasting effects, a feature that limits their
utility in nutritional epidemiology.
In general, experimental epidemiological study
designs are well suited to the identifi cation of causal
relationships between specifi c exposures and indica-
tors of health or disease status. Application of these
methods is limited, however, by the diffi culty in con-
trolling exposures and by the enormous expense
associated with population-based intervention trials
aimed at modifying risk or chronic diseases. It is
perhaps more feasible to apply experimental study
designs to contrast the effects of pharmacological
doses of specifi c nutrients or food components the
exposures of which can be more easily controlled.
This approach has been increasingly selected from the
1990s to assess the effects of specifi c micronutrients
(β-carotene, α-tocopherol, folic acid, and other
minerals and vitamins) using large-scale randomized
trials.
When only one micronutrient is compared with a
placebo, the study is called a single trial, whereas mul-
tiple or factorial trials involve designs where several
micronutrients are compared with a placebo. In a
2 × 2 factorial design, two treatments are evaluated
simultaneously by forming four groups (treatment A,
treatment B, both treatments, and placebo).
Experimental studies keep the highest internal
validity among epidemiological designs. However,
they may lack generalization (i.e., they may have low
external validity) and their applicability to free-living
populations may be poor insofar as the dietary intake
patterns do not correspond to isolated nutrients but
to the combination of more complex food items.
Moreover, the induction time needed to appraise the
effect of a postulated cause may last longer than the
observation period of a randomized trial, thus pre-
cluding the ability of the trial to ascertain the causal
relationship.
Quasi-experimental studies are those in which
the assignment of exposure is controlled by the
investigator, but subjects are not randomly allocated.
They are sometimes called intervention trials (Figure
13.2).
Some randomized trials are referred to as primary
prevention trials and others as secondary prevention
trials. Primary prevention trials are those conducted
among healthy individuals with the aim of preventing
the onset of disease. For example, in the Women’s
Health Initiative (Howard et al., 2006) more than
48 000 healthy postmenopausal women were ran-
domly assigned to receive either a low-fat diet or
placebo to prevent the onset of cardiovascular disease
(CVD). All participants were free of this disease at
the start of the study and they were followed up for
several years to assess the incidence of fatal and non-
fatal coronary heart disease, fatal and nonfatal stroke,
and CVD (composite of both). This is an example of
a primary prevention trial. Primary prevention trials
are also called fi eld trials.
Secondary prevention trials are conducted among
patients who already suffer from a particular disease
and they are randomly assigned to treatment or
placebo groups to prevent adverse outcomes. For
example, to study the benefi ts of a Mediterranean-
style diet, in the Lyon Diet Heart Study, patients were
randomized to two different dietary patterns after
suffering a myocardial infarction (de Lorgeril et al.,
1999). The outcome was not the onset of disease but
the incidence of reinfarction or cardiac death during
the follow-up period.Nonexperimental (observational)
epidemiological studies
When experiments are not feasible or are unethical,
other nonexperimental designs are used. In nonex-
perimental (observational) studies the investigator
has no control over the exposure, because the
participants freely assign themselves or not to the
exposure. In nonexperimental studies the investigator
may take advantage of “natural experiments,” where
exposure only appears in some defi ned groups. An
example of this would be an “experiment” where