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Clinical Epidemiology
Designing a Prognostic Study
Prognostic research aims to address complex, multivariable problems, which generally require a large
amount of information to be gathered in order to obtain meaningful results. The general recipe for
prognostic research involves first identifying the kinds of prognostic information you are interested in
gathering, and then setting up a study to collect this information in a large group of people. The aim of
this is to arrive at practical guidance or even a kind of decision tool, often a rule or scoring system, that
clinicians can apply to their patients in order to help in the process of prognostication. While there are
many similarities between prognostic and diagnostic research, both being of a descriptive nature, there
are fundamental differences, and as a result, the way in which you design and conduct a prognostic
study should take this into account.

As with other clinical epidemiologic studies, it is vital that you first carefully consider how you will
translate your clinical problem into a researchable question. Prognostic problems arise when clinicians
have difficulties in accurately predicting the course of their patients’ health. So as researchers, we would
like to know what information we can use to come up with the most accurate predictions as possible. So
a general research question could be “Which characteristics about my patient and their disease can help
me predict their health status over a certain time period?”.

Let us think back to our patient with lymphoma. In this scenario, we wanted to know the probability that
she would survive the next five years. An appropriate research question might be “Which combination
of characteristics (formally known as prognostic factors, or predictors) of lymphoma patients best
predict their response to treatment and 5-year survival?”.

Alternatively, an increasingly popular branche of research involves looking at whether individual new
predictors, such as biomarkers or some other new kind of measurement, can improve prediction
accuracy when added to an already existing prediction rule. This kind of research, known as added value
research, can be conducted in a similar way to the development research mentioned just now, but
brings different analytical challenges.

So now that we have defined our research question, we need to decide which information we have to
collect, the group of people who we want to collect this from, and how we will go about actually
acquiring the information.

First let us talk about the research domain. Unlike diagnostic research which focuses on patients
suspected of a certain disease or health status, in prognostic research, we already know the current
health status of our patient. For our lymphoma research, the domain we are interested in is restricted to
patients who have been diagnosed with lymphoma cancer, possibly even just those patients just
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diagnosed. For some kinds of research the domain could be much broader. Consider a situation where
you are interested in predicting the 10-year risk of insulin dependent diabetes development in children.
Here the domain can be extended to all children, with the exception of those who have already have
diabetes. It is essential in prognostic research that we focus on studying patients who are currently at
risk of developing the outcome and for which the prognosis is clinically relevant.

So what kind of outcome are we interested in? As prognosis is intrinsically linked to the passage of time,
our outcome of research is usually associated with some kind of time period. For our example, we are
interested not just in mortality, but mortality within 5 years of diagnosis.

Careful thought must be put into selecting the prognostic factors that we are interested in studying.
Ideally, the aim is to collect as much useful information on as many relevant predictors as possible,
providing they are likely to be truly useful in making predictions. This usually includes general patient
information, such as age, sex, health factors and treatments, but may include lifestyle factors, test
results, imaging and biomarkers. The predictors that you choose to study should be decided on before
collecting any data, and your choices should be based on evidence from literature or the opinions of
experts within the field.

It is worth noting that because this is descriptive research, as with diagnostic research confounding is
not an issue. There is no single key factor that we focus on studying, and instead we want to utilize
information from several different factors in order to try to describe the occurrence of the outcome.

So how should we go about collecting all the information that need? A cross-sectional design, like that
commonly used in diagnostic research will not suffice because we need to observe how a patient’s
health changes over time. Really, we need to recruit our patients, measure all of the characteristics we
are interested in, and then see which of our patients develop the outcome we are interested in over a
certain time period. In this, different groups of patients may experience different routes.

Why not choose an experimental approach, such as a randomized trial, to gather the information we
need in a controlled manner? Yet, trials are costly, and randomization is only really necessary when you
are interested in addressing causal research questions. Trials are generally not the most appropriate
kind of study for prognostic problems, but they might be useful in the situation where you want to
assess the impact that the clinical use of a prognostic score has on health outcomes in practice.

For most situations, a prospective cohort study, that is, a longitudinal study that follows patients in an
observational manner over time, is the best choice. As it would be an for our lymphoma research
question. First, we could recruit a large number of newly diagnosed lymphoma patients over a period of
time and then gather all of the predictor information we are interested in immediately after
recruitment. We would then follow those patients for five years, or until they die or leave the study for
other reasons. You can see from this example that prognostic research can be laborious, and potentially
takes a very long time to conduct although sometimes data are available to do the study retrospectively.
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On a final note, before you begin your study, you will need to know how many participants to recruit. A
study with only 50 participants might be affordable, but will it provide you with valuable results? In
general, the more prognostic predictors that you wish to study and potentially include in your analyses,
the more participants and in turn outcome events you will need. As with diagnostic research, there are
no clear-cut ways to derive the necessary sample size, but it has been recommended that enough
participants should be studied to ensure that 100 or more outcome events occur during the study, but
again, this really depends on the number of predictors you are interested in.

Now that we have designed our study, it is time to begin enrollment, taking measurements of our
patient characteristics of interest at baseline. Then it is a matter of carefully following up our patients
over the study period.