Evidence forms the basis of modern medicine. Clinical research provides us with this evidence, guiding health professionals towards solutions to problems that they face in daily practice. Transferring existing problems in medical practice to a research setting is a challenging process that requires careful consideration. The practice of clinical epidemiology aims to address this through the application of established approaches for research in human populations, while at all times focussing on the problem at hand from a clinical perspective. This course teaches the principles and practice of clinical epidemiology, drawing on real problems faced by medical professionals and elaborating on existing examples of clinical research. Medical researchers will lean how to translate real clinical problems into tangible research questions for investigation, gaining insight into some of the most important considerations when designing an epidemiological study along the way. Core concepts will be introduced along four key themes: diagnosis, prognosis, treatment and etiology. Followers of this course will develop their understanding of the topics addressed through lectures from experts, peer interaction and review assignments.
Case Study: Pneumococcal Vaccination in Adults
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En provenance du cours de Utrecht University
Clinical Epidemiology
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À partir de la leçon
Intervention Research
In our final week of lectures, you will step into the world of intervention research, exploring the "Therapeutic" branch of the DEPTh model. We will focus on the study of intended and unintended effects, exploring a new kind of study design: the randomized controlled trial.
Rencontrer les enseignants
Diederick E. GrobbeeProfessor
Clinical Epidemiology
Arno W. HoesProfessor
Clinical Epidemiology
In the final case study of this course,
we are going to take a look at an example of how intervention research
can address critically important issues related to public health.
We will see that this branch of clinical epidemiology
not only addresses the safety and efficacy of treatment for sick patients but also
plays a key role in providing evidence for disease prevention strategies.
Community acquired pneumonia is the most common kind of pneumonia and
is the leading cause of respiratory complications worldwide.
While there are multiple causes of agents, a leading cause is Streptococcus pneumonia
infection, which poses a significant risk to a broad range of age groups.
Effective ways to control and
manage the burden of disease have long been sought for.
The urgency of this problem has been compounded
by the emergence of penicillin resistant strains of Streptococcus, bacteria for
which treatment options remain limited.
A different way to approach this problem would be to focus on preventing
community acquired pneumonia.
An effective vaccination scheme
could massively reduce the overall burden of disease.
In recent years, pneumococcal vaccines have been developed, and
evidence suggests that they are effective in preventing disease in children.
Until recently, however, there was limited evidence to support
any recommendations for vaccination in the elderly population
in whom there is a high risk of mortality due to pneumococcal infection.
A situation has arisen where there is insufficient
evidence to firmly conclude that vaccinating elderly patients will help to
prevent community-acquired infection.
We could, therefore, approach this problem by conducting our own clinical research.
Before designing our study, it is important that we carefully consider
exactly which aspect of the clinical problem we want to address.
Vaccination is a complex intervention and
has implications at both the individual and public health level.
We could choose to investigate the effectiveness of a pneumococcal
vaccination scheme at a community level.
However, it would first be sensible to truly assess the efficacy of the vaccine
in elderly patients.
Our primary objective would be to investigate whether pneumococcal
vaccination prevents the occurrence of community-acquired pneumonia
in elderly people.
A secondary research question could look at whether vaccination
increases the risk of adverse events.
The next step will be to decide exactly which information we need to
collect during our study.
While the issue of community-acquired pneumonia affects the general population,
our interests lie with the one specific subset, the elderly.
It would, therefore, be preferable to restrict our domain to
older adult patients, perhaps patients over 65,
as the vaccine may behave differently in the subpopulation.
But we need to bear in mind, that in doing this,
our results may not be generalizable to younger populations.
Next, let's consider the determinants in our study.
We are interested in the efficacy of a specific pneumonial vaccine, and so
this will be the primary determinant.
As this is a therapeutic or more specifically a preventative study, and
thus our aim is to study a causal relationship between vaccination and
pneumonia incidents, we will need to consider other factors that could
confound the relationship that we observe.
There are numerous potential confounders that we could consider such as age,
immune status, comorbidities and smoking.
And we need to keep in mind that it could be difficult to obtain information on all
of these factors.
Now we need to come to a decision over our study outcomes.
As we are interested in the efficacy of the vaccine,
a reasonable choice would be vaccine type community-acquired pneumonia,
or more specifically, a first episode of the disease.
We can also study secondary efficacy endpoints,
such as other kinds of pneumonia in order to make a more general assessment of
the impact the vaccine has on the burden of pneumonia.
Depending on the body of currently existing evidence,
we may consider studying safety endpoints, particularly,
the incidence of type A unintended effects.
While type B adverse effects are often of great interest to both clinicians and
the general public, it may not be feasible in this situation
to investigate these outcomes thoroughly, should they occur,
as we are unlikely to involve enough patients to reach any firm conclusions.
Now we have to decide on the type of study that we'll conduct.
As our research lies within the therapeutic branch of the depth model and
our primary outcome is an intended effect of our intervention,
a placebo-controlled randomized trial design seems like a natural choice.
However, there's one major caveat to this approach and that's the cost.
Most commonly in intervention research were interested in comparing
two interventions to see which is more effective in treating our patients.
But preventative intervention is somewhat different in that we start with
an un-diseased population and outcomes are therefore rare.
If we want to see how well our intervention has worked, we will need to
recruit a large number of patients, and follow them for quite some time.
If the disease has a low incidence in the general population,
we would need to recruit thousands, if not tens of thousands, of patients and
follow them for several years, which would be an extremely costly endeavor.
An alternative approach would be to use an observational design,
which would potentially reduce the cost of the study but
would generally weaken any claims of causality within the study.
Even with modern techniques that aim to circumvent issues of unobserved
confounding to a certain level, we'd be lacking a comparison arm that is truly and
fully comparable to the vaccinated population,
which could be provided by a placebo arm in our trial design.
Let's assume that fortunately, we have received funding for
a large randomized trial.
We now need to focus on how we can obtain valid estimates of the causal relationship
between our determinants and our outcomes, and to do this,
we will need to achieve comparability at several levels of the study.
As mentioned in a previous lecture,
inclusion of a placebo arm in a trial will help to prevent
any associations that we see in our study from being obscured by extraneous effects.
This means taking an explanatory approach to answer our research question,
which is appropriate,
as we are specifically interested in the efficacy of this particular vaccine.
As always,
when choosing to use a placebo, the ethical implications should be considered.
But as the efficacy of the vaccine is truly unknown and it's unlikely to cause
any serious harm to our patients, the use of a placebo can be justified.
Of course, randomized allocations of the vaccine and placebo will be essential and
should ensure comparability between the natural histories or
prognosis of the individuals in each trial arm.
We'll also need to take into account the potential for observer bias in our trial.
So, blinding of the conditions in charge of vaccinations and
outcome assessments to the treatment of a patient will also be necessary.
Once we have designed the trial, we'll need to begin recruiting patients,
designating the randomly assigned treatments and following our
patients until they develop pneumonia or after several years, when our study ends.
We will need to think very carefully about the inclusion criteria for
the trial as this will have an impact on both the validity and
the generalizability of the results.
Finally, after a great amount of effort,
we should have enough evidence to answer our research question and
inform others of the efficacy of pneumococcal vaccination in the elderly.
In fact, a very large placebo controlled double blind [INAUDIBLE] trial,
similar to the one that we've just designed, has already been conducted.
Results have shown that pneumococcal vaccination is effective
in protecting elderly patients against several types of pneumonia but
not community-acquired pneumonia from any course.
The study also demonstrated minimal type A side effects.
But observational research may be necessary
to gain more insight into an unintended effects.
By conducting such a large trial, taking into account
key factors that may impact the validity and generalizability of the findings,
the results can now provide guidance for health care professionals and
policy makers when considering pneumococcal vaccine in practice.
Overall, we have seen that well designed intervention research is essential,
not only to get newly developed therapies onto the market but
also to assess the safety and efficacy of commonly used interventions,
providing evidence to inform current clinical practice.
While the analyses of trials may not generally be as complicated as in other
kinds of studies, a great amount of thought and
planning needs to go into the design, set up and management of such a study.
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