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Epidemiology: the methods to quantitatively
assess the causation, diffusion, transmission,
evolution, prevention, diagnosis, cure of diseases in
human subjects.
• Its quantitative assessment tool is medical statistics • It sometimes uses the experimental methods developed in .g. griculture). • The results obtained using epidemiology are sometimes named "Epidemiology" as well (e.g. the diffusion of diseases), but more often, they take the names of their specific target: e.g. Hygiene, Diagnostic Procedure, Clinical Treatment, etc. Clinical epidemiology
investigates (presumed) patients.
P pul
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i n Epi
investigates presumably healthy subjects Epidemiological techniques can be:
• Observational: they do not change the natural
course of events nor the established practice, they just state the measurement procedure for the wanted ass • Experimental (limited to prevention, diagnosis and
treatment), they alter the clinical practice in a deliberate way (and state the appropriate measurement procedure). With few exceptions, they are the prerogative of clinical epidemiology Kinds of observational studies:
•Routine data analysis•Register •Cr Case-control studies •Longitudinal studies Rationale of clinical experiments
•To be sure that the experimental treatment is superior to the usual one, it is necessary to compare the results obtained by both.
•If a difference is found, its origin has to be ascertained to be the experimental factor, thereby excluding the concomitant ci •Because of the unavoidable random variation of the studied outcome, its possible non random improvement can only be found statistically. Therefore clinical experiment have to enrol many units (e.g. patients) A clinical trial is ethically feasible under
three main conditions
1. The experimental treatment is meant to improve the health conditions of the experimental subjects.
2. The experimental subjects have understood the nature and their consent. When the trial subjects are minors or unconscious, the informed choice to participate is made by their care takers.
3. The experimenter is convinced that the treatment is potentially useful to the subjects.
Phases of a clinical trial
The trial is conducted on healthy volunteers or oncology patients, to assess the absence of forbidding unwanted effects and/or the maximum dose safely administrable. There is no control group, but there can be different dosage gr The trial is conducted on a small number of patients to look for clues to the action mechanism of the treatment and/or, to chose the optimally effective dose. It can be controlled (and randomised) or not. It is not meant to be the final proof of the effectiveness of the treatment.
Phases of clinical trials (second part)
III. The trial should conclusively prove the worthiness of the experimental treatment. It is always controlled, randomised and (if possible) double blind. It should be adequately powered and analysed following the "by intention to treat" protocol. It should mimic the usual routine practice, where the treatment will be administered if approved. It is conduc with the treatment effectiveness.
IV. The trial is conducted once the treatment is on the market. It is controlled and randomised. Its aim is finding new indications for the treatment, or to assess its continuing validity in new situations and patient populations.
Main specific characteristics of a well
conducted phase III clinical trial
1. Concomitant control group 2. Randomised allocation of treatments 3. Double blindness (if feasible) Adequate power is also desirable Flaws of non-concomitant
Non concomitant control patients can have a better or worse prognosis, due to different general characteristics. They can even have a different disease from the experimental subjects, due to outdated diagnostic criteria Some reasons to randomly allocate
patients to the compared treatments
• If the experimenter or the patients themselves choose the treatments they can, on purpose or inad treatment individuals with a poorer (or better) prognosis than the control.
• So called systematic association (eg. Patients enrolled on Monday undergo the experimental treatment, those of Tuesday undergo the control treatment), doesn't allow blinding.
Techniques and methods of
(they are not mutually exclusive)
• Randomly permuted blocks • Within strata randomization (e.g. within gender) allocating a subject to the experimental group changes among strata and during the course of recruitment. • Cluster randomization: groups instead of single units are randomized, egg.
How to blind a trial
• Make the different treatment appearance indistinguishable, for the treating doctor as well as for the patient • If the compared treatments have differing assumption protocols (e.g. pills vs. injections), administer dummies.
Volume 379, Issue 9811 14–20 January 2012, Pages 123–129
Enoxaparin followed by once-weekly
idrabiotaparinux versus enoxaparin plus warfarin for
patien
embolism: a randomised, double-blind, double-
dummy, non-inferiority trial
Harry R Büller, Alex S Gallus, Gerard Pillion, Martin H Prins,
Gary E Raskob, on behalf of the Cassiopea Investigators
.patients were randomly assigned to receive 5–10 days of low-molecularweight heparin (enoxaparin) followed by idrabiotaparinuxor enoxaparin overlapped with and followed by warfarin.
Patients started subcutaneous enoxaparin 1.0 mg/kg twice per day.
Warfarin or an identical placebo tablet was started within 24 h and
adjusted to maintain an international normalised ratio of between 2.0
and 3.0 (target 2.5) with a point-of-care coagulometer programmed
according to randomisation to yield a true or sham ratio…
After enoxaparin, all patients received subcutaneous injections (3.0
mg idrabiotaparinux or matching placebo) once per week…
Simple vs. cluster randomisation
In cluster randomisation, instead of single subjects, small sets
(named clusters) of units are allocated randomly to different
treatments.
•Hospital wards allocated to different nursing protocols •The sets of patients who booked a surgical intervention a given date•Schools classes in dental prevention trials•Town communities in anti-malaria intervention trials July 2011 Volume 8 Issue 7 e1000443 A Multi-Country Non-Inferiority Cluster Randomized Trial
of Frontloaded Smear Microscopy for the Diagnosis of
Pulmonary Tuberculosis
Luis Eduardo Cuevas, Mohammed Ahmed Yassin, Najla Al-Sonboli, Lovett Lawson, Isabel Arbide, Nasher Al-Aghbari, Jeevan Bahadur Sherchand, Amin Al-Absi, Emmanuel Nnamdi Emenyonu, Yared Merid, Mosis Ifenyi Okobi, Juliana Olubunmi Onuoha, Melkamsew Aschalew, Abraham Aseffa, Greg Harper, Rachel Mary Anderson de Cuevas, Kristin Kremer, Dick van Soolingen, Carl-Michael Nathanson, Jean Joly, Brian Faragher, Stephen Bertel Squire, Andrew Ramsay Study Interventions and Randomization
Participants were asked to submit sputum specimens using the
standard SMS or the new SSM scheme.
The SMS scheme required one on-the-spot specimen at the time of the first visit, one specimen collected at home the following mor patient brought the morning sample to the laboratory. The SSM scheme required one on-the-spot specimen collected at the time of the first visit, a second on-the-spot specimen collected one hour later, and one morning specimen collected at home the following morning

The scheme to be used each week by each centre was
allocated by block randomization.
After generating a list of random numbers ranging from 1
to 5 … the scheme to be used in a specific week in each
centre was allocated using a permuted block design.
allocations - allocated as AABB, ABAB, BABA, ABBA,
and BAAB, where A was the standard and B the
frontloaded scheme.
The schemes allocated were distributed to study centres concealed in sealed envelopes. The study coordinators were unaware of the
block size and were only allowed to open the
envelope at the start of each week.
test the study hypothesis within a context of a systems change, and it was considered that randomization of individuals was not feasible.
Diverse experimental designs are possible for clinical trials: when applicable, they offset some components of the unexplained variability of the observations, thereby reducing it.
1. The design choice determines the appropriated statistical
analysis, this in turn determines the sample size required
to ge
2. The possible gain of a design vs. another is measured by the In simple cases, the relative efficiency of two designs can be expressed as the ratio of the sample sizes required to achieve a given objective Simple two Parallel Group Experimental Design
Two treatment two group Cross-over
Experimental Design Depending on the involved outcomes and
explanatory variables, a two parallel group
experiment can be analyzed by:
• Independent sample t test.
• Multivariable models (e.g.: general linear model, logistic regression, Cox model) containing the treatment factor plus the putative prognostic variables) Depending on the outcome and the explanatory
variables, a two treatment two group cross-over
experiment can be analyzed by:
• Paired sample t-test •A multivariable model (e.g.: mixed effect general
linear model, mixed effect logistic regression) that
contains the treatment factor, the putative prognostic
variables and the blocking factor (i.e. the patient
identity)
Non inferiority limit Minimal clinically significant effect

Source: http://ssnc.unipv.eu/site/home/didattica/documento930003253.html