Transcript Group 2 - Gilberto De Nucci

Arquivo
Ensaios Clínicos –
Ciência ou Literatura
Site
www.gilbertodenucci.com
Bíblia Sagrada
Bíblia Sagrada – Tradução da CNBB – 5° edição – pag 1109 (Daniel 1-2)
Classificação de estudos
•
•
•
•
Aleatorização
Cegamento
Comparativo
Condução dos tratamentos
Testes Clínicos
• Fase 0 – voluntários sadios (microdosagem) – não é
regulatória
• Fase I – voluntários sadios
• Fase II – pacientes para prova conceitual
• Fase III – grande número de pacientes – estudos
multicêntricos
• Fase IV – vigilância pós-mercado – pesquisa sobre novas
indicações
Ames Test (Salmonella typhimurium)
 Bacterial reverse mutation assays are widely used to evaluate the
mutagenic potential of chemicals, formulations, or extracts. The most
common assay involves the use of amino acid-requiring strains of
Salmonella typhimurium and is commonly referred to as the "Ames
Test".
 In the absence of an external amino acid source (histidine for
Salmonella), the cells cannot grow to form colonies unless a reversion of
the mutation allows the synthesis of the amino acid to resume.
 Spontaneous reversions occur with each of the strains. However,
some compounds induce a mutagenic response and thereby increase the
number of revertant colonies substantially over the spontaneous
reversion level.
The bacterial reverse mutation assay involves
the measurement of revertant colony
frequencies that are obtained when Salmonella
strains are treated in the presence and absence
of a test article.
Positive and negative controls are included for
each strain tested. Metabolic activation using
rat liver S9 is included to mimic the in vivo
activity of the liver enzymes in transforming
some pro-mutagens to mutagens
Was the animal model used suitable to predict the effectiveness of
nimodipine in stroke patients? Several authors have discussed the
discrepancies between the results of animal models in stroke and the results
of clinical studies. A possible explanation for these discrepancies was the
difference in the age of the patients. Older stroke patients often have
comorbidity, such as diabetes and hypertension. Furthermore, in animal
experiments, physiological parameters (blood pressure, [brain] temperature,
and blood glucose levels) can be kept within strict limits, and
neuroprotective treatment can be started immediately or shortly after the
induction of ischemia. Finally, major differences exist in the assessment of
the effectiveness of animal experiments measuring histopathologic
parameters compared with trials measuring functional ability in stroke
patients.
We found that the methodological quality of the included studies was
poor. Issues such as randomization, masked treatment allocation, blinded
outcome assessment, and intention to treat analyses, which are very
important issues and are now generally required in clinical studies, were
Surprisingly, 1
study reported a double-blind assessment of
effectiveness.
especially neglected in these animal experiments.
Detecção de reações adversas
Incidência esperada de uma
reação adversa
Número de pacientes necessários
para detecção do evento
1 evento
2 eventos
3 eventos
1 em 100
300
480
650
1 em 200
600
960
1.300
1 em 1.000
3.000
4.800
6.500
1 em 2.000
6.000
9.600
13.000
1 em 10.000
30.000
48.000
65.000
Testing multiple statistical hypotheses resulted in spurious associations:
a study of astrological signs and health
Peter C. Austina,b,c,* , Muhammad M. Mamdani a,d, David N. Juurlinka,e,f, Janet E. Huxa,c,e,f
a
Institute for Clinical Evaluative Sciences, G1 06, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5 Canada
b
Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
c
Department of Health Policy, Management and Evaluation, University of Toronto, Canada
d
Faculty of Pharmacy, University of Toronto, Canada
e
Clinical Epidemiology and Health Care Research Program (Sunnybrook & Women’s College Site), Canada
f
Division of General Internal Medicine, Sunnybrook & Women’s College Health Sciences Centre and the University of Toronto, Canada
Accepted 19 January 2006
Abstr act
Obj ectives: To illustrate how multiple hypotheses testing can produce associations with no clinical plausibility.
Study Design and Setting: We conducted a study of all 10,674,945 residents of Ontario aged between 18 and 100 years in 2000. Residents were randomly assigned to equally sized derivation and validation cohorts and classified according to their astrological sign. Using
the derivation cohort, we searched through 223 of the most common diagnoses for hospitalization until we identified two for which subjects
born under one astrological sign had a significantly higher probability of hospitalization compared to subjects born under the remaining
signs combined (P ! 0.05).
Results: We tested these 24 associations in the independent validation cohort. Residents born under Leo had a higher probability of
gastrointestinal hemorrhage (P 5 0.0447), while Sagittarians had a higher probability of humerus fracture (P 5 0.0123) compared to all
other signs combined. After adjusting the significance level to account for multiple comparisons, none of the identified associations
remained significant in either the derivation or validation cohort.
Conclusions: Our analyses illustrate how the testing of multiple, non-prespecified hypotheses increases the likelihood of detecting
implausible associations. Our findings have important implications for the analysis and interpretation of clinical studies. Ó 2006 Elsevier
Inc. All rights reserved.
Keywords: Subgroup analyses; Multiple comparisons; Hypothesis testing; Astrology; Data mining; Statistical methods
Am J Psychiatry 2006; 163:185–194
Kidney Stones
Treatment A
Treatment B
78% (273/350)
83% (289/350)
Kidney Stones
Large Stones
Treatment A
Treatment B
Group 3
73% (192/263)
Group 4
69% (55/80)
Kidney Stones
Small Stones
Treatment A
Treatment B
Group 1
93% (81/87)
Group 2
87% (234/270)
Kidney Stones
Treatment A
Treatment B
Small Stones
Group 1
93% (81/87)
Group 2
87% (234/270)
Large Stones
Group 3
73% (192/263)
Group 4
69% (55/80)
Both
78% (273/350)
83% (289/350)
Int J STD AIDS. 1999 Jan;10(1):8-16.
Circumcision and HIV infection: review of the literature and meta-analysis.
Van Howe RS.
Source
Department of Pediatrics, Marshfield Clinic, Lakeland Center, USA. [email protected]
Abstract
Thirty-five articles and a number of abstracts have been published in the medical literature looking at the relationship between male
circumcision and HIV infection. Study designs have included geographical analysis, studies of high-risk patients, partner studies and
random population surveys. Most of the studies have been conducted in Africa. A meta-analysis was performed on the 29 published
articles where data were available. When the raw data are combined, a man with a circumcised penis is at greater risk of acquiring and
transmitting HIV than a man with a non-circumcised penis (odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.12). Based on
the studies published to date, recommending routine circumcision as a prophylactic measure to prevent HIV infection in Africa, or
elsewhere, is scientifically unfounded.
PIP:
This article reviews the literature on circumcision and HIV infection. Recent studies show raw figures suggesting circumcised men to
be at greater risk for HIV infection. Circumcised men have been found to also have more sexual partners. Findings explain that
circumcision may be responsible for the increased number of partners, and therefore, the increased risk. In Africa, the use of dirty
instruments and mass ritual events, including group circumcision, may increase the number of young boys developing HIV infections.
Based on the studies published in the scientific literature, it is incorrect to assert that circumcision
prevents HIV infection. Moreover, even if studies showing circumcision to be beneficial are accurate, the risk from
circumcision outweighs any small benefit it may have. Thus, promoting circumcision as protection against HIV infection would lead to
the belief that circumcised men are being protected from contracting AIDS, which would result in increased HIV infections.
Int J STD AIDS. 2000 Mar;11(3):137-42.
Circumcision in men and the prevention of HIV infection: a 'meta-analysis' revisited.
O'Farrell N, Egger M.
Source
Department of Genitourinary Medicine, Milne Clinic, Bristol Royal Infirmary, UK.
Abstract
There is debate on the role of male circumcision in HIV transmission. Most case-control and cohort studies from Africa have shown an association between a
lack of circumcision and an increased risk of HIV infection in men. The evidence is conflicting, however, with cross-sectional surveys from Tanzania and
Rwanda either showing no relationship or an association in the opposite direction. A recent review and meta-analysis of the literature concluded that the risk
of HIV infection was lower in uncircumcised men (combined odds ratio 0.94, 95% confidence interval 0.89 to 0.99). However, the analysis was performed by
simply pooling the data from 33 diverse studies, which is an inappropriate method for combining studies. We re-analysed the data, stratifying by study, and
found that an intact foreskin was associated with an increased risk of HIV infection: combined odds ratio 1.43 (1.32 to 1.54) with a fixed effect model and
1.67 (1.25 to 2.24) with a random effect model. There was significant between-study heterogeneity (P<0.0001) which was partly explained by stronger
associations in studies in high-risk groups. The
results from this re-analysis thus support the contention that male
circumcision may offer protection against HIV infection, particularly in high-risk groups where
genital ulcers and other STDs 'drive' the HIV epidemic. A systematic review is required to clarify this issue. Such a review
should be based on an extensive search for relevant studies, published and unpublished, and should include a careful assessment of the design and
methodological quality of studies. Much emphasis should be given to the exploration of possible sources of heterogeneity. In view of the continued high
prevalence and incidence of HIV in many countries in sub-Saharan Africa, the question of whether circumcision could contribute to prevent infections is of
great importance, and a sound systematic review of the available evidence should be performed without delay.
Circumcision and HIV infection: review of the literature and meta-analysis. [Int J STD AIDS. 1999]
Control Clin Trials. 1997 Oct;18(5):431-44.
Lancet. 1993 Feb 13;341(8842):418-22.
Why Most Published Research Findings Are False
John P. A. Ioannidis
Summary
There is increasing concern that most current published research findings are false. The probability that a
research claim is true may depend on study power and bias, the number of other studies on the same
question, and, importantly, the ratio of true to no relationships among the relationships probed in each
scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a
field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of
tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical
modes; when there is greater financial and other interest and prejudice; and when more teams are involved
in a scientific field in chase of statistical significance. Simulations show that for most study designs and
settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific
fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay,
I discuss the implications of these problems for the conduct and interpretation of research.
Far better an approximate answer to the right
question, which is often vague, than an exact
answer to the wrong question, which can always
be made precise.
John W. Tukey (1962)