ESTUDOS CASO-CONTROLE
Estudo caso-controle – os indivíduos são selecionados
segundo o status de doença, sendo classificados segundo o
status de exposição. Os casos de doenças podem ser
incidentes (mais comum) ou prevalentes.
Nos estudos caso-controle clássico os controles são
representados pelos não casos. Devem representar a
distribuição de exposição na população que originou os
casos;
O processo de seleção independe do status de exposição;
Quantidade (máximo 4 controles para um caso).
Profile of the Framingham Heart Study
http://framingham.com/heart/profile.htm
(February 2006)
Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. In 1948, the
Framingham Heart Study -- under the direction of the National Heart Institute (now known as the National Heart, Lung, and
Blood Institute; NHLBI) -- embarked on an ambitious project in health research. At the time, little was known about the
general causes of heart disease and stroke, but the death rates for CVD had been increasing steadily since the beginning of the
century and had become an American epidemic.
The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to
CVD by following its development over a long period of time in a large group of participants who had not yet developed overt
symptoms of CVD or suffered a heart attack or stroke.
The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham,
Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later
analyze for common patterns related to CVD development. Since 1948, the subjects have continued to return to the study
every two years for a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a
second-generation group -- 5,124 of the original participants' adult children and their spouses -- to participate in similar
examinations. In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the
grandchildren of the original cohort. This step is of vital importance to increase our understanding of heart disease and stroke
and how these conditions affect families. With the help of another generation of participants, the Study may close in on the
root causes of cardiovascular disease and help in the development of new and better ways to prevent, diagnose and treat
cardiovascular disease. The first phase of the Third Generation Study was completed in July 2005 and involved approximately
4,095 participants. The Framingham Heart Study is joint project of the National Heart, Lung and Blood Institute and Boston
University.
Over the years, careful monitoring of the Framingham Study population has led to the identification of the major CVD
risk factors -- high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity -- as well as a
great deal of valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age,
gender, and psychosocial issues. Although the Framingham cohort is primarily white, the importance of the major CVD risk
factors identified in this group have been shown in other studies to apply almost universally among racial and ethnic groups,
even though the patterns of distribution may vary from group to group. In the past half century, the study has produced
approximately 1,200 articles in leading medical journals. The concept of CVD risk factors has become an integral part of the
modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice.
The Framingham Heart Study continues to make important scientific contributions by enhancing its research capabilities
and capitalizing on its inherent resources. New diagnostic technologies, such as echocardiography (an ultrasound examination
of the heart), carotid artery ultrasound, magnetic resonance imaging of the heart and brain, CT scans of the heart and its
vessels and bone densitometry (for monitoring osteoporosis), have been integrated into past and ongoing protocols.
Nurses’ Health Study (original cohort)
The Nurses' Health Study was established by Dr. Frank Speizer in 1976 with funding from the National
Institutes of Health. The primary motiviation in starting the NHS was to investigate the potential long
term consequences of the use of oral contraceptives, a potent drug that was being prescribed to hundreds
of millions of normal women.
Registered nurses were selected to be followed prospectively. We anticipated because of their nursing
education, they would be able to respond with a high degree of accuracy to brief, technically-worded
questionnaires and would be motivated to participate in a long term study.
Married registered nurses who were aged 30 to 55 in 1976, who lived in the 11 most populous states and
whose nursing boards agreed to supply the study with their members' names and addresses were enrolled
in the cohort if they responded to our baseline questionnaire. The original states were California,
Connecticut, Florida, Maryland, Massachusetts, Michigan, New Jersey, New York, Ohio, Pennsylvania
and Texas.
Approximately 122,000 nurses out of the 170,000 mailed responded. Every two years cohort members
receive a follow-up questionnaire with questions about diseases and health-related topics including
smoking, hormone use and menopausal status.
Because we recognized that diet and nutrition would play important roles in the development chronic
diseases, in 1980, the first food frequency questionnaire was collected. Subsequent diet questionnaires
were collected in 1984, 1986 and every four years since.
At the request of some of the nurses and with the addition of investigators to the research team interested
in quality of life issues, question related to quality-of-life were added in 1992 and repeated every four
years.
Because certain aspects of diet cannot be measured by questionnaire, particularly minerals that become
incorporated in food from the soil in which it is grown, the nurses submitted 68,000 sets of toenail
samples between the 1982 and 1984 questionnaires.
Similarly, to identify potential biomarkers, such as hormone levels and genetic markers, 33,000 blood
samples were collected in 1989-90 followed by second samples from 18,700 of these participants in 2000-01.
These samples are stored and used in case/control analyses.
As of this writing, response rates to our questionnaires are at 90% for each two-year cycle.
http://www.channing.harvard.edu/nhs/history/index.shtml
Nurses’ Health Study II
The Nurses' Health Study II was established by Dr. Walter Willett and colleagues in 1989 with funding from the National
Institutes of Health. The primary motivation for developing the Nurses' Health Study II was to study oral contraceptives, diet and
lifestyle risk factors in a population younger than the original Nurses' Health Study cohort.
This younger generation included women who started using oral contraceptives during adolescence and were thus maximally
exposed during their early reproductive life. Several case-control studies suggesting such exposures might be associated with
substantial increases in risk of breast cancer provided a particularly strong justification for investment in this large cohort. Further,
we planned to collect detailed information on type of oral contraceptive used, which was not obtained in the Nurses' Health Study.
The initial target population was women between the ages of 25 and 42 years in 1989; the upper age was to correspond with the
lowest age group in the Nurses' Health Study. The original goal was to enroll 125,000 women. Our strategy was to do a single
mailing inviting women to enroll and then only enroll the most enthusiastic potential participants who would complete a single
questionnaire after one request, thus identifying those who would be most likely to continue participation during the follow-up
period.
We anticipated that follow-up in this population might be complicated and difficult because it represented the time of life where
names might change because of marriage, professional changes would be frequent, and women would have complicated, busy lives
because of child-bearing.
We contacted state nursing boards in states with large populations and in states whose nursing boards were able to provide
information on gender and date of birth or age. The following states were included in the initial mailing: California, Connecticut,
Indiana, Iowa, Kentucky, Massachusetts, Michigan, Missouri, New York, North Carolina, Ohio, Pennsylvania, South Carolina and
Texas. The overall response rate to the baseline mailing was approximately 24% (123,000 of 517,000.) After exclusions for incomplete
forms and women who did not meet study criteria, a total of 116,686 women remained in Nurses' Health Study II.
Developing the baseline questionnaire, we relied heavily on our experience from the Nurses' Health Study. We conducted a number
of small pilot studies to optimize the wording for the complex questions on lifetime oral contraceptive use, particularly to make
them suitable for an optically scannable format. We also sent draft versions of the questionnaire to leading colleagues in the field of
breast cancer research and incorporated their feedback into the final version. A color booklet containing pictures of all oral
contraceptive preparations ever sold in the United States was developed and mailed to participants with the baseline questionnaire.
Every two years, cohort members receive a followfollow-up questionnaire with questions about diseases and healthhealth-related topics including
including
smoking, hormone use, pregnancy history, menopausal status. In 1991, the first foodfood-frequency questionnaire was collected and
subsequent foodfood-frequency questionnaires are administered at fourfour-year intervals. A twotwo-page qualityquality-ofof-life supplement was
included in the first mailing of the 1993 and 1997 questionnaires.
Blood and urine samples from approximately 30,000 nurses were collected in the late 1990's.
As of this writing, response rates to NHS II questionnaires are at 90% for each twotwo-year cycle.
http://www.channing.harvard.edu/nhs/history/index.shtml
ESTUDOS DE INTERVENÇÃO
O pesquisador manipula o fator de exposição.
Nos experimentos verdadeiros as unidades são alocadas de
forma aleatória (randomização) nos grupos de expostos
e de não expostos. Quando a alocação não é aleatória
os estudos recebem a denominação de quase-experimentos.
ESTUDOS DE INTERVENÇÃO
Ensaio Clínico – desenvolvido entre indivíduos já doentes. Busca-se avaliar um
tratamento que cure a doença ou previna as seqüelas/complicações da doença.
Após a alocação aleatória os pacientes são seguidos para avaliar a incidência de
cura ou de seqüelas/complicações da doença.
Ensaio de Campo – desenvolvido entre indivíduos saudáveis da comunidade.
Busca-se avaliar um tratamento preventivo (vacinas, por exemplo). Após a
alocação aleatória os indivíduos são seguidos para avaliar a incidência da doença.
Ensaio de Intervenção em Comunidade – a unidade de análise não é o indivíduo,
mas sim o grupo (cidade, por exemplo). Busca-se avaliar uma intervenção na
comunidade (fluoração da água, por exemplo). Após a alocação as comunidades
são seguidas para avaliar a incidência da doença.
ENSAIO CLÍNICO CONTROLADO
Randomização - Todos os participantes têm a mesma
chance de serem alocados para cada grupo de estudo.
A alocação não é determinada pelos investigadores, pelos
clínicos ou pelos participantes do estudo – reduz viés de
seleção e confundimento.
Comparabilidade - distribuição balanceada de possíveis
fatores de confundimento
ENSAIO CLÍNICO CONTROLADO
Seleção do tratamento “teste” e do tratamento controle:
•Os tratamentos devem ser diferentes (a melhor cirurgia
disponível; outra droga, o placebo ou não tratamento);
•Base ética
•Deve haver realmente dúvida acerca do tratamento. E
realmente deve se esperar que os benefícios venham superar
os riscos.
•A forma de administração deve ser compatível com o
desenho do estudo e ser semelhante a que será usada na
prática.
ENSAIO CLÍNICO CONTROLADO
Seleção da medida de desfecho:
•Evento clínico (ex: óbito, desenvolvimento de retinopatia)
x medidas indiretas (colesterol, glicemia). Relevância
clínica.
•Fácil de ser observada (nos dois grupos), não devem
ocorrer erros de mensuração.
•Deve ser escolhida no início do estudo.
ENSAIO CLÍNICO
Mascaramento:
Qualquer tentativa de evitar que os participantes de um estudo saibam o
tratamento que é administrado.
Objetiva evitar o viés relacionado ao tipo de tratamento (condição na qual
as operações de leitura, mensuração ou classificação, podem ser
influenciadas pelo fato do indivíduo responsável por estas atividades
conhecer o status de tratamento dos pacientes).
É mais necessário quando a ocorrência e o relato dos efeitos clínicos em
consideração (dor, náuseas, etc...) possam ser influenciados pelo
conhecimento do tratamento.
uni-mascaramento (uni-cego) - o paciente desconhece o tipo de
tratamento.
duplo-mascaramento (duplo-cego) - pacientes e demais membros da
equipe (prescrição do tratamento, coleta de dados, etc...) desconhecem o
tipo de tratamento.