practical issues of conducting epidemiological studies

Electromagnetic Fields and Epidemiology / Practical issues of conducting epidemiol. studies / B. Schlehofer, DKFZ Heidelberg, Germany Erice, March/April 2008

29.11.2005 Gitta Schlehofer Qualifizierungsprogramm „Klinische Forschung“ Med. Klinik II

Practical Issues of Conducting

Epidemiological Studies

Brigitte Schlehofer Brigitte Schlehofer

Unit of Environmental-EpidemiologyUnit of Environmental-Epidemiology

German Cancer Research Centre, Heidelberg German Cancer Research Centre, Heidelberg


Guidelines and Recommendations(based on: „Good Epidemiological Practise“ (GEP) in Germany issued by the

AG Epidemiologische Methoden der Deutschen Arbeitsgemeinschaft Epidemiologie (DAE))

1. Scientific issue

2. Ethical concerns

3. Study design, writing a project protocol

4. Storing biological specimens

5. Data management: Data quality and protection, accessibility and analysis

6. Statistical analysis

7. Interpretation

8. Presentation of study results, publication, communication and public health


1. Ethical concerns

The prime ethical principle is to respect human dignity as well as

human rights.

Epidemiological studies have to ensure that humans are

treated with respect and protected from harm

Recommendation:

Before conducting an epidemiological study obtain the agreement

of the respective Ethic Committee.

(if conducting a research study together with US institutions a certificate is now requested that can

be achieved by completing the online course “Human Participant Protections Education for

Research Teams” from e.g. The National Institutes of Health [http.//www.nih.gov] or the Indiana

University [http://www.research.indiana.edu/]) (caveat: time consuming!)


Expl:

Checklist for a non-biomedical research with human subjects

Legal and ethical aspects

Declaration of Helsinki, Version 1996

Statement of the respective Ethic Committee

Data protection

Education of study participants (written and verbal)

Informed consent

Voluntary participation

Right of withdrawal from study participation

(Information of radiological diagnostics in frame of the study)

Signature


Expl:

Phrasing for „Data protection“ in epidemiological studies

• “This study follows the regulation on physicians confidentiality

and data protection.”

• “Questionnaires will be anonymous / synonymous

(not containing the names of the participants).”

• “Other party is not allowed to have insight into the

original medical documents.”


2. Scientific Issue

When planning an epidemiologic study the scientific topic should

be explicit and operationally defined.

The study goals have to be described as specific and

precise as possible.

In general: The scientific goals have to be defined a priori!

(occasionally, also secondary analyses will be meaningful

explorative analysis)


The choice of the study population is

caused by the scientific goal!


What has to be considered when

performing a study?

Scientific goal

Literature review

Communication with other scientists in this field

Identification (definition/detection) of data sources

International multi-centred Case-Control Study of

Cancers of the Brain

and Salivary Gland and Leukaemia

so called „Interphone Study“

co-ordinated by

International Agency for Research on Cancer, Lyon

Study Centres

Australia Canada Denmark England Finland France

Israel Italy Japan New Zealand Norway Scotland Sweden

Germany

Expl:


Data sources I

Primary data (collected directly)

Definition:

All data will be collected by persons, who are responsible

for the study design and the study method.

Advantage :

Data collection concerning the study question: all data are

relevant for the aim of the study

Disadvantage:

- Data collection relies on the researcher’s responsibility

- Time consuming

- Costly

- If data are missing an additional study will be necessary costs!!!


Data sources II

Secondary data (e.g. data from mortality or morbidity registers...)

Definition:

Data have not been specifically collected for a defined

epidemiological study goal

Advantage :

- cost-efficient

- large databases over long time periods

- in general: completeness is sufficient

Disadvantage:

- lacking of information on the prevalence of relevant risk factors

(confounder)

- the collected data might be useless for the respective study


3. Study design

An epidemiologic study should to be based on a

detailed and mandatory study design,

which covers all study characteristics in a written form.


Elements of the study design I

• Study questions / study hypotheses

• Study type, e.g. case control study, cohort study,...

• Population under consideration and study population

• Size of the study (justification by power calculation)

• Selection and recruitment method of the study participants

• Definition of the outcome variable(s) (measurements and

detection method)


Detailed steps I

Definition of the study design: study type, study region etc.

Incidence- and/or mortality rates (e.g. population based or hospital based)

Estimation of the number of expected cases

Calculation of the power of the study under various conditions

Calculation of the data collection period

Definition of cases and controls

Recruiting procedures of cases and controls

Definition of the matching criteria

Establishing of a list of possible confounders under consideration


Calculation of size of staff (principal investigator, scientists, technicalassistants, interviewers, secretary, out sourcing...)

Funding (identification of possible financial support / sources)

Writing scientific proposal

Management structure

Intellectual property rights, publication rights and use and dissemination of

data and results

Establishing of the major points of the analysis strategies

Proposal for the ethic commission

Preparation of study materials

Definition of measurements

Detailed steps II


Epidemiological study designs

Deskriptive

Epidemiology

Analytical

Epidemiology

Frequencies

Time trends

Regional distributionEcological studies Cross-sectional

Studies

Prospective studiesProspective studies

Intervention studies

RetrospectiveRetrospective studiesstudies


Epidemiological study types

Exposed

Not-

Exposed

diseased

diseased

not

diseased

not

diseased

cases

(diseased)

controls

(not diseased)

exposed

exposed

not

exposed

not

exposed

prospective studyprospective study

= = Cohort study Cohort study

retrospective study retrospective study

= = Case control studyCase control study


Definition of cases

Minimum: Definition of disease under consideration

Age range

Gender

Ethnicity

important:

defined and reproducible diagnostic criteria,

(e.g. based on: International Classification of Diseases: ICD)

study participants (cases and controls):

only persons who could be potentially exposed

(incident cases or mortality cases)


Population based case-control study

Cases: Recruited from the neurosurgical clinics of the study regions or by

cancer registers in between 3 weeks after diagnosis (proxy interviews possible)

Direct computer assistant interview (CAPI) assessed in the clinic or at home;

collecting period: 2-3 years

Only patients with incident histological confirmed :

glioma, meningioma, Acoustic neuroma; (parotis gland tumours;

acute leukaemia)

(ICD-9: 191.0-191.9; 192.1; 225.0 - 225.2; 142.0; 142.1-142.9; 210.2-210.4;

204.0; 205.0; 206.0; 207.0; 208.0)

Population based controls (especially large cities and surrounding)

Age of study participants: 30 to 59 years

International StudiendesignExpl:


continuation:

Numbers of cases: estimated collected

Glioma and Meningioma n = 7000 n = 7420

Acoustic neuroma n = 1000 n = 1080

Parotis gland tumours n = 800 n = 796

Acut leukaemia n = 1000 n = 1298

Matching for age and gender: 1:1 Glioma und Meningioma

1:2 Acoustic neuroma

1:3 Parotis gland tumours and leukaemia

Power calculation :

2 years of recruitment: 100% power to detect a risk of 1.5-fach (95%CI)

Expl:


Definition of controls I

Population controls (golden standard):

Random selection from the population of the study region

* Registration office

* Random digit dialling

* Register of voters

Hospital controls:

Patients from a clinic affected with diseases which are not

associated with the disease of interest

(can be from the same clinic where the cases are selected)


Neighbourhood controls:

Random selection from the entire population but recruited

from the same city or from the same district of the city

For all controls further specifications are:

- age and gender

- nationality

- ethnic group

Definition of controls II


Matching procedures in case controls studies

unmatched design

Controls are randomly selected from the underlying population

matched design (1:n)

Controls correspond to the cases concerning the distribution of

specific factors (matching variables, e.g. age, gender...)


Steps of case recruitment I

• Identification of hospitals of the study region, treating patients

with the respective „disease of interest“

• Searching for „case migration“ in hospitals from the surrounding

areas of the study region

• Contact with the heads of the respective medical departments

to establish the co-operation (including short study description)

• Estimation of numbers of patients (cases) of each hospital

(based on the numbers of previous years)

• (caveat: changes in structure of the hospital!)


• Contacting the respective pathology departments (histology)

• Contacting the staff of the ward (nurses, doctors) to establish

the case recruitment in that specific hospital and to introduce the

interviewees

(best would be: one contact person in each clinic).

Steps of case recruitment II

most important:

the study should not disturb the daily routine of the hospital!!


Conclusion:

Case selection could be performed in all

neurosurgical clinics without major problems

Participation rate in interview differs by method:

a. Interview in the clinic: participation rate: > 90%

b. Interview at home: participation rate: > 70 %

c. Interview with self-administered questionnaire and

additional telephone interview:

participation rate: > 60 %

Expl:


(matched by age and gender to the cases; 1:n1,2,3,..)

- Out sourcing (e.g. asking for a market research institution)

Master sample:

Random sample from the population register of the study region

Steps of control recruitment I

random selection of controls


- First invitation by letter:

- Acceptance a) scheduling appointments by phone

b) scheduling the interviewers

c) performing of the interviews

d) plausibility checks, coding, data management

- Refusal a) personal contact

b) acceptance (see above)

c) cause of refusal

- No reaction: reminder letter after 3 - 4 weeks a) if accepting or refusal > procedure like above

b) if no reaction > try to contact by phone or personally

Steps of control recruitment II


Designing the invitation letter I

• official letter, personally written

• up dated

• signed

• clear language, not using to complicated scientific words

• letter type size not too small (elderly participants!), easy to read

• describing all necessary information of the study, e.g.

rational and goal of the study (recommendation of the Ethic Committee!)

• presentation of the cooperating institutions


• inclusion of official letters of support (by well known institutions,

e.g. WHO, ministries etc., or news papers...)

•marking the importance of the study and the participation of each

study participant

• assurance of data security

• possibility of posing questions

• acknowledgement for participation

• self-addressed stamped envelope for answering

• when sending the letter: be aware of holiday time!

Designing the invitation letter II


Possibilities of data collection from participants

of case control studies

by questionnaires or computer assistant interviews (CAPI)

• Self administered questionnaire: personally distributed or by letter

• Interview type: direct interview

telephone interview

• mixed interview (first self administered questionnaire by letter,

then personal interview)

• ( Proxy-interview )


Conclusion:

Evaluating different control selection methods showed:

Participation rates change with method between

39% and 65 %.

First contact by an official letter from the Institute

helps to increase the numbers of participants.

To get in contact with persons by mobile phone was

more difficult than by regular telephone; in addition

mobile phone users tended to refuse.

Direct interview was more accepted than self-administered

questionnaire with additional telephone interview.

Expl:


Criteria of a questionnaire

• ID (identification) number (participant and interviewer)

• standardized style of each part of the questionnaire

(technically and graphically); the same for cases and controls

• easy to fill in (simple and clear advices = questionnaire manual)

• start with easy questions (e.g. demographic data)

• sensitive questions at the end of the questionnaire

• combining questions of the same content

• including time of start and end of the interview

• possibility for remarks of the interviewer


Further matters of the study design

• Exposure, respectively, risk variables

• Potential confounders and effect modifiers

• Data management and data storing methods

• Data analysis (incl. statistical models)

• Arrangements for quality security

• Arrangements to guarantee data security and ethical principles

• Time table and determination of the responsibilities


Topics of CAPI

Demographic information

Use of mobile phone

Occupational history and exposure vs. EMF

Smoking history

Medical history

Medical exposure vs. ionising radiation

Comments of the interviewer

Expl:


Why cohort studies?

• (Epidemiological) golden standard to investigate the association betweenexposure (risk factors) and disease

• Chronology between exposure and effect (outcome).

• Qualified to investigate (incl. prognosis). incidence rates, risk factors andthe native course of a disease

• Several outcomes can be investigated independently and in parallel

• Multiple exposures (risk factors) can be investigated simultaneously (e.g.interactions) and independently

Study population

(cohort)

exposed groupOutcome

no outcome

The course is not influenced by the researcher

not exposed group Outcome

no outcome

Follow up


Practical issues for cohort studies

• Establishing of the cohort (persons under risk)

• Assessment of the exposure (independent variable)

• Selection of the „controls“ (non-exposed)

• Follow-up of the cohort

• Assessment of the outcome variable

• Latency

• Diagnostic criteria

• Disease

• Confounder

• Effect of non participants


Prospective or historical cohort study?

- Dependent of the data

(secondary data)

- Data quality

- Data availability (confounder)

+ Costs

+ Duration

+ Design Baseline-Assessment

+ Design Follow-up

- Costs

- Duration

- Uncertain validity of the

results at the time when study

is finished (because of the

duration of the study)

Historical CohortProspective Cohort


Setting, study population

Cohorts can be established using:

– General population

– Specific exposure (e.g. smoker, mine workers, asbestos

exposure,...)

– Defined group (pupils, physicians, workers.....)

– Geographical defined (regional area)

– Only patients


Follow-up

• Depends on end point, e.g.

– Vital status (cause of death),

– disability

– meantime morbidity (cancer heart attack, dementia,,...)

• Depends on data availability (e.g.. medical records, retention period deathcertification)

• Early planningInformation of the study participants (informed consent).Data security aspects!

• Handling with personal data

• Involving data protection officer


Types of Follow-up

A: personal Follow-up

study participants are directly involved in the study, e.g by answeringquestionnaires to

- change of life style

- newly diagnosed diseases etc...

an informed consent exists, so that physicians and relatives can giveinformation

B: Follow-up by

Follow-up only by authorities or registries. Study participants have no knowledge about this.


Special issues

• Incomplete Follow-up (migration)

• Misclassification of exposure

• few or no information about confounder

• Multiple testing (e.g. „all“ tumour types)

• Negative results ???


4. Biological Samples

Informed consent is needed (as comprehensive as possible)

Requirements of the ethic commission have to be taken into account!


5. Quality security

The proofed quality of all instrument and methods has to be assured.


Possibilities for Biases

• Non-response bias

• Selection bias

• Recall bias

• Interviewer bias

• Bias by not comparable databases

• Referral bias („specify“ of the data bases)

• Healthy Worker Effect

• Healthy Migrant Effect


Verzerrrungen (BIAS)

• non-response bias (Verzerrung durch Nichtantwort)

> Tritt vornehmlich bei Populationskontrollen auf.

Die Gruppe der Verweigerer stellt eine selektierte Gruppe der

Gesamtstichprobe dar (Selbstselektion).

> Bei Kohortenstudien: non-response bei Verlusten im follow-up

(wenn differentiell für Exponierte und Nicht-Exponierte)

• selection bias

kann auftreten, wenn die Einbeziehung von Individuen in die

Studie nicht zufällig erfolgt (bes. Kontrollen)

Beispiel: Krankenhauskontrollen bei der Untersuchung des

Zusammenhangs von Thrombose und Pilleneinnahme.


Verzerrrungen (BIAS) - Vermeidung

• recall bias

> Verzerrung durch unterschiedliche Erinnerungsfähigkeit bzw.

Verdrängung

> CAVE: insbesondere beiden Fällen (?)Beispiel:

• ein Lungenkrebspatient gibt an, weniger geraucht zu haben als tatsächlich zutreffend (Expos ) oder

• Fälle „suchen" nach zurückliegenden Erklärungen für ihre Erkrankung (Expos )

• interviewer bias ( Verzerrung durch Interviewer)

> Interviewer treten Fallpatienten (mit ihrer schweren Erkrankung)

anders gegenüber als den gesunden Kontrollen



• bias durch unterschiedliche Grundgesamtheiten

> Wenn der Rahmen (sampling frame), aus dem Fälle und Kontrollen

stammen, unterschiedlich ist, kann dies zu Verzerrungen führen,

da eine unterschiedliche Verteilung der Risikofaktoren zugrunde

liegen kann.

• referral bias

> z.B.: Bei einer "hospital based" Fall-Kontroll-Studie hängt der

Anteil der aufgenommenen Fälle oder Krankenhauskontrollen

vom Expositionsstatus ab (nur Schwerkranke kommen ins

Krankenhaus)



• Healthy worker Effekt

>Arbeiter sind gesünder als die Allgemeinbevölkerung,

besonders bei Arbeitsaufnahme

• Healthy migrant Effekt

>Migranten sind gesünder als die Allgemeinbevölkerung


6. Data cleaning, - management and -

documentation(caveat: needs a lot of time!)

A detailed concept has to be provided in advance


7. Analysis

The analysis of an epidemiologic study should be done with the

appropriate statistical methods and without unnecessary delay.

The original data on which the results are based have to be stored

for at least 10 years (in order to replicate the results).


Data analysis

separated for glioma, meningioma and acoustic neuroma,

but also analysis of histological sub groups

investigation of non-responders concerning age, gender, study region,

case-control status

adjustment for age, gender, SES, study region

test for heterogeneity

main focus: analysis of HF-EMF exposure due to mobile phone use:

exposure categories (number of years (-5 years), duration and number of calls )

in addition:

use of other HF- communication devices

occupational exposure concerning HF-EMF

other occupational exposure

smoking history

medical history

genetic disposition (familiar history)

Expl:


8. Data security

Data security regulations have to be taken into account.


9. General conditions for a Contract

Defined legal and financial contracts are necessary between

co-operating partners and funding institutions.


10. Interpretation

The interpretation of the research results of an epidemiologic

study is task of the authors of the publication.

Basis of the interpretation is a critical discussion of the methods,

the data and the results of the investigation in context with

the existing knowledge.

All publications should be peer reviewed.

(GEP, 2000)


11. Communication und Public Health

Epidemiologic studies may sometimes have the intension to influences

environment or public health arrangements,

therefore the respective population should be informed by a

qualified risk communication.


29.11.2005 Gitta Schlehofer Qualifizierungsprogramm „Klinische Forschung“ Med. Klinik II

Thank you for your attention!Thank you for your attention!

practical issues of conducting epidemiological studies

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