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Overview in Health Science Research

ATIPORN INGSATHIT, MD. PhD.

Section for Clinical Epidemiology and BiostatisticsFaculty of Medicine, Ramathibodi HospitalEmail: atiporn.ing@mahidol.ac.thPhone: 022011284, 0899183399

This course will help you learn about

How to solve the health science problems by Measuring in health Evaluating health services Knowing the association and causality Choosing the appropriate study designs Concerning of confounding factors &

interactions Applying epidemiology in health policy

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Health science research

Health science Research

Applied science dealing with health

Creative work undertaken systematically to increase

the stock of knowledge

Epidemiology The branch of medicine that deals with the

incidence, distribution, and possible control of diseases and other factors relating to health, or the study of how often diseases occur in different groups of people and why

Epidemiological information is used to plan and evaluate strategies to prevent illness and as a guide to the management of patients in whom disease has already developed:

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Clinical Epidemiology

The term of science that studies the patterns, causes, and effects of health and disease conditions in defined populations.

It is the cornerstone of public health, and informs policy decisions and evidence-based practice by identifying risk factors for disease and targets for preventive healthcare.

Types of health care professional

EvidenceFinders

Evidence Users Evidence generator

Evidence Ignorer

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Good question?

Require research?

DesignPopulation

Methodology

Measurement

Statistics

Stop

Research

What research is made of? Element Purpose

Research questions What questions will the study address?

Significance (background)

Why are these questions important?

Design How is the study structured?

Subjects Who are the subjects and how will they be selected?

Variables What measurements will be made?

Statistical issues How large is the study and how will it be analyzed?

Hulley SB. Designing Clinical Research. 2001

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Population Parameter

Sample Statistics

Statistical inference

Internal vs. External validity

Description

Selection

Comparison

Bias

Chance

Conclusion

External validity Internal validity

Target population

Study subject

Study subject

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Study design

•The investigator’s plan of action for answering the research question(s)

•To maximize the reliability and validity of data

•To minimize possible errors

Measurement

Measurement Validity = accuracy Internal validity: the results can be

considered a good approximation to the truth.

External validity: the results can be applied/generalized outside the study.

Precision The quality of being sharply defined/stated. To reduce random error

Precision

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A

C

B

D

ReliabilityHigh Low

High

Low

Validity

Accuracy and precision

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Accuracy and precision

Errors Random error: a portion of variation in a

measurement that has no apparent connection to any other measurement or variable, generally regarded as due to chance.

Type I error (alpha)type II error (beta)

Systematic error (bias): a process at any stage of inference tending to

produce results that depart systematically from the true values.

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Ho: µSBP(A) = µSBP(B)Ha: µSBP(A) ≠ µSBP(B)

In population

Different exist No difference

Different existReject H0

Power1-B

FP (Type I error

No differenceDo not reject H0

FN (B)Type II error

TN1-

Statistical Testing

The process of designing and implementing a research project

Research Question

Truth in the

universe

Study Plan

Truth in the study

Conduct study

Findings in the study

design implement

inferinfer

Hulley SB. Designing Clinical Research. 2001

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The process of designing and implementing a research project

Research Question

Truth in the

universe

Study Plan

Truth in the study

Conduct study

Findings in the study

design implement

inferinfer

Random &

Systematic error

Random &

Systematic error

Hulley SB. Designing Clinical Research. 2001

Tools for assessing random error

The P value Confidence Intervals

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P-value

A numeric representation of the degree to which random variation alone could account for the difference observed between groups or data being compared.

The probability of a given (more extreme) finding if no association truly exists.

No clear cutoff point.

Confidence Intervals

Provide a plausible range within which the true association lies.

Provide all the information in P values and more.

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Confidence Intervals

-50 -25 0 25 50 75

Relative risk reduction(%)

Power

Ability of a study to detect a true difference.

Probability of rejecting Ho when Ho is fault.

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7 Step to do research

1. Research question2. Review & do literature search3. Create study design: protocol writing4. Perform data collection5. Data management: entry & cleaning 6. Data analysis7. Conclusion

1. Research questions

•Relevant •Interesting •Focused

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Focused research question

• PopulationP• InterventionI

• ComparisonC• OutcomeO

Study question

The protocol should start with a clear and precise formulation of the research question. It is good practice to write this in the form of a question, not a statement.

Example:

What is the most proper treatment in lupus nephritis?

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Objectives

Even a precise study question is often too broad for one study to answer, like “What is the most proper treatment in lupus nephritis?” You must therefore break down the question into several objectives.

Example:

Is Tacrolimus regimen better than Mycophenolate mofetil regimen as an induction therapy to induce complete remission in active lupus nephritis?

Focused research question

• Active lupus nephritis patientsP

• Tacrolimus inductionI

• Mycophenolate mofetil inductionC

• Complete remission rateO

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7 Step to do research

1. Research question2. Review & do literature search3. Create study design: protocol writing4. Perform data collection5. Data management: entry & cleaning 6. Data analysis7. Conclusion

When?

Clinical problemTopic presentationResearch Teaching

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Why?

Enormous volume stored in searchable databases

Ever-increasing number of important clinical research

Everyone know how to do electronic literature search

Where?

Primary sources (unfiltered) Medline database: Pubmed, Ovid Google Scopus

Secondary sources (filtered) Uptodate Cochrane library TRIP database

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How?

1. Formulate your PICO question

2. Try secondary sources

3. Choose primary database(s)

4. Combine textwords

5. Filter for the right type of study

Step 1. Formulate your PICO question

Forming Clinical Question (PICO) Patient Intervention Comparison Outcome

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Step 2. Try secondary sources

Uptodatehttp://www.uptodate.com

Cochrane libraryhttp://www.thecochranelibrary.com

TRIP databasehttp://www.tripdatabase.com

Step 3. Primary sources Choosing the right bibliographic database(s)

Database Coverage

MEDLINE US database covering all aspects of clinical medicine, biological sciences, education and technology

EMBASE European equivalent of MEDLINE, with emphasis on drugs and pharmacology

CINAHL Nursing and allied heath, health education, occupational and physiotherapy, social services

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Intersection (AND) only those citations that contain selected

terms. Union (OR) citations that contain at least one of the

selected terms. Difference (NOT) exclude citations with the selected term

Step 4. Combine textwordsBoolean Operators

Boolean Search

Relevant articles

AND

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Relevant articles

Boolean SearchOR

Boolean SearchNOT

Relevant articles

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MEDLINE searching skills

Searched with keywords

Applied “‘‘Limits’’

Used “‘‘Related articles’’ option

Used “Clinical Queries”

Used Medical Subject Headings (MeSH)

Step 5. Filter for the right type of study

Relevant P I C O

High impact factor journal Appropriate study design Up date Well-known authors

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7 Step to do research

1. Research question2. Review & do literature search3. Create study design: protocol writing4. Perform data collection5. Data management: entry & cleaning 6. Data analysis7. Conclusion

Research form

By study design Experimental, Observational study Descriptive, Analytic study

By category of clinical question Therapy, diagnosis, causation,

prognosis

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Quasi

Hierarchy of EvidenceSystematic reviews

Randomized Controlled Trials

Cohort studies

Case-control studies

Cross-sectionalstudies

Cases reports

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Observational Research

Descriptive study

•Case series

•Cross-sectional study

•Surveillance

•Ecological correlation study

Analytic study

•Cross-sectional study

•Case-control study

•Cohort study

Descriptive study

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Case seriesVertical dengue infection:case reports and review.

Two vertical dengue infection cases are presented, and 15 others are reviewed.

Twelve mothers had fever 0-9 (median, 2) days antepartum.

The fevers of 17 neonates occurred at 1-11 (median, 4) days of life and lasted for 1-5 (median, 3) days.

Neonatal thrombocytopenia was detected at 1-11 (median, 6) days of life and lasted for 3-18 (median, 6) days; the lowest platelet counts were 5-75 x 10(3) (median, 19 x 10 (3))/mm3. One neonate died.

Sirinavin S. Pediatr Infect Dis J. 2004

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Examples of early leads from descriptive studies

Epidemiology series. Lancet 2002; 359:145

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Surveillance “the ongoing systematic collection,

analysis, and interpretation of health data essential to the planning, implementation, and evaluation of public health practice, closely integrated with the timely dissemination of these data to those who need to know.”

Feed back Surveillance can be either active or passive.

Ecological correlational studies Look for associations between

exposures and outcomes in populations rather than in individuals.

For example, death rates from coronary artery disease correlate with per capita sales of cigarettes.

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Rate of skin biopsy correlate with the incidence of melanoma

Descriptive: Cross-sectional Study

Population

One measurement

tSample

Population

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Descriptive: Cross-sectional Study

Prevalence of diseases: Microalbuminuria in type2 DM

Morbidity survey: -post-spinal headache

Distribution:-mean, S.D. of Hb in ESRD

1995 1996 1997

Describe the prevalence of malaria

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Descriptive vs. Analytic

Descriptive:To describe

Analytic:To explain

Descriptive study

What they can doTrend analysis (forecasting)PlanningClues about cause (generate hypothesis)

What they cannot doconclusions about cause of diseaseOver- or misinterpretation of data

(absence of clear, specific, and reproducible of case definition)

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Analytic studies

Analytic Cross-sectional Study

50 100

20 80

ex+

ex-

O+ O-

Relative prevalence O+ =

(50/150)/(20/100)= 1.67

exercise

Obesity

Association, no sequence

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Cross-Sectional Study Advantage Inexpensive, simple (no follow-up)

No exposure, No drop out

DisadvantageCan establish association but not causation

Can not control confounder

Recall bias

Incidence-prevalence bias

Disease/Outcome

No disease/No outcomes

Exposed

Unexposed

Exposed

Unexposed

Time

Direction of study

Case-control Study Design

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Case-Control StudyAdvantageQuickly and inexpensive

Feasible for rare disorder or long follow-up

May required fewer subjects

DisadvantageRecall Bias

More effect of confounder

Difficult to find control group

Exposed

Non-exposed

With outcome

Without outcome

With outcome

Without outcome

TimeDirection of study

Prospective cohort study

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Exposed

Non-exposed

With outcome

Without outcome

With outcome

Without outcome

Time

Direction of study

Retrospective/Historical cohort study

Cohort StudyAdvantageCan be standardized in eligible criteria &

outcome assessment

Can establish temporal association

DisadvantageUsually expensive

Hard to blind

Long follow-up period for rare disorder

Difficult to find controls and confounders

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sample

Population

Randomization

Treatment Control

OutcomeNo

outcome OutcomeNo

outcome

Blind assessment

Randomized Control Trial

Randomized Control TrialAdvantageConfounding variables can be balance by

randomization

Blinding of subjects, medical staff and investigators are achievable

DisadvantageCostly in term of time and money

Dropout or loss to follow-up are common events

Need time for final results

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Research questions

Diagnostic study Treatment study Risk/Harm study or Etiologic study Prognostic study

Broad topics of research

Diagnosis - Demonstrate that a new diagnosis test is valid and reliable

Preferred cross-sectional study

Causation or Risk- Determine that a agent is related to development of illness

Preferred cohort or case-control study

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Therapy - Testing the efficacy of interventions

Preferred randomized controlled trial

Prognosis - Determine what happen to someone with some stage of disease

Preferred prospective cohort study

Broad topics of research

Is the exposure or intervention under the

control of the investigator?

Are the subjects followed up over time?

Are the subjects selected according to the

outcome?

Cross-sectional

No

No

No

Experiment

Cohort

Case-Control

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Key methodologic strengths and weakness

Bias

Bias is defined as ‘‘any process at any stage of inference which tends to produce results or conclusions that differ systematically from the truth’’

The consistent deviation of analytical results from the "true" value causes by systematic errors in a procedure.

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Bias

Selection biasMeasurement bias

Confounding

Selection bias

A nonrandom selection of study participants leads to erroneous conclusions or method or conduct to absence of comparability between groups being studied.

Absence of comparability between groups being studied.

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Common types of selection bias Berkson Bias (Hospital case differ than

community population) Unmasking bias/Ascertainment bias/

Surveillance bias Healthy worker effect (EGAT Good v.s Poor) Volunteer Bias (Healthy or diseases sample

e.g. MRI brain) Non-Response Bias (eg. Questionnaire

sexual issue, confidential issue, not interest issues)

Berkson bias If hospital based cases/controls have different

exposures than population based cases/controls, OR will be biased

Case control study of pancreatic cancer and coffee drinking.

Controls were selected from gastroenterologist’s patients in same hospital. However, GI patients are less likely to drink coffee than the rest of the population because of their disease.

Hence the OR for coffee drinking was artificially increased due to the under-representation of coffee drinkers among controls.

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Unmasking bias Exposure “causes a sign or symptom

which precipitates a search for the disease”

Case Control Study of Oral Contraceptive Use and Diabetes OC users more likely to have medical visits,

resulting in higher probability of subclinical disease being detected.

Any association with OC use and diabetes would be an overestimate of risk because subclinical diabetics with no OC use would have a lower probability of being selected.

Measurement bias

Incorrect determination of exposure or outcome, or both.

Gathering information in different wayExample

Case: Bed side Control: telephone

Measurement bias, diagnostic suspicion bias, or recall bias

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Confounding

A confounding variable is associated with the exposure and it affects outcome, but it is not in an intermediate link in the chain of causation between exposure and outcome

7 Step to do research

1. Research question2. Review & do literature search3. Create study design: protocol writing4. Perform data collection5. Data management: entry & cleaning 6. Data analysis7. Conclusion

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Focused research question

• Active lupus nephritis patientsP

• Tacrolimus inductionI

• Mycophenolate mofetil inductionC

• Complete remission rateO

4. Data collection

Procedure/visits

Screening Randomization Induction Phase

Visit

1 2 3 4 5 6 7 8 9

Week

-4 0 2 4 8 12 16 20 24

Informed consent ✓

Check inclusion/exclusion

criteria ✓

Demography & history ✓

Height ✓

Weight ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

BP ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

SLEDAI2K✓ ✓ ✓ ✓

SLICC

✓ ✓

CBC ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

U/A ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

UPT ✓ ✓

24hr urine protein or UPCR ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

FBS, Kidney & liver function ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

Serum & urine biomarkers ✓ ✓ ✓ ✓

SF-36, EQ5D, SLEQOL✓ ✓

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5. Data management

6. Data analysis Baseline characteristics of LN patients who

were stratified by renal pathology were described using mean ± SD or median (interquartile range) for the continuous data and frequency and percentage for the categorical data.

Primary outcome: CR The Kaplan-Meier method was applied to estimate

the incidence rate and median time to CR after receiving TAC and MMF.

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Health service & policy

Evaluation of health serviceApply epidemiology in health policy

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Generating research question

Study design & planning

Grant applicati

on

IRB/IEC approval

Writing study

protocol

Conducting study

Recruitment

Consent obtaining

Follow up

Data entry & analysis

Writing report/

publication

Completing CRF/AE

Monitoring/ QA/Regulatory compliance

Clinical Research Process

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Institutional Review Board (IRB)

An independent body constituted of medical scientific and non-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects.

Reviewing, approving, and providing continuing review of trials.

Proposals that require ethical review

All proposals for research that involve human subjects, or laboratory animals, must be submitted to independent ethical review.

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Why concern about Ethic?

Medical practices vs. research

Ethical principles for practice and research

Respect for persons Beneficence & Do no harm Justice

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Respect for persons

All individual human beings are presumed to be free and responsible persons and should be treated as such in proportion to their ability in the circumstances.

Autonomy is the capacity for self-determination.

Beneficence & Do no harm

Beneficence To maximize possible benefits and to

minimize possible harms and wrongs Do no harm Guards against avoidable harm to

research subjects

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Justice

Studies should be designed to obtain knowledge that benefits the class of persons of which the subjects are representative.

In the context of health care, distributive justice requires that everyone receive equitable access to the basic health care necessary for living a fully human life insofar as there is a basic human right to health care.

The Tuskegee Study of Untreated Syphilis in the Negro Male

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Tuskegee Syphilis Experiment (1932-1972)

US Public Health Service study on natural history of syphilis

399 black men with syphillis were recruited. they were mostly illiterate

They were not Informed about their disease, the nature of the study, the risk to the partner

Offers for free examination ,medicines, insurance, hot meal, transportation.

No treatment for the disease.

Declaration of Helsinki (1964)

Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964

Revised by the World Medical Assembly in Tokyo, Japan in 1975, in Venice, Italy in 1983, and in Hong Kong in 1989 and the 48th General Assembly, Somerset West, Republic of South Africa, October 1996 and 2000 (Edinburgh, Scotland). added by the WMA General Assembly, Washington 2002.

It is the mission of the physician to safeguard the health of the people

Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects

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Respect for Persons – people are not a means to an end; researchers have duty to protect life, health, privacy and dignity of research participants

Standard of care must be best available, even for control group

Proxy consent(การอนุญาต) and assent(เห็นด้วย) for vulnerable populations

Placebo

Declaration of Helsinki

Informed consent Regarded as part of the project proposal Include 1. Information sheet (Statement): Describe the study and the nature of

subject’s involvement in it 2. Certificate of consent: Attesting the subject’s consent Simple language Given to or read to each prospective subject By signing, the staff member confirms that

consent was given freely A copy should be offered to the subject

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Confidentiality

Unlinked information Subjects need to be informed for how

long personal identifiable data will be maintained. And they will be destroyed.

Good Clinical Practice (GCP)

A standard for clinical studies which encompasses the design, conduct, monitoring, termination audit, analyses, reporting and documentation of the studies.

To ensure that the studies are scientifically and ethically sound.

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Clinical Research Team

Principal investigator Coinvestigators Research project manager Clinical research coordinator (CRCs) Clinical research assistants (CRAs)

Major problem areas for clinical research

Study design What is the question posed – what type of study can best answer the question and is most practicable?

Population selection

Who should be studied?How many should be studied?

Information gathering

How should the information be obtained?Is the information obtained correct?Is the method used to obtain the information consistent?

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Major problem areas for clinical research

Analysis How should the data gathered be prepared for analysis?What are the appropriate analytical methods?

Interpretation of results

Can any associations observed be explained by confounding?Are the results explained by bias?Are the results generalizable?

Logistics Is the research ethical?Is the research affordable?

Documents needed in a clinical research

Study protocol IRB/IEC approval document +/- grant application document Instruction sheets for investigator Patient information sheet & Informed

consent Case record form & Adverse event

record form

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RACE 612Study designs & Measurements

Lecture Self study 5 Assignments (75%) Cohort Cross-sectional Case-control Association & causation Nested case-control

Final examination (25%)

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Question?