In the Name of Allah · In the Name of the Almighty Evidence Based Medicine Alipasha Meysamie, MD, MPH Professor in Community and Preventive Medicine Tehran University of Medical

Alipasha Meysamie, MD, MPHProfessor in Community and Preventive MedicineTehran University of Medical [email protected]

11/4/2016

Evidence Based Medicine 1

In the Name of the Almighty Evidence Based MedicineAlipasha Meysamie, MD, MPH

Professor in Community and Preventive Medicine

Tehran University of Medical Sciences

Level of Evidence Level of Evidence

Level of EvidenceMEDICAL EVIDENCE HIERARCHY

1. Meta-analysis

2. Systematic Review

3. Randomized Clinical Trials

4. Clinical Trials

5. Cohort

6. Case-control

7. Case Series

8. Case Reports

9. Expert Opinion


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RCT23 Patients

1960

1 20.5

Odds Ratio

Treatment Control

Thrombolytic Therapy & MI mortality

Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC: A comparison of results of meta-analyses ofrandomised control trials and recommendations of clinical experts. JAMA 1992;268:240-8

Cumulative

Year RCTs Pts

1960

1965

1 20.5

1 232 653 1494 3167 1793

Odds Ratio

Treatment Control

Antman JAMA 92

Thrombolytic Therapy & MI mortality

Cumulative

Year RCTs Pts

1960

1965

1970

1975

1980

1985

1990

1 20.5

1 232 653 149

4 3167 179310 254411 265115 331117 392922 545223 576727 612533 657165 4718570 48154

Odds Ratio

Treatment Control

p < 0.01

p < 0.001

p < 0.00001

Antman JAMA 92

Thrombolytic Therapy & MI mortality Thrombolytic Therapy & MI mortality

Cumulative

Year RCTs Pts

1960

1965

1970

1975

1980

1985

1990

1 20.5

1 232 653 149

4 3167 179310 254411 265115 331117 392922 545223 576727 612533 657165 4718570 48154

Odds Ratio

Treatment Control

p < 0.01

p < 0.001

p < 0.00001

TextbookRecommendations

Rout Specif Exp NOT

21

5

10

2

8

7

8

12

4

3

1

1

1

1

2

8

7

2

1

112

81

5

156

Antman JAMA 92

Hypothesis?

Sample size

estimation

None!

Failure to detect

a difference

=

Equivalence?


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Assume non-inferiority if

the lower limit of 95% CI is

less than –5%,

N=904 per group!

What evidence-based medicine is

•“The conscientious, explicit and judicious use of current best evidence in making clinical decisions about the care of individual patients.”

Sackett et al, 2000

Scientific Search in EBM

Search Principles 1. Finding the best question.

• Background ( what, where, when, why, how, who )

• Foreground (PICO)

2. Setting the best keywords.

• The most specific

Search Principles 3. Planning Search strategies.

• Grounded pattern

• Web directory

• Multiple search assembly

• (and, +; or, /; not, -; Near/Proximity Search, /adj#

;(Nested Search) ;”Phrasal Search”; Wildcard

Search,* ,?,$)

• Limitation assignment

• Field Search, Date Search

Search Principles

4. Sorting search results

• By relevancy to keywords

5. Rating search results

• By quality of evidence

6. Relating evidences to question

• By comparing attributes


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Search Properties

• Sensitivity

• % of related found

• Specifity

• % of non related not found

• Accuracy

• Sensitivity + Specifity + Relevancy

Sensitivity, Specificity, Accuracy

• 101000 Documents• 100000 Non Related 10000 Found

• Spe=90% 90000 Not found

• 1000 Related 900 Found• Sen=90% 100 Not Found

• 10900 Results with only 900 Related• Accuracy about 8%


• 101000 Documents• 100000 Non Related 10000 Found

• Spe=90% 90000 Not found

• 1000 Related Sen=99% 990 Found• 10 Not Found



• 101000 Documents• 100000 Non Related Spe=99% 1000 Found

• 99000 Not found

• 1000 Related 900 Found• Sen=90% 100 Not Found


Kind of Databases• General Databases

• ( www.searchenginewatch.com)

• ( www.pandia.com )• www.google.com 1st

• www.altavista.com 4th CS

• www.yahoo.com sub Google ,Best web directory

• www.hotbot.com 3rd CS ,Multimedia

• www.ask.com

• www.netscape.com sub Google

• www.msn.com

• www.lycos.com 2nd , Multimedia

• www.northernlight.com 5th

• www.excite.com 6th

Kind of Databases

• Meta searchers

• Searching multiple databases

• www.metacrawler.com

• www.dogpile.com

• www.infind.com

• www.profusion.com

• www.search.com

http://www.searchenginewatch.com/

http://www.pandia.com/

http://www.google.com/

http://www.altavista.com/

http://www.yahoo.com/

http://www.hotbot.com/

http://www.ask.com/

http://www.netscape.com/

http://www.msn.com/

http://www.lycos.com/

http://www.northernlight.com/

http://www.excite.com/

http://www.metacrawler.com/

http://www.dogpile.com/

http://www.infind.com/

http://www.profusion.com/

http://www.search.com/


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Kind of Databases

• Specific databases

• http://www.blackwell-synergy.com/

• http://search.epnet.com/

• http://www.sciencedirect.com/

• http://www3.interscience.wiley.com/journalfinder.html

• http://www3.oup.co.uk/jnls/online/

• http://www.daneshyar.org/show.php?id=16493

• http://www.bellhowell.infolearning.com/pqdauto

• http://www.springerlink.com/

IE Hot keys

• Alt+left arrow key

• Alt+right arrow key

• Ctrl+D (add to favorate)

• Ctrl+B (manage favorate)

• Ctrl+I (open favorate)

• Ctrl+X (cut)

• Ctrl+C (copy)

• Ctrl+V (paste)

• Save target as…

• Ctrl+F (find)

• Ctrl+P (print)

• Ctrl+H (open history)

• Ctrl+L (new URL)

• Ctrl+N (New page)

• Shift+Click (Open in new window)

• Ctrl + Enter (add site specifications)

WWW.Google.com• Most important features

• Choosing search terms • Capitalization ; NOT case sensitive• Automatic "and" queries • Automatic exclusion of common words

• Ignores common words and characters

• Word variations (stemming) • Also for similar terms

• Phrase searches • Space before "+" sign• Quotation marks around two or more words , exact phrase

• Negative terms • Term more than one meaning , minus sign ("-") in front of words

related meaning to avoid.

• And finally... "I'm Feeling Lucky" • Site , homepage

Advanced Search

• ALL terms

• Exact phrase

• At least one of the words

• NOT contain any of the words

• Certain language

• Certain file format

• Updated within a certain period of time

• Numbers within a certain range

• Within a certain domain, or website

• Don't contain "adult" material

Advanced search "operators"• Include Search

• "+" search

• Synonym Search • Tilde sign ("~") immediately in front of search term

• OR Search • Either of two search terms, an uppercase OR between terms

• Domain Search • Within one specific website, followed by word "site:" followed by

domain name

• Num range Search • Results containing numbers in a given range

• Two numbers, separated by two periods, with no spaces• Specify a unit of measurement or some other indicator

• Other Advanced Search Features• Safe search• Link• Info • Related

Other advanced search features• Google Local:

• Find products and services in a specific U.S. town or zip code.

• Language: • Specify in which language you'd like your results.

• Technology Search: • Find information related to Apple Macintosh, BSD Unix, Linux or

Microsoft.

• Date: • Restrict your results to the past three, six, or twelve month periods.

• Occurrences:• Specify where your search terms occur on the page - anywhere on the

page, in the title, or in the url.

• Domains: • Search only a specific website, or exclude that site from your search.

• Safe Search: • Eliminates adult sites from search results

http://www.blackwell-synergy.com/

http://search.epnet.com/

http://www.sciencedirect.com/

http://www3.interscience.wiley.com/journalfinder.html

http://www3.oup.co.uk/jnls/online/

http://www.daneshyar.org/show.php?id=16493

http://www.bellhowell.infolearning.com/pqdauto

http://www.springerlink.com/

http://www.google.com/


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Google search results

• A. Top links• Google service you

• B. Google search button• Submit another search query. also 'Enter' key.

• C. Advanced search• Links to more precise searches.

• D. Search field• Type a few descriptive search terms

• E. Preferences• Set your personal search preferences, including language, number of results per

page, and whether Safe Search filter.

• F. Statistics bar• Describes your search and indicates total number of results, as well as how long

search took to complete.

• G. Tip• Information helps search more efficiently and effectively

• H. One Box results• Include news, stock quotes, weather and local websites related to search.

Google search results• I. Page title

• Title of web page found. • URL instead of a title, then either page has no title or haven't yet indexed

• J. Text below the title• Excerpt from result page with query terms bolded.

• K. URL of result• web address of returned result.

• L. Size• s ize of text portion of web page,

• M. Cached• Contents of web page last indexed. For links doesn't connect.

• N. Similar pages• Automatically scouts Web for pages related to result.

• O. Indented result• Multiple results from same website, most relevant listed first,

• P. More results• More than two results from same site, remaining results accessed by clicking on

"More results from..." link.

PubMed

• Entrez retrieval system• http://www.ncbi.nlm.nih.gov/Database/index.html

• National Center for Biotechnology Information (NCBI)• http://www.ncbi.nlm.nih.gov/

• National Library of Medicine (NLM)• http://www.nlm.nih.gov/

• National Institutes of Health (NIH)• http://www.nih.gov/

PubMed

• Text-based search• Including

• PubMed, • Access to ci tations from biomedical literature.

• Nucleotide and Protein Sequences,

• Protein Structures,

• Complete Genomes,

• Taxonomy,

• OMIM, …

• LinkOut• http://www.ncbi.nlm.nih.gov/entrez/linkout/

• Access to full-text articles at journal Web sites and other related Web resources.

PubMed

• Publishers participating in PubMed• Electronically submit

• http://www.ncbi.nlm.nih.gov/entrez/query/static/publisher.html

• Citations to NCBI prior to or at the time of publication.

• Batch Citation Matcher, • http://www.ncbi.nlm.nih.gov/entrez/getids.cgi

• Allows users to match their citations to PubMed citations • Using bibliographic information as journal, volume, issue, page number,

and year.

http://www.ncbi.nlm.nih.gov/Database/index.html

http://www.ncbi.nlm.nih.gov/Database/index.html

http://www.ncbi.nlm.nih.gov/

http://www.ncbi.nlm.nih.gov/

http://www.nlm.nih.gov/

http://www.nlm.nih.gov/

http://www.nih.gov/

http://www.nih.gov/

http://www.ncbi.nlm.nih.gov/entrez/linkout/

http://www.ncbi.nlm.nih.gov/entrez/linkout/

http://www.ncbi.nlm.nih.gov/entrez/query/static/publisher.html

http://www.ncbi.nlm.nih.gov/entrez/query/static/publisher.html

http://www.ncbi.nlm.nih.gov/entrez/getids.cgi



11/4/2016


PubMed Coverage

• MEDLINE• http://www.nlm.nih.gov/pubs/factsheets/medline.html

• Premier bibliographic database , 12 million citations dating back to the mid-1960's

• OLDMEDLINE• http://www.nlm.nih.gov/databases/databases_oldmedline.html

• From 1950 through 1965.

• Not been updated with MeSH Terms

• Not contain abstracts.

PubMed Coverage

• In Process Citations• Basic citation information and abstracts before indexed with NLM's

MeSH Terms and added to MEDLINE. • Tag [PubMed - in process].

• Tag [PubMed - indexed for MEDLINE].

• Publisher-Supplied Citations• Citations received electronically from publishers

• Tag [PubMed - as supplied by publisher].

• Not all will be indexed for MEDLINE

PubMed Journal Information• Journals Database

• http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=journals

• Searched using journal title,

• MEDLINE/PubMed title abbreviation,

• NLM ID (NLM's unique journal identifier),

• International Organization for Standardization (ISO) abbreviation,

• Print and electronic International Standard Serial Numbers (pISSNs and eISSNs). • Includes all journals in all Entrez databases (e.g., PubMed, Nucleotide,

Protein).

PubMed Journal Information• Journal LinkOut Providers

• http://www.ncbi.nlm.nih.gov/entrez/journals/loftext_noprov.html

• List of Web-based journals to which PubMed currently provides links.

• Full list of PubMed journals• http://www.ncbi.nlm.nih.gov/entrez/getids_help.html#JournalLists

PubMed Citation Matcher

• Allows users to match their own list of citations to PubMed citations, • Using bibliographic information as journal, volume, issue, page

number, and year.

• Single Citation Matcher• http://www.ncbi.nlm.nih.gov/entrez/query/static/citmatch.html

• To find a single article.

• Batch Citation Matcher• http://www.ncbi.nlm.nih.gov/entrez/getids.cgi

• To look for many articles.

Medical advice?

• MEDLINEplus

• http://medlineplus.gov/

• Easy-to-understand resource for public

http://www.nlm.nih.gov/pubs/factsheets/medline.html

http://www.nlm.nih.gov/pubs/factsheets/medline.html

http://www.nlm.nih.gov/services/oldmed.html

http://www.nlm.nih.gov/databases/databases_oldmedline.html

http://www.nlm.nih.gov/databases/databases_oldmedline.html

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=journals

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=journals

http://www.ncbi.nlm.nih.gov/entrez/journals/loftext_noprov.html


http://www.ncbi.nlm.nih.gov/entrez/getids_help.html#JournalLists

http://www.ncbi.nlm.nih.gov/entrez/getids_help.html#JournalLists

http://www.ncbi.nlm.nih.gov/entrez/query/static/citmatch.html

http://www.ncbi.nlm.nih.gov/entrez/query/static/citmatch.html



http://medlineplus.gov/


11/4/2016


Full article?

• Full-Text Links:

• Links available for journal publishers and full-text

providers that participate in LinkOut.

• May require a subscription or fee.

• list of journals with links to full-text

• http://www.ncbi.nlm.nih.gov/entrez/journals/loftext_noprov.html

Find a journal, issue, or citation for a specific article.

• Single Citation Matcher

• Fill-in-the-blank form

• Allows to enter partial journal citation information to locate a record

PubMed Searches

• Author

• Last name plus initials (no punctuation), e.g., smith ja, jones k.

• Automatically truncates author's name

• Only search in author field

• Only author's last name, PubMed searches name in All Fields,

• Except when author name found in MeSH (National Library of Medicine's

Medical Subject Headings)

• Translation table(e.g., Yang will search as Yin-Yang [MeSH] or Yang [Text

Word].)

• To search for an author in author field only last name available,

• Author name with author search field tag [au], e.g., yang [au].

• Double quotes around author's name with author search field tag [au] to

turn off automatic truncation, e.g., "smith j" [au].

PubMed Searches

• Journal Titles

• Full journal title,

• e.g., molecular biology of the cell;

• MEDLINE abbreviation,

• e.g., mol biol cell;

• ISSN number (standardized international code),

• e.g., 1059-1524;

• variant title as appears in NLM catalog

• Journal is also a MeSH term (e.g., Gene Therapy, Science,

or Cell),

• Journal Title search field tag, [ta],

PubMed Searches

• Journal Titles

• Single word journal titles

• Journal Title search field tag, [ta],

• Includes a special character (e.g., parentheses, brackets,

&),

• Enter title or abbreviation without special characters.

• For example: to search, j hand surg [am],

• enter j hand surg am.

PubMed Searches

• Automatic Term Mapping

1. MeSH Translation Table

• Mappings (also known as entry terms) for

• MeSH terms,

• MeSH Subheadings,

• Publication Types,

• Pharmacologic Action terms,

• Terms derived from Unified Medical Language System (UMLS) that have

equivalent synonyms or lexical variants in English,

• Supplementary Concept (Substance) Names and their synonyms.

• MeSH hierarchy, and as Text Word

• vi tamin h

• Translate to: ("Biotin“ [MeSH Terms] OR vitamin h [Text Word]).

http://www.ncbi.nlm.nih.gov/entrez/query/static/help/pmhelp.html#LinkOut



http://www.ncbi.nlm.nih.gov/entrez/query/static/help/pmhelp.html#SingleCitationMatcher

http://www.nlm.nih.gov/pubs/factsheets/umls.html

http://www.nlm.nih.gov/pubs/factsheets/mesh.html


11/4/2016


PubMed Searches


2. Journals Translation Table

• Contains

• Full journal title,

• MEDLINE abbreviation,

• ISSN number

• New england journal of medicine

• Translate to: "N Engl J Med"[Journal].

3. Author Index

• Not found in above tables and not a single term

PubMed Searches


• If no match is found?

• Breaks apart phrase

• Repeats above automatic term mapping

• No match,

• Individual terms combined (ANDed) together and searched in

All Fields

PubMed Searches

• Truncation

• Finding all terms begin with a given text string

• Asterisk at the end of a term

• For the first 600 variations

• Turns off

• automatic term mapping and

• Automatic explosion of a MeSH term

PubMed Searches

• Phrase Searches

• Not actually perform adjacency searching

• Entering the phrase in quotes, e.g., "single cell" or

• using a search tag, e.g., single cell [ti].

• Not in the index of searchable terms

• Ignores

• Not perform automatic term mapping that includes explosion of

MeSH terms

• For example, "health planning"

PubMed Searches• Boolean and Syntax

• combining terms with search tags

• Boolean operators should be entered in uppercase

characters,

• i .e., AND, OR, NOT.

• Not entered, PubMed assumes AND operator

• Processes all Boolean connectors in a left-to-right sequence

• Change order by enclosing concepts in parentheses

• e.g., common cold AND (vitamin c OR zinc).

• search term [tag] BOOLEAN OPERATOR search term [tag]

PubMed Searches• Search Field tags.

• Affiliation [AD]

• All Fields [ALL]

• Author [AU]

• Corporate Author [CN]

• EC/RN Number [RN]

• Enzyme Commission (EC) by Chemical Abstracts Service (CAS) for

Registry Numbers

• Entrez Date [EDAT]

• Date range, insert a colon (:) between each date (e.g., 1996:1997

[edat] or 1998/01:1998/04 [edat]).


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• Grant Number [GR]

• Issue [IP]

• Investigator [IR]

• NASA-funded principal investigator(s)

• Journal Title [TA]

• Language [LA]

• MeSH Date [MHDA]

• MeSH Major Topic [MAJR]

• MeSH Subheadings [SH]

• MeSH Terms [MH]


• NLM Unique ID [JID]

• Other Term [OT]

• Owner

• Pagination [PG]

• Only first page number that article appears on

• Personal Name as Subject [PS]

• Pharmacologic Action MeSH Terms [PA]

• Place of Publication [PL]

• Publication Date [DP]

• Search X days, months or years immediately preceding today’s date where X = numeric value:• “last X days” [dp]

• “last X months” [dp]

• “last X year” [dp]


• Publication Type [PT]

• e.g., Review, Clinical Trial, Retracted Publication, Letter

• Publisher Identifier [AID]

• Secondary Source ID [SI]

• Subset [SB]

• Substance Name [NM]

• Text Words [TW]

• Title [TI]

• Title/Abstract [TIAB]

• Unique Identifier [UID]

• Volume [VI]

PubMed Searches• PubMed's Date Fields

• Date of Publication [DP]

• Entrez Date [EDAT]

• Date citation first entered PubMed.

• MeSH Date [MHDA]

• Date citation indexed with MeSH terms.

PubMed Searches• Examples of Boolean Search Statements:

• Find citations on DNA that were authored by Dr. Crick in 1993. • dna [mh] AND crick [au] AND 1993 [dp]

• Find articles that deal with the effects of heat or humidity on multiple sclerosis, where

these words appear in all fields in the citation. • (heat OR humidity) AND multiple sclerosis

• Find English language review articles that discuss the treatment of asthma in preschool children. • asthma/therapy [mh] AND review [pt] AND child, preschool [mh] AND

english [la]

• Find citations about arthritis excluding the Publication Type Letter. • arthritis NOT letter [pt]

PubMed Searches• Feature Tabs

• Limits

• Field Selection

• Only Items with Abstracts

• Publication Types • Cl inical Trial , Editorial ,Letter ,Meta-Analysis ,Practice Guideline

,Randomized Controlled Trial ,Review

• Languages • English ,French ,German ,Italian ,Japanese ,Russian ,Spanish

• Gender

• Humans or Animals


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• Limits

• Ages • Al l Infant: birth-23 months ,All Child: 0-18 years ,All Adult:19+ years

,Newborn: birth-1 month ,Infant: 1-23 months ,Preschool Child: 2-5 years ,Chi ld: 6-12 years ,Adolescent: 13-18 years ,Adult: 19-44 years ,Middle Aged: 45-64 years ,Middle Aged + Aged: 45+ years ,Aged: 65+ years ,80 and over: 80+ years

• Humans or Animals

• Subsets • AIDS ,Bioethics ,Cancer ,Complementary Medicine ,Core clinical journals

,Dental journals ,History of Medicine ,MEDLINE ,Nursing journals,OLDMEDLINE ,PubMed Central ,Space Life Sciences ,Toxicology

• Dates • Entrez Date

• Publication Date


• Preview/Index

• View and select terms

• Preview number of search results

• Refine searches by adding one or more terms

• Add terms to a strategy from specific search fields

• Available Boolean operators :

• 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


• History

• Display searches in order run

• Combine searches

• Add additional terms to an existing search

• by us ing the pound sign (#) before the search number, e.g., #2 AND #6,

or #3 AND (drug therapy OR diet therapy).

• Maximum number of searches in History ; 100

• Remove oldest search and add most current

• Lost after eight hours of inactivity

• Separate Search History for each Entrez databases

• accept cookies


• Clipboard

• Collect selected citations from one search or several searches

• Add citations to Clipboard,

• Send to a file or order.

• Maximum number of items in Clipboard ; 500

• Save from the Clipboard

• Sort

• Order Documents in the Clipboard

• Order Documents

• Delete Citations from the Clipboard

• Check box ,select Clip Remove


• Details

• automatic term mapping

• search rules and syntax

• Edit Your Search

• Save a Search

• From Details, use URL button to display current search as a URL and then

bookmark URL for future use

Research Methodology

Levels of Evidences

http://www.nlm.nih.gov/bsd/aim.html


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Why Different Methods in Clinical Research?

Reasons for Different Methods in Clinical Research

• Different Levels of Information

• Different Goals

• Different MMM

• Different Practical Usage

Different Results of Different Methods

1. Measuring Vital Statistics• Mortality, Morbidity and Other Rates

• Normal Rage and Cut offs• Mean±2SD or Percentiles

2. Epidemiological Surveys• Diagnosis

• Interventions

• Risk Factors, Incident and Prevalence

• Researches in Surveillance System

Different Results of Different Methods

3. Intervention Evaluation• For one patient

4. Screening Tests Evaluation• Sensitivity, Specificity, Reliability and Safety

4. Critical Appraisal

5. Proposal Preparation, Report Generation

6. Research Leadership or Contribution

Usual Methods In Clinical Research

• How to design a study?

1. What will be the practical usage of results?

2. What are the Biases (Limitations of each study)?

A. Chance Error

B. Selection or Classification Bias

C. Measurement Bias

1. Observer

2. Instrument

D. Confounding

Coffee DiseaseD+C+ 83%C- 18%

Smoking

D+S+ 90%S- 12%

C+S+ 85%S- 8%D+

C+ 90%S+C- 88%

C+ 14%S-C- 12.5%

D+S+ 90%C+S- 14%

S+ 88%C-S- 12.5%


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Classification of Methods1. Observational

• No objective related to any intervention

• Even there is an intervention in the study

• Assessment of the effect of Philadelphia Chromosome in the

response rate in AML patients

2. Experimental

• Objectives directly related to an intervention

• Even interventions performed previously or by the other

professions

• Assessment of the outcomes of 1000 cases of apendectomy in

Imam Khomaini Hospital

Classification of Observational Studies1. Descriptive

A. Case Series; Case Report

2. AnalyticA. Cross Sectional (Prevalence Study)

• Disease Description • Diagnosis & Staging • Disease Processes, Mechanisms

B. Case-Control (Retrospective) • Prevalence of Risk Factors• Identification of Probable Risk Factors

C. Cohort (Prospective)• Incidence of Disease• Natura l History , Prognosis• Identification of Probable Risk Factors

Cross Sectional Studies

Al l of the sampleSelected from the population

With Outcome or Characteristic

Without Outcome or Characteristic

Time (Past)

Study Duration

No Priority for Measurement of Variables (Outcome or Exposure)

Time (Future)

Case-control studies Cases

(Usually Diseased)

Controls(Usually Healthy)

Exposed

Not Exposed

Exposed

Not Exposed

Data Collection Direction

Retrospectively Time (Future)

Study Starts

Time (Past)

Cohort Studies

Selected CohortFrom Population

Exposed

Not Exposed

Outcome Happens

No Outcome Happens

No Outcome Happens

Outcome Happens


Prospectively Time (Future)

Study Starts

Time (Now)

Classification of Interventional Studies1. Controlled

A. Concurrent or Parallel Controls

• Randomized (RCT)

• Not Randomized (Quasi Experimental)

B. Sequential Controls

• Sel f Controlled

C. Combination of Concurrent and Sequential Controls

• Crossover Design

D. External Controls (Including Historical)

2. Experiments Without Controls


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Interventional Studies with Concurrent Controls

Selected

Candidates

Intervention

Control

Outcome Happens

No Outcome Happens

Outcome Happens

No Outcome Happens

Time (Future)

Study Start Interventions

Prescribed

Self Controlled Trials

Cure

No Cure

Cure

NoCure

SelectedCandidates

Intervention 1 Intervention 2

StudyStart

Time (Future)


WashoutPeriod

Cross Over Design

Cure

NoCure

Cure

NoCure

Cure

NoCure

Cure

NoCure

Selected Candidates

Intervention 1

Intervention 2

Intervention 1

Intervention 2

StudyStart

Time(Future)

InterventionPhase 1

WashoutPeriod

CASE

CR

OSS

OV

ER

InterventionPhase 2

Key Points in Case Series/Case report

Case Series/Case Report

• Interesting and outstanding characteristics

• Case Report: Less than 5 Cases

• Case Series: Less than 30 Cases

• Descriptive only; Not Analytic

• Practica l Usage: Preliminary Hypothesis for analytic s tudies

• No need to proposal

• Short time for writing the report

• No Control Group

• No Sample Size Ca lculation


• High Impact for Recently Evolved Diseases

• Crime Congo Hemorrhagic Fever (CCHF)

• Surveillance System

• Settings with Structured Reporting Syetem and Data Collection


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• Ophthalmic Branch of Facial Nerve Zoster

• Clinical, Virological and Historical Assessment

• Herpes ZosterDisease Usually

• HSV in Some Cases Detected Instead of HZV

• Importance of Herpes Simplex Disease

• Herpetic keratitis and Herpetic encephalitis

• Antiviral Therapy is Crucial

• Suggestions of this report

• Design studies for Differential Diagnosis and Risk Factor Assessment


• No Need to Sample Size Calculation• But Report Number of Cases

• Duration in which cases collected

• No need for sampling frame introduction• But report setting position in referral system

• Aim in the study:• Just reporting; No conclusion; No Suggestion

• Only use descriptive statistics

• No representativeness of results


• Common Biases

• Chance error: Small Sample Size

• Selection Bias: Case selection, Referral system

• Measurement Bias

• No control group

• Observer Bias:

• Measurements and observations

• Interpretation

Key Points in Cross Sectional Studies

Cross Sectional Studies• No priority between measurement of exposures or outcome

• Data collection in a period of time (usually a limited period)

• Events and exposures both has happened previously

• Practical Usages

• Prevalence Studies; Usually with influencing factors

• Case finding for Case-Control or Cohort studies

• Description, Diagnosis, Staging, Grading

• Screening test assessment

• One time sampling• Pol ls; Opinion assessment

• KAP Studies


Al l of the sampleSelected from the population

With Outcome or Characteristic

Without Outcome or Characteristic

Time (Past)

Study Duration

No Priority for Measurement of Variables (Outcome or Exposure)

Time (Future)


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Cross Sectional Studies• Assessment of correlation between variables

• Age and Cholesterol

• Ideal:

• Longitudinal Cohort Studies

• Collection of data of both age and cholestrole level

• Assessment of correlation


• Assessment of Screening Tests

• Performing both methods Simultaneously in patients

• Venography and Doppler Sonography in DVT Patients

• Non invasive, Cheaper, Faster methods for Dx

• Sensitivity: 95%

• Specificity: Not important


• Faster and Cheaper than Case-Control or Cohort Studies on the same subject

• A frame of A film• Many Biases

• Birth cohort effect

• Aging cohort effect• No temporality; preexistence of cause before outcome

• Being disease Versus Becoming disease

Cross Sectional StudiesFramingham Study• First step: Cross Sectional

• Same mean diastolic BP for all age groups• 80 mm Hg

• Second step: Cohort, Longitudinal• Increase in BP with Increase in Age

• Birth cohort or aging cohort effects• Higher mortality in Higher BP Groups with Aging• Los ing very high BP patients in higher Age groups

• But every person shows increase in BP with Aging

Cross Sectional StudiesAging and Birth Cohort effects

55 60 65 70 75 80

0-5 1.00% 2.00% 2.50% 3.00% 3.25% 3.45%

5-10 4.00% 5.00% 5.50% 6.00% 6.25% 6.45%

10-15 7.00% 8.00% 8.50% 9.00% 9.25% 9.45%

15-20 10.00% 11.00% 11.50% 12.00% 12.25% 12.45%

20-25 13.00% 14.00% 14.50% 15.00% 15.25% 15.45%

25-30 16.00% 17.00% 17.50% 18.00% 18.25% 18.45%

30-35 19.00% 20.00% 20.50% 21.00% 21.25% 21.45%

Cross Sectional StudiesAging and Birth Cohort effects

55 60 65 70 75 80

0-5 5.00% 2.00% 2.50% 3.00% 3.25% 3.45%

5-10 4.00% 9.00% 5.50% 6.00% 6.25% 6.45%

10-15 7.00% 8.00% 13.00% 9.00% 9.25% 9.45%

15-20 10.00% 11.00% 11.50% 17.00% 12.25% 12.45%

20-25 13.00% 14.00% 14.50% 15.00% 21.00% 15.45%

25-30 16.00% 17.00% 17.50% 18.00% 18.25% 25.00%

30-35 19.00% 20.00% 20.50% 21.00% 21.25% 21.45%


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• Selection Bias in Cross Sectional Studies

• Inevitable events

• Non participants

• Attrition

• Incomplete response

• No chance to follow up

• Representativeness or Generalizability of results

Cross Sectional Studies• Evitable Biases

• Sampling Frame or Structure

• Probable Sampling• Random Sampling

• Non Probable Sampling• Convenient Sampling

• Subgroups in population• Quota Sampling

• Stratified Sampling

• Clustered Sampling• Complex Sampling


• Sample size calculation

• Estimation formulas

• Numeric Variables

• Categorical Variables

d

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• Measures of association between variables

• Intra & Inter-Rater Agreement

• Kappa Statistic

• Screening test assessment

• Sensitivity, Specificity, PPV, NPV, Accuracy

• Correlation

• Pearson Correlation Coefficient

Cross Sectional Studies• Common Biases

• Selection Biases

• Sampling Techniques

• Non participants

• Missing data

• Absence of samples

• Measurement Biases

• Observer Variations

• Instrument Biases

• Chance Error

• Small number in subgroups with low frequency

• Multiple Risk Factor Assessment

Cross Sectional Studies• Chance Error


• For each comparison (Risk Factor)

• Acceptable Chance Error=0.05

• N Risk Factors→0.05 Error for each Risk factor assessment

• 0.95; Chance of correctly assess the relationship

• Chance of all n Risk Factors assessed correctly=

• Chance of one error in n Risk Factor assessment=

• n=10 Error= 40.1%


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Key Points in Case-Control Studies

Case-Control Studies Cases

(Usually Diseased)

Controls(Usually Healthy)

Exposed

Not Exposed

Exposed

Not Exposed


RetrospectivelyTime (Future)

Study Starts

Time (Past)

Case-Control Studies

• Probable Risk Factor Detection

• Low Frequency Outcomes

• Long Latent/Incubation Period

• No Temporality; No Causality

• Selection Biases

• Measurement Biases

Case-Control Studies • 1s t Step

• Definite Case Definition• Disease (Criteria)• Complications of a disease

• Metastasis, Recurrence, Complications

• Healthy Status• High Normal Tests

• High Quality of Life

• Case Selection (Diseased Patients)• Hospitals• Clinics

• Screening• Different Severity and chronicity


• Different Cases• Incident Case

• Etiological Risk Factors

• Prevalent Case• Prognostic Risk Factors

• Case Selection• Hospital; Prevalent Cases; Prognostic Risk Factors• Clinics; Incident and Prevalent Cases; Diagnostic Risk Factors• Screening; Incident Cases; Etiological Risk Factors

Case-Control Studies • 2nd Step

• Control Selection• According to Case Selection Bias

• Hospitals; Multiple Various Diseases• No positive or negative relation with risk factors

• Community Based• Only in a Cohort

• Specific Groups

• Friends, Neighbors, Spouse, …


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Case-Control Studies • 2nd Step

• Number of Control Group• One (Hospital Based)• Two (Hospital & Community Based)

• Composition of Control Group• One Disease

• Multiple Various Disease

• Numbers in Control Group• Same as Cases• More than Cases (Rare Disease)• Less than Cases (Ethical Considerations)

• Up to 3 times for significant increase in power of the study


• Increasing the similarity between Cases and Controls• Matching

• Numeric Variables• Individual Matching

• Cal iper Matching• Group Matching

• Categorical Variables• Only Group Matching

• Never for unknown risk factors

• Never for factors shall be assessed in study

• Treats of Over Matching


• Common Biases• Measurement Biases

• Different Assessment in cases and controls

• Different Data Sources for cases and controls• Different Data Type in cases and controls• Recall Bias

• Chance Error



• Common Biases• Selection Bias

• Case Selection• Control Selection

• Multiple Control Groups

ControlsCommunity

Controls Hospital

CasesSituation No

10%20%20%1

20%10%20%2

10%10%20%3

20%20%20%4

20%20%10%5


• Statistical Methods in Data Analysis• Two independent group comparison• Case with Controls

• Categorical Risk Factors• Chi Square Test

• Fisher Exact Test

• Measure of Association• OR

• Numeric Risk Factors• Independent Samples T test• Mann Whitney U test

• Measure of Association

• Mean Difference


• Sample Size Calculation• Comparison of Exposures

• Numeric Exposures (RFs)

• Categorical Exposures (RFs)

• Multiple Risk Factors• 30 for each RFs

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• RFs of Nocturia In children

• Case: Wet bed in recent Month

• Control: No wet bed in recent Month

• Assessing the Factors

• Lower age, Boys, Stressful environment


• Diagnostic Factors

• Carcinoid Tumor

• Cardiac form

• Gasterointestinal form

• Case: Cardiac involvement in autopsy

• Control: No cardiac involvement in autopsy

• Matching for BP, Duration of disease, Age


• Selective Study in:• Rare conditions• Long latent period or long natural history

• High probability of Biases• Needs high quality documents of previous exposures

• Needs good control group• Two control group

• Hospital based• Community based


• Proxy instead of Risk factor

• HBV infection in health care workers

• Duration after graduation instead of

• Number of accidental exposure to Blood driven materials (Needle

sticks)

• No good Proxy

Case-Control Studies • Assessment of associations between pancreatic

cancer with• Tea, Coffee, Tobacco, Alcohol• Cases: Pancreatic CA• Controls: Patients without Pancreatic CA of same physicians

• Exclusion criteria for controls:• Pancreatic, Liver or Biliary, Cardiac diseases, Diabetes, Lung CA,

Bladder CA, Peptic Ulcer

• Results:• Coffee is associated with Pancreatic CA• Higher coffee use in Case

• Controls included: Stomach CA, Gastritis, enteritis and colitis• Lower than population coffee consumption in controls

Key Points in Cohort Studies


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Cohort Studies• Cohort• A population with common

characteristic• Can be followed during the time

• Characteristic• Exposure ; Probable Risk Factor

• Prospective Follow Up1. Sample Selection2. Exposure Status Determination3. Follow Up for Outcomes

Cohort Studies• With Temporality• Becoming Diseased

• Proved Causality?• Confounding Factors

• Limited Evidence• Specially in:

• Rare Conditions

• Long Incubation Period

Cohort Studies

Selected CohortFrom Population

Exposed

Not Exposed

Outcome Happens

No Outcome Happens

No Outcome Happens

Outcome Happens


Prospectively Time (Future)

Study Starts

Time (Now)

Cohort Studies

• Framingham Study

• Study for CAD Risk Factors

• More than 6000 person with more than 15 years follow up

• Every 2 year assessment and lab tests

• Continued on next generations

Cohort Studies

• Survival Analysis

• A group of patients for survival assessment

• Needs follow up

• Disease free survival

• Survival

• Assessing the role of chromosomal defects in survival of CLL patients

Cohort Studies

• Starts from exposure

• Classification according to exposure

• Kind of exposures

• Risk factor

• Predisposing factor for risk factors

• Proxies for risk factors

• Severity and Frequency of Exposure


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Cohort Studies

• Sub Groups in Cohort (Sub Cohorts)

• One

• Two

• More than Two

• Multiple Outcomes

• Prevalence of Outcomes

• The Incubation Period

Cohort Studies

• Sample Size Calculation• Usually Comparison• Some times estimate

• Numeric Outcomes

• Categorical Outcomes

• Multiple Outcomes assessment pp

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Cohort Studies• Common Biases

• Different Follow Up in Groups• Frequency of Visits

• Visit Interval

• Different Observations for Outcomes• Subjective & Objective Outcomes

• Multiple Outcomes (Chance Error)

• Long Incubation Period• Contamination (Confounding)

• Attrition• Missing Data

• Change in Sub Cohort

Cohort Studies

• The most powerful Observational Study

• Causality?

• Natural History

• Probable Risk Factors

• Temporality

• Biases

• Selection and Information (Measurement)

• Confounding

Cohort Studies

• High Cost and Time

• Attrition

• Confounding

• Missing data

• Specially in long time follow up

• Not effective in Rare Conditions

Cohort Vs Case-Control Studies

• Cohort Study• Risk factor assessment

• Starts from Exposure

• Prospective

• Control of Biases

• Temporality

• For high frequency and short incubation period

• Case Control Study• Risk factor assessment

• Starts From Outcome

• Retrospective

• More Biases

• No Temporality

• For low frequency and long incubation period


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Cohort Vs Case-Control Studies

• 1950 Case- Control Study• Higher history of cigarette smoking in lung CA

• 10 year Cohort study on UK Physicians• 10 times Lung CA Mortality in Smoker Physicians

• 26 Years Later• RCT for Harm Reduction

• 40% decrease in Smoker Physicians who decreases smoking about 50%

Specific Types of Common Observational Studies

• Stratified Cross Sectional Study• Classification of Sample according to Exposure without Follow Up

• Simultaneous measurement of Exposure and Outcome

• Leukemia in Child and Mother Depression

• Comparison approach for Sample Size Calculation


• HistoricalCohort Studies • Exposure data:

• According to registered data in past

• Outcome:• Now Happened• Prospective; but Historical

• Study starts from exposure

• Validity of study• Related to Exposure Data Quality • Unique ID for Data Linkage

Historical Cohort Studies

Selected Data

of Specific Sample of a Population

Exposed

Not Exposed

With Outcome

Without Outcome

Without Outcome

With Outcome

Prospective Data LinkageTime

Study Starts

Specific Types of Common Observational Studies• HistoricalCohort Studies

• Exposure data: • Normal Delivery or Cesarean Section

• Outcome:• Grade in national university examination

• Data linkage:• According to the National ID

• National Insurance Data Base • National Organization of Educational Assessment


• Case-control studies within a defined cohort

• Nested Case-Control study

• Case-Cohort Study


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Case

Control

Cohort under study

Nested Case Control Study

Case

Control

Cohort under study

Study Time

Case-Cohort Study


•Nested Case-Control Studies• Begins with a defined cohort

• Identifies cases when occur

• For each case, • A specified number of controls

• Selected from among the cohort

• Not developed the disease

• By the time of disease occurrence in the case.


• Essential Feature of Nested Case-Control Studies• Time-matching

• Controls matched to cases on• Age,

• Date of entry into the cohort,

• Length of time in the cohort, or

• Combination of these measures.

• Who serves as a control at one point in time • May later become a case;

• May be selected as a control for more than one case.

Nested Case-Control Studies

Urinary Aflatoxin biomarkers and risk of hepatocellurlar carcinoma

COHORT (DIET-CANCER COHORT):18,244 men

aged 45-64 years in metropolitan Shanghai with

questionnaire data, blood and urine samples obtained at baseline recruitment between 1/86 and 9/89

By March, 1990:35299 person-years

CASES: Primary l iver cancer cases (n=22)

CONTROLS:Five or ten per case

(matched on age, residence, andtime of sample collection)

(n=140)

Comparison of detectable urinary aflatoxins/DNA adducts in cases and controls

Ross RK, Yuan JM, Yu MC, Wogan GN, Qian GS, Tu JT, Groopman JD, Gao YT, Henderson BE. Urinary aflatoxinbiomarkers and risk of hepatocellular carcinoma. Lancet 1992;339:943-946.


• Advantages of Nested Case-Control Studies

• Controls from the same population as the cases.

• Less expensive and less time-consuming

• In laboratory tests and analysis of data of full cohort.

• Data on exposure more likely collected prior to diagnosis of disease

• Than in the conventional case-control study.


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Specific Types of Common Observational Studies• Case-Cohort Studies

• Takes place within a cohort.• Cases

• Happened in the cohort during the time

• Controls • From a random sample (or a stratified random sample) of the entire cohort

• Healthy Sub Cohort

Specific Types of Common Observational Studies• Features of Case-Cohort Studies

• Group matching Not individual matching

• No time matching

• Preferred design for • Calculating incidence rates and

• Standardized mortality ratios and

• For making external comparisons.

Case-Cohort StudiesChlamydia pneumonia infection and incident coronary heart disease

Basic cohort:15792 participants aged 45-64 years

both sexes examined between fall 1986 and end of 1989

Exclusion:races other than white or black (n=48)

evidence of missing information on prevalent clinical cardiovascular disease at baseline

(n=1,338)

Eligible population n=14,406 Sampling frame for sub-cohort

Incident CHD cases n=257

(including 10 cases from the sub-cohort)

Sub-cohort n=556 (stratified random sample)


• Advantages of Case-cohort Studies• Economy of cost and effort.

• For multiple outcomes;

• Controls from the same population source of Cases

Key Points in Experimental Studies

Experimental (Interventional) Studies

1. With Control Group• Experiment Vs:

• Conventional Therapy

• Placebo

• Approved Therapy• Another Experiment

2. Without Control Group

• Objective:• Exploring any difference between experiments

• Positive or Negative


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Controlled Experimental Studies

1. Concurrent or Parallel Controls

• Randomized (RCT)

• Without Randomization (Quasi Experimental)

2. Self-controlled

3. Cross-Over Design

4. External or Historical Controls

RCTRandomized Concurrent Controlled Clinical Trial• Sample of Population (Patients Usually)

• Randomly Divided into two Groups

1. Experiment

2. Control: Placebo, Conventional or Approved Therapy

• Confounding Factors Controlled by Randomization

and Same time Intervention

Interventional Studies with Concurrent Controls

Selected

Candidates

Intervention

Control

Outcome Happens

No Outcome Happens

Outcome Happens

No Outcome Happens

Time (Future)

Study Start Interventions

Prescribed

Randomized Controlled TrialsRCT

• The most powerful study

• Can prove Causality• Key Point:

• Random assignment or Randomization

• Types of Randomization

• Sequential Randomization

• Simple Randomization

• Block Randomization

• Strati fied Block Randomization

Randomized Controlled TrialsRCT• Sequential Randomization

• One and the other

• Sequence is associated with outcomes

• Simple Randomization• Random sample size number distribution

• Odds and Even for Experiments• Non Uniform distribution of experiments

• Unequal Samples during the study

• Learning Curve Bias

1st 20 Cases 2nd 20 Cases



1. Number of experiments

2. Number of patients in each Block

3. Al l types of Block

4. Number of Blocks needed according to Sample size

5. Maximum Number of Repeated Blocks

6. Random Selection of Blocks

7. Random Arrangement of Blocks Order

8. Random Assignment of Experiments


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1. Two Intervention: A & B

2. Block Size: 2*Number of Interventions

• 4

3. All types of Block

• 1.AABB, 2.ABAB, 3.ABBA, 4.BABA, 5.BBAA, 6.BAAB

)!(!

!

TnBcTn

BcBn



4. Number of Blocks Needed

– Sample Size divided by Block Cells

– 40/4=10

5. Maximum number of repeated Blocks

• Needed Blocks divided by Number of Blocks

• 10/6≈2

Bc

nB



6. Random Selection of Blocks

– 10 Random Number from 1 to 6 with two times repeat

– 4, 3, 5, 1, 2, 3, 4, 6, 1, 2

7. Random Order of Selected Blocks

• Random numbers from 1 to 10

• 3, 5, 7, 4, 2, 1, 10, 8, 9, 6



1. AABB,

2. ABAB,

3. ABBA,

4. BABA,

5. BBAA,

6. BAAB,

4, 3, 5, 1, 2, 3, 4, 6, 1, 23, 5, 7, 4, 2, 1, 10, 8, 9, 6

ABBA, ABAB, BABA, AABB, ABBA, ABAB, BBAA, BAAB, AABB, BABA

Finally Randomly Assign Interventions to A & B


• Stratified Block Randomization

• Proved Different Outcomes in Different Groups

• Gender Response to any Hypertensive Drug

• 75% F/ 25% M

• 40 Sample Size

• 30 F → 8 of 4 Cell Blocks Randomly Selected

• 10 M → 3 of 4 Cell Blocks Randomly Selected


• Blinding//Concealment• Single Blinding//Concealment:

• Only Patients

• Double Blinding//Concealment:• Patients + Observers

• Triple Blinding//Concealment:• Patients + Observers + Data Interpreters


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Randomized Controlled TrialsRCT• Sample Size Calculation

• Comparison of Outcomes• Numeric Outcomes


• Multiple Outcomes pp

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• CASS (Coronary Artery Surgery Study)• Surgical Vs Medical Treatment of IHD

• Inclusion criteria:

• More than 70% Stenosis in one major Vessel

• Exclusion criteria:

• EF<35% or LAD >70% Stenosis

• Multicenter Study; Stratified Block Randomization


• CASS ( Coronary Artery Surgery Study )

• Outcomes :

• Quality of Life

• Survival

• Results

• No difference in survival

• Better QOL in CABG (Coronary Artery Bypass Graft)

Experimental Studies With Parallel Controls Without Randomization

• Comparative Studies; Quasi Experimental

• Biases and Confounding

• Better Patients in Experiment Group

• Something Rather than Experiment Differs

• Comparison of Results of Surgery between 3rd and 4th grades of Colon

CA

• Different Stages and Grades of Disease

• Different Interventions

• Different Situations of Patients

Self-Controlled Clinical Trials

• Before After Study• First Intervention

• Wash out

• Second Intervention

• Conditions• Reversible Outcomes

• No Cure

• No Carry Over effect

• Before After Variables

Self Controlled Trials

Cure

No Cure

Cure

NoCure

SelectedCandidates


StudyStart

Time (Future)


WashoutPeriod


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Self-Controlled Clinical Trials

• Contamination; Confounding• Concomitant Interventions

• Time Difference of Interventions

• Sample Size Calculation• One Group; Comparison Methods

Cross-Over Clinical Trials

• Both Self and Parallel Controls• The Most Powerful Study

1. RCT2. Washout Period for Both Groups

3. RCT with Intervention Switch• 2 RCT; Phase 1 and Phase 2

• 2 Self Controlled Trial; Line 1 ad line 2

• Carry Over Effect Assessment of Both Interventions

Cross Over Design

Cure

NoCure

Cure

NoCure

Cure

NoCure

Cure

NoCure

Selected Candidates

Intervention 1

Intervention 2

Intervention 1

Intervention 2

StudyStart

Time Future

InterventionPhase 1

WashoutPeriod

CASE

CR

OSS

OV

ER

InterventionPhase 2

Experiments with External Controls

• Controls in the same time but Not in the same Setting

• External Controls

• Biases

• Different Patients

• Different Settings

• Different Observers

• Different Researchers

• Different Nursing Care

• Different Skills and Experiences


• Laparoscopic Cholecystectomy Vs Laparotomy

Experiments with Historical Controls

• Controls from the Past of Same Setting

• Historical Controls• Biases

• Different Patients

• Different Settings

• Different Observers

• Different Researchers

• Different Nursing Care


• Different Skills and Experiences

• Different Stages of Disease

• Screening Improvement

• New Chemotherapy Vs Prior One in AML

Trials with Historical//External Controls

Studied

Patients

Results of Previous

or External Patients

Intervention Only in Studied Patients

Time (Future)Study Starts

Cure

Cure

No Cure

No Cure


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Experiments with Historical//External Controls

• Sample Size Calculation

• Estimation

• Numeric Outcomes


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RCT

• Gold Standard for Assessment of Effect• Diagnostic or Therapeutic Means

• Compared with:• Standard care• Reference Standard• Placebo• Conventional Methods

• No Randomization; No Validity• High Cost• Long Time• Slower than Technology

Uncontrolled Experimental Studies

• No Reliability and Validity of Results

• 15 patients

• Treated with Stem Cells

• 5 Survived

Which Methodology?

1. Fish Oil Regimen; RA Treatment

Which Methodology?

2. Efficacy of Breast Self Examination (BSE) for Breast CA screening

Which Methodology?

3. Epidemic Investigation; Acute Chest Paint & Dyspnea


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Which Methodology?

4. Burning Treatment; by Honey

Which Methodology?

5. Menopause and CVD Risk

Which Methodology?

6. NSAID & Upper GI Bleeding Risk