Research Design & EBM

Ravi Kant
MS, DNB, FAMS, FRCS (Edin), FRCS (Glasg), FRCS
(Engl.), FRCS (Irel.), FACS, FICS, FAIS
Professor of Surgery

1
Science
 Intelligent Hypothesis
 Experiments & analysis of results prove
that hypothesis is correct.
 Replicable universally= Most Important

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Evidence based medicine:
what it is and what it isn't
 Integrating individual clinical
expertise and the best external
evidence

 BMJ 1996;312:71-72 (13 January)

 Editorial

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4
 Evidence-based health care?

 = best evidence

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Evidence-based health care?

 decision-making

6
 Type of study Definition

Evaluating results of condition or treatment in a defined

population
Observational
Retrospective: analyzing past events
Prospective: collecting data contemporaneously

Series of patients with a particular disease or condition contrasted

Case-control
with matched control patients

Measurements mode on a single occasion, not looking at whole

Cross-sectional
population but selecting small similar group & expanding results

Measurements are taken over a period of time, not looking at

Longitudinal whole population but selecting small similar group & expanding
results

Two or more treatments are compared. Allocation to treatment

Experimental
groups is under the control of the researcher

Randomized Two randomly allocated treatments

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Randomized controlled Includes control group with no treatment
Observational study
 Evaluating results of condition or
treatment in a defined population

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Retrospective:
analyzing past events

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Prospective:
 collecting data
contemporaneously

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Case-control
 Series of patients with a
particular disease or condition
contrasted with matched
control patients

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Cross-sectional
Measurements mode on a
single occasion, not looking at
whole population but selecting
small similar group &
expanding results
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Longitudinal
 Measurements are taken over
a period of time, not looking at
whole population but selecting
small similar group &
expanding results

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Experimental
 Two or more treatments are
compared. Allocation to
treatment groups is under the
control of the researcher

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Randomized
 Two randomly allocated
treatments

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 Prospective Randomized
controlled
Includes control group with no
treatment

= GOLD STANDARD

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Confidence Interval
 To p or not to p

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RR
 Relative Risk

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Hazard ratio/ Odds ratio

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Systemic Review
 reliable
 systematic
 predefined, explicit methodology
 minimize bias
 Systemic review+ Statistics= meta-
analysis

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Systemic Review
 =?

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 Levels of evidence
 1= Meta-analyses of Prospective Double
blind randomized controlled trials
 2=Prospective Randomized Controlled study/
Meta-analyses of retrospective studies
 3= Case series/ Cohort study
 4= Case report/ observational
 5= Expert opinion

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Evidence grade: I
 I (High): the described effect is
plausible, precisely quantified and not
vulnerable to bias

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Evidence grade: I

 II (Intermediate): the described effect is

plausible but is not quantified precisely or
may be vulnerable to bias

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Evidence grade : III
 III (Low): concerns about plausibility or
vulnerability to bias severely limit the value
of the effect being described and
quantified

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 Strength of recommendation
Definition A
 A=Recommendation based on consistent
and good quality patient-oriented evidence

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 Strength of recommendation
Definition B

 B=Recommendation based on inconsistent

or limited quality patient-oriented evidence

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 Strength of recommendation
Definition C

 C=Recommendation based on consensus,

usual practice, opinion, disease-oriented
evidence or case series for studies of
diagnosis, treatment, prevention, or
screening.

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Recommendation grade: A

 A (Recommendation): there is robust

evidence to recommend a pattern of care

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Recommendation grade : B

 B (Provisional recommendation): on
balance of evidence, a pattern of care is
recommended with caution

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Recommendation grade : C

 C (Consensus opinion): evidence being

inadequate, a pattern of care is
recommended by consensus

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US Government Agency for
Health Care Policy and Research
(AHCPR):A
 A: requires at least one randomized
controlled trial as part of the body of
evidence.

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US Government Agency for
Health Care Policy and Research
(AHCPR):B
 B: requires availability of well-
conducted clinical studies but no
randomized controlled trials in the body
of evidence.

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US Government Agency for
Health Care Policy and Research
(AHCPR):C
 C: requires evidence from expert
committee reports or opinions and/ or
clinical experience of respected
authorities. Indicates absence of
directly applicable studies of good
quality

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 Grading of evidence
 Ia: Systematic review or meta-analysis of
randomized controlled trials
 Ib: at least one randomized controlled trial
 IIa: at least one well-designed controlled study
without randomization
 IIb: at least one well-designed quasi-experimental
study, such as a cohort study
 III: well-designed non-experimental descriptive
studies, such as comparative studies, correlation
studies, case–control studies and case series
 IV: expert committee reports, opinions and/or
clinical experience of respected authorities
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Grading of
recommendations
 A: based on hierarchy I evidence
 B: based on hierarchy II evidence or
extrapolated from hierarchy I evidence
 C: based on hierarchy III evidence or
extrapolated from hierarchy I or II evidence
 D: directly based on hierarchy IV evidence or
extrapolated from hierarchy I, II or III
evidence

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Research can be Quantitative:

A medical condition is analyzed

systematically using hard, objective end
point such as death or amputation.

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Research can be Qualitative

Data come from patient narratives, and

the psychosocial impact of the disease
and its treatment are analyzed, for
example narratives of breast cancer.

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Project design include:

 Sample size.
 Eliminating bias.

 Study protocol.

 Ethics.

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Sample size

 An incorrect sample size is probably the

most frequent reason for research to be
invalid.
 Never forget that more patients will
need to be randomized than the final
sample size to take into account
patients who die, drop out or are lost to
follow up.
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Sample size
 nX[r(100-r)+s(100-s)]/(r-s)2

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Type I error

 Benefit is perceived when

really there is none (false
positive)

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Type II error

 Benefit is missed because the

study has small numbers (false
negative)

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Eliminating bias: Single blind

 The observers or recorders who do not

know which treatment has been used.

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Eliminating bias: Double blind

Neither patient nor researcher is aware

of which therapy has been used until
after study has finished, & these are
the best randomized studies.

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 The Cochrane Collaboration
 Best evidence
 an international not-for-profit and independent
organization,
 It produces and disseminates systematic
reviews of healthcare interventions and
promotes the search for evidence in the form
of clinical trials and other studies of
interventions.
 The Cochrane Collaboration was founded in
1993 and named after the British
epidemiologist, Archie Cochrane. 49
 Current reliable evidence-
based medicine resources for
the busy clinician -1
 American College of Physicians Journal Club
http://www.acpj.org
 American Family Physician
http://www.aafp.org/afp
 Bandolier http://www.rj2.ox.ac.uk/bandolie
 Clinical Evidence
http://www.clinicalevidence.com

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 Current reliable evidence-
based medicine resources for
the busy clinician -2
 Cochrane Database of Systematic Reviews
http://www.cochrane.org/reviews/en/
 Database of Abstracts of Reviews of Effects (DARE)
http://www.york.ac.uk/inst/crd/crddatabases.htm
 Dr. Alper's Useful Links
http://www.myhq.com/public/a/l/alperDynaMed http:
//www.dynamicmedical.com
 Family Practitioners Inquiries Network (FPIN) Clinical
Inquiries http://www.fpin.org
 FIRSTConsult http://www.firstconsult.comInfoPOEMs
– The Clinical Awareness
Systemhttp://www.infopoems.com
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 Current reliable evidence-
based medicine resources for
the busy clinician -3
 Institute for Clinical Systems Improvement
(ISCI) http://www.icsi.org/knowledge
 Journal of Family Practice
http://www.jfponline.org
 SUM Search http://sumsearch.uthscsa.edu
 TRIP Database
 http://www.tripdatabase.comUpToDate http://
www.uptodate.com
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 Current reliable evidence-
based medicine resources for
the busy clinician -4
 US National Guideline Clearinghouse
http://www.guidelines.gov
 U.S. Preventive Services Task Force (USPSTF)
Recommendations
http://www.ahrq.gov/clinic/uspstfix.htm

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Current reliable evidence-
based medicine resources for
the busy clinician -5
 Bandolier
 Evidence based thinking about healthcare
 Cochrane Library Database of Systematic Reviews
 Full text systematic reviews of health care interventions, prepared by The Cochrane
Collaboration.
 The Database of Abstracts of Reviews of Effects (DARE)
 Critical appraisal of systematic reviews published in the medical literature.
 Health Technology Assessment Database (HTA)
 Completed and on-going health technology assessments from around the world
 NHS Economic Evaluation Database (NHS EED)
 Reliable information about the costs as well as the effects of drugs, treatments and
procedures, to inform decisions.
 UK Database of Uncertainties about the Effects of Treatments
 Publishes those patients' and clinicians' questions about the effects of treatments
which cannot currently be answered reliably by referring to up-to-date systematic
reviews of existing research.

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Web search-6
 Clinical evidence.com
 Cochrane.org
 Consolidated Standards of Reporting
trials= consort-statement.htm
 National Institute for Health & Clinical
excellence (NICE.org.uk
 Scottish Intercollegiate Guideline
Network (SIGN) www.sign.ac.uk
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Cochrane

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Bandolier

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DARE= data base of abstracts
of reviews of effects

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 Web-based evidence-
based medicine courses-1
• http://www.poems.msu.edu/infomastery:
• http://www.hsl.unc.edu/services/tutorials/
ebm/welcome.htm:
• http://www.uic.edu/depts/lib/lhsp/resourc
es/ebm.shtml:.
• http://library.ncahec.net/ebm/pages/index
.htm:

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 Web-based evidence-
based medicine courses-2
 http://www.urmc.rochester.edu/hslt/miner/re
sources/evidence_based/index.cfm:
 http://library.downstate.edu/EBM2/contents.
htm:
 http://www.healthsystem.virginia.edu/intern
et/library/collections/ebm/index.cfm:
 http://www.cebm.net/:
 http://www.sheffield.ac.uk/∼scharr/ir/netting
/: 64
POEMS
 Journals with highest frequency of

patient
articles that contain

oriented evidence
that matters (POEMs)
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Impact factor
 = average number of citations
to those papers that were
published during the two
preceding years.

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 Impact factor
For example, the 2008 impact factor of a
journal would be calculated as follows:
 A = the number of times articles published in
2006 and 2007 were cited by indexed journals
during 2008
 B = the total number of "citable items" published
in 2006 and 2007. ("Citable items" are usually
articles, reviews, proceedings, or notes; not
editorials or Letters-to-the-Editor.)
 2008 impact factor = A/B
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High-impact journals (those
cited most frequently by others)
 Annals of Internal Medicine
 British Medical Journal
 Journal of the American Medical
Association
 Lancet
 New England Journal of Medicine

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A new drug project

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Preclinical studies
 Even animal studies need ethical
clearance in Europe
 Efficacy, toxicity and pharmacokinetic
 data

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Phase 0
 Human microdosing
 Distinctive features of Phase 0 trials include
the administration of single subtherapeutic
doses of the study drug to a small number of
subjects (10 to 15) to gather preliminary data
on the agent's pharmacokinetics (how the
body processes the drug)
and pharmacodynamics (how the drug works
in the body)
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Phase 1 trial
 Dose escalation =Dose ranging
 Pharmacovigilance

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 SAD
 Single Ascending Dose studies
 MAD
 Multiple Ascending Dose studies
 Crossover study
 A short trial designed to investigate any differences in
absorption of the drug by the body, caused by eating before
the drug is given. These studies are usually run as
a crossover study, with volunteers being given two identical
doses of the drug on different occasions; one while fasted,
and one after being fed.

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Phase II
 Larger group
 Phase IIA is specifically designed to
assess dosing requirements (how much
drug should be given).
 Phase IIB is specifically designed to
study efficacy (how well the drug works
at the prescribed dose(s)).

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Phase II
 Toxixity & efficacy defines go ahead or
not

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Phase III
 Phase III studies are randomized
controlled multicenter trials on large
patient groups (300–3,000 or more
depending upon the disease/medical
condition studied)

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Phase IV
 Phase IV trial is also known as Post
Marketing Surveillance Trial
 = Pharmacovigilance

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Research Design
 It's always easier to explain design
notation through examples than it is to
describe it in words. The figure shows
the design notation for apretest-
posttest (or before-after)
treatment versus comparison
group randomized

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Research Design

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Experimental study- steps
 Animal model
 Induce tumor by viral inoculation
 Treat tumor by various laser
wavelength
 Correct wavelength applied in incurable
humans
 Regular Clinical approach

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Pilot study
 Somprakas Basu, Bina Ravi & Ravi
Kant: Interstitial laser Hyperthermia, a
New Method in the Management of
Fibroadenoma of the Breast: A Pilot
Study. Lasers in Surgery and
Medicine, 1999: Vol. 25: p 148-152.

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Interstitial Laser Hyperthermia
 For solid tumors of-
 Liver
 Pancreas

 Lymph nodes

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ILH & Pancreas
 Kant Ravi, Masters A, Lees WR, Bown
SG: Interstitial Laser Hyperthermia in
Human pancreas tumors: GUT,
supplement 1992. Vol. 33 No 1 W69,
p S18.

91
 Lab studies► need
infrastructure
Hedau S, Jain N, Husain SA, Mandal AK, Ray
G, Shahid M, Kant R, Gupta V, Shukla NK,
Deo SS, & Das BC. Novel germ line
mutations in breast cancer susceptibility
genes BRCA1, BRCA2 and p53 gene in
breast cancer patients from India. Breast
Cancer Research Treat 2004 Nov,
88(2):177-86.
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The Liver: The drains do not
offer any benefit after
elective liver resections.
 Marcello Spampinato Hassan Elberm & Colin D
Johnson in Recent Advances in Surgery # 31, by
Irving Taylor & Colin Johnson, The Royal Society
of Medicine Press, 2008 page 189-
 Gurusamy KS, Samraj K, Davidson BR. Routine
abdominal drainage for uncomplicated liver
resections. Cochrane Database Systemic Rev
2007; CD006232

93
GB
 The Gall Bladder: The drains do not
offer any benefit after routine
uncomplicated laparoscopic
cholecystectomy.
 Marcello Spampinato Hassan Elberm & Colin D
Johnson in Recent Advances in Surgery # 31, by
Irving Taylor & Colin Johnson, The Royal Society
of Medicine Press, 2008 page 196-
 Gurusamy KS, Samraj K, Mullerat P et al.
Routine abdominal drainage for uncomplicated
laparoscopic cholecystectomy. Cochrane
Database Systemic Rev 2007; CD006004

94
The Thyroid: No drain is
required following
thyroidectomy.
 Khanna J, Mohil RS, Chintamani, Bhatnagar D, Mittal MK,
Sahoo M, Mehrotra M. Is the routine drainage after
surgery for thyroid necessary? A prospective randomized
clinical study [ISRCTN63623153]. BMC Surg. 2005 May
19; 5:11.
 Suslu N, Vural S, Oncel M, Demirca B, Gezen FC, Tuzun B,
Erginel T, Dalkilic G. Is the insertion of drains after
uncomplicated thyroid surgery always necessary? Surg
Today. 2006; 36(3):215-8.
 Lee SW, Choi EC, Lee YM et al. Is lack of placement of
drains after thyroidectomy with central neck dissections
safe? A prospective randomized study. Laryngoscope
2006;116:1632-1635

95
The Breast: No drain is
required after conservation
surgery for breast cancer
 Stojkovic C, Smeulders MJ, Van der Horst
CM. Wound drainage after plastic and
reconstructive surgery of the breast
(Protocol). Cochrane Database of
Systematic Reviews 2008, Issue 3. Art.
No.: CD007258. DOI:
10.1002/14651858.CD007258.

96
 Rectal Surgery: The pelvic
drainage after rectal surgery adds
no benefit.
 Urbach DR, Kennedy ED, Cohen MM.
Colon and rectal anastomosis donot
require routine drainage: a systemic
review and meta-analysis. Ann Surg
1999; 229:174-180.

97
 Incision by electrocautery heal as
well as incision by knife. No
difference in either postoperative
results or in cosmesis.
 Kears SR, Connolly EM, Mc Nally S,
McNamara DA, Deasy J. Randomized
clinical trial of diathermy versus scalpel
incision in elective midline laparotomy.
 Br J Surg 2001; 88:41-44.

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Summary

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Evidence-Based surgery

 Evidence-base study is a move to find out the

best ways of managing patients using clinical
evidence from collected studies.
 Collecting published evidence together and
analyzing it often requires review of multiple
randomized trials.
 These meta-analysis involve complex
statistical analysis designed to interpret
multiple findings and synthesize the results of
multiple studies.
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 Important advantages of
evidence-based medicine
 Has the potential to improve quality of patient care
 Identifies and promotes practices that are proven
scientifically to be effective
 Identifies practices that are ineffective or harmful
 Promotes critical thinking
 Requires clinicians to be open-minded
 Encourages researchers to focus on evidence and
outcomes that are important to clinicians and
patients

101
 Type of study Definition

Evaluating results of condition or treatment in a defined

population
Observational
Retrospective: analyzing past events
Prospective: collecting data contemporaneously

Series of patients with a particular disease or condition contrasted

Case-control
with matched control patients

Measurements mode on a single occasion, not looking at whole

Cross-sectional
population but selecting small similar group & expanding results

Measurements are taken over a period of time, not looking at

Longitudinal whole population but selecting small similar group & expanding
results

Two or more treatments are compared. Allocation to treatment

Experimental
groups is under the control of the researcher

Randomized Two randomly allocated treatments

102
Randomized controlled Includes control group with no treatment
103
POEMS
 patient-oriented evidence that matters
(POEMs)

104
Drains & Evidence
 Presented in your book as a chapter

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Cochrane

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