Research%20Design%20

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Research Design EBM
Ravi Kant MS, DNB, FAMS, FRCS (Edin), FRCS
(Glasg), FRCS (Engl.), FRCS (Irel.), FACS, FICS,
FAIS Professor of Surgery
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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 199631271-72 (13 January) 
• Editorial

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Evidence-based health care?

• best evidence

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Evidence-based health care?

• decision-making

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Type of study Definition
Observational Evaluating results of condition or treatment in a defined population Retrospective analyzing past events Prospective collecting data contemporaneously
Case-control Series of patients with a particular disease or condition contrasted with matched control patients
Cross-sectional Measurements mode on a single occasion, not looking at whole population but selecting small similar group expanding results
Longitudinal Measurements are taken over a period of time, not looking at whole population but selecting small similar group expanding results
Experimental Two or more treatments are compared. Allocation to treatment groups is under the control of the researcher
Randomized Two randomly allocated treatments
Randomized controlled Includes control group with no treatment
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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
• 2Prospective 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

• ARecommendation based on consistent and good
  quality patient-oriented evidence

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Strength of recommendation Definition B

• BRecommendation based on inconsistent or limited
  quality patient-oriented evidence

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Strength of recommendation Definition C

• CRecommendation 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, casecontrol 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

• nXr(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.

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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/publi
  c/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.infopoem
  s.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.or
  g
• SUM Search http//sumsearch.uthscsa.edu
• TRIP Database  
• http//www.tripdatabase.comUpToDate http//www.upt
  odate.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/uspstfi
  x.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/l
  hsp/resources/ebm.shtml.    http//library.ncah
  ec.net/ebm/pages/index.htm

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Web-based evidence-based medicine courses-2

• http//www.urmc.rochester.edu/hslt/miner/resources
  /evidence_based/index.cfm
• http//library.downstate.edu/EBM2/contents.htm
• http//www.healthsystem.virginia.edu/internet/libr
  ary/collections/ebm/index.cfm
• http//www.cebm.net/
• http//www.sheffield.ac.uk/scharr/ir/netting/

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POEMS

• Journals with highest frequency of articles that
  contain patient 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 (3003,000 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.

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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

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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

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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 19 511.
• 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 20061161632-1635

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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
  .

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• 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
  229174-180.

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• 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 8841-44. 

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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

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Type of study Definition
Observational Evaluating results of condition or treatment in a defined population Retrospective analyzing past events Prospective collecting data contemporaneously
Case-control Series of patients with a particular disease or condition contrasted with matched control patients
Cross-sectional Measurements mode on a single occasion, not looking at whole population but selecting small similar group expanding results
Longitudinal Measurements are taken over a period of time, not looking at whole population but selecting small similar group expanding results
Experimental Two or more treatments are compared. Allocation to treatment groups is under the control of the researcher
Randomized Two randomly allocated treatments
Randomized controlled Includes control group with no treatment
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POEMS

• patient-oriented evidence that matters (POEMs)

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Drains Evidence

• Presented in your book as a chapter

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Cochrane
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