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					             Methodological Issues in Systematic
                         Reviews:
                   Formulating Questions

                      Thomas A Trikalinos, MD, PhD

                     Co-Director, Tufts Evidence-based Practice Center




Author has no actual or potential conflicts of interest in relation to this activity
Asking the right question
               We will cover

 PICO(TS) approach to generate
  answerable research questions
 Analytic framework to identify potential
  questions
 Other considerations in formulating
  questions
                      Systematic Review/Meta-Analysis

        ?
      QUESTION


                             Refining the
                              question

                                Study
                            identification/
                               retrieval

                                 Quality
Systematic Review /          assessment/
                            critical apraisal
  Meta-Analysis
                           Study selection/
                              inclusion
                               criteria

                            Data extraction

                              Statistical
                              methods

                            Interpretation/
                            generalizability

         !
      ANSWER
        Systematic review protocol

 Well focused study question [ PICO(TS) ]

 Identification of studies (studies design,
  source, search strategy)

 Eligibility criteria (study, patient, and disease
  characteristics, treatments, outcomes)

 Data extraction (definition of outcomes,
   quality assessment)

 Data summary and analysis (outcomes
  used, intention to treat)
     PICO(TS) approach to formulating
      answerable research questions


 Population (participants)
 Intervention
 Comparator
 Outcome
 Time (duration)
 Study design (experimental / observational, N)
Poorly formulated question:

What drugs should be used to treat
patients with hypertension?
                                                                                      Example: The Well Formulated Question


                       Example: The Well - Formulated Question
                      The Cochrane Collaboration "How to Conduct a Cochrane Systematic Review" 1996


                                                                                  Population               Condition of
  Intervention                             Outcomes
                                                                                  Setting                  interest




Does drug therapy decrease long-term morbidity and mortality in older persons with mild to moderate hypertension?




  ACE inhibitors                               Fatal and non-fatal strokes
  Angiotensin Receptor                         Fatal and non-fatal           > 60 yrs old       Systolic 140-179
    Antagonists
                                > 1 year        Coronary Heart Disease       outpatients        Diastolic 90-109
  Combined Alpha and Beta                       (MI, sudden death)
   Blockers                                    Cardiovascular events
  Calcium-Channel Blockers                      (above plus aneurysm,
  Diuretics                                     congestive heart failure,
  Alpha Adrenergic                              transient ischemic
   Blockers                                     attacks)
  Central Sympatholytics                       Total Mortality
  Direct Vasodilators
  Peripheral Adrenergic
   Antagonist
                  Diagnostic test research question
                        - test performance -

                Outcomes           Intervention      Condition of      Setting
                                                     interest          population




What is the diagnostic accuracy of sestamibi scan to detect ACI in patients in the ED?




                 sensitivity                                          Adults with
                                   technetium-99m       - AMI
                 specificity                                          symptoms
                                   sestamibi scan       - unstable
                                                                      suggestive of
                                                        angina
                                                                      acute cardiac
                                                                      ischemia and
                                                                      non-diagnostic
                                                                      ECG seen in
                                     Comparator                       the ED
             Diagnostic test research question
                    - clinical impact -

            Outcomes           Intervention       Condition of      Setting
                                                  interest          population




What is the clinical impact of sestamibi scan to detect ACI in patients in the ED?




         False negative                                            Adults with
                                technetium-99m        - AMI
         discharges                                   - unstable   symptoms
                                sestamibi scan                     suggestive of
         from the ED                                  angina
                                                                   acute cardiac
         False positive                                            ischemia and
         admits                                                    non-diagnostic
                                                                   ECG seen in
                                 Comparator                        the ED
         Deaths
               We will cover

 PICO(TS) approach to generate
  answerable research questions
 Analytic framework to identify potential
  questions
 Other considerations in formulating
  questions
       Approach to (de)constructing
            research question


 Question of interest is often over-arching and
  not directly addressable
   – Ex. How to manage hypercholesterolemia?
 Need to break it down into answerable
  subunits
 Multiple questions frequently needed
 Final answers (recommendations) typically
  involve additional information, balancing the
  benefits and harms, feasibility, costs, etc
               Simplified Evidence Model Linking Biological
                Effects (intermediate) and Health Outcomes
                                                       C




 Intervention                  A               Biological                    B              Health
                                                effect(s)                                 outcome(s)



                                                      E
                       D
                                               Additional
                                               biological
                                                effect(s)



Simplified Evidence Model Linking Biological Effects (intermediate) and Health Outcomes      .
USPSTF generic analytic framework for
         screening topics
                       Analytic framework for omega-3 FA intake and CVD
                                                                  Target Populations
                            Healthy Adults                 Adults with elevated risk for CVD              Adults with known CVD
                                                             Diabetes, Hypertension, Hyperlipidemia




                                                        Omega-3 Fatty Acid Consumption                                        Adverse
                                                                 Source, Dosage, Duration                                     Events



            Tissue / Plasma Levels
                                                                                                        Modifiers
Plasma Phospholipid FAs     RBC Phospholipid FAs                                                       Drug Interactions
Platelet Phospholipid FAs   WBC ghost Phosphlipid FAs                                                       Other
                            Others




                                                 Intermediate Outcomes / Biological Effects
                                           Cholesterol              Blood Pressure           Carotid Intima Media Thickness
                                           Lipoprotein (a)          Diabetes Markers         Coronary Arteriography Markers
                                           C Reactive Protein       Heart Rate Variability   Others
                                           Fibrinogen




                                                                   Clinical Outcomes
                                                  Death
                                                                                              Ventricular Arrhythmia
                                                  Myocardial Infarction
                                                                                              Others
                                                  Stroke
                                                  Unstable Angina
               We will cover

 PICO(TS) approach to generate
  answerable research questions
 Analytic framework to identify potential
  questions
 Other considerations in formulating
  questions
            Problems defining interventions and
                      comparators

        Pulmonary rehabilitation vs conventional care

            Exercise training

     AND OPTIONALLY:

Education             Inspiratory muscle                       “Conventional”
                            training                Vs
                                                                   care
Breathing               Psychosocial/
exercises                 behavioral
                        interventions




                           AHRQ Evidence Report/Technology Assessment
                           Pulmonary rehabilitation for COPD, 2007; http://www.ahrq.gov
OK, but there are things that are self-
            evident, no?
                      Would You Say You “Had Sex” If… ?




JAMA 1999;281:275-7
                      Percentage Indicating “Had Sex”




JAMA 1999;281:275-7
          Problems in coming up with
                  questions
 Sometimes you don’t know what should be the
  question because there is not yet agreement among
  investigators about the meaning
 Pre-emptive analgesia: different investigators have
  different ideas about what it is
 Solution: Rather than pick an arbitrary definition, try
  to group what has been studied into several similar
  categories and address them, this will provide
  evidence of the spectrum of mechanisms
 Question: What is the effect of timing of analgesics
  on post-op requirements of pain medication and
  patient outcomes?
     Problems with diagnosis

 varying definitions (lack of an
  adequate reference standard)
 different levels of rigor
 tradeoffs between rigor and real
  world practice (sinus puncture to
  diagnose sinusitis vs. actual
  clinical practice: efficacy vs.
  effectiveness)
Sinus Trouble
        Possible definitions of acute bacterial
              sinusitis and their effect

      Duration of < 2 weeks < 3 weeks                   < 4 weeks
      symptoms
Diagnostic
criteria
Sinus puncture
and culture         Low likelihood for false positive

Radiography
                    May include many patients with viral infections

Clinical findings
                    May include many patients with viral infections
   Management of Clinically
   Inapparent Adrenal Mass
   (Adrenal Incidentaloma):
        The Evidence Report

NIH State-of-the-Science Conference
          February 4, 2002
       Incidentaloma is NOT a disease

The prevalence of this phenomenon
  and the pathologies and their
  likelihood will depend on:
 Patients with known cancers or not
 Presenting signs and symptoms
 Patient’s age and sex
 Biochemical activity findings
 Initial diagnostic test used (CT, US, MRI)
 Size of the mass (lower limit)
         What are the pathologies reported
         among adrenal incidentaloma?

 Adenoma              Metastases
 Adrenocortical       Myelolipoma
  carcinoma            Neurinoma
 Angiomyelolipoma     Pheochromocytoma
                       Regenerative hepatic
 Cyst                  nodule
 Epithelial           Renal angiomyolipoma
  carcinoma            Retroperitoneal fibrosis
 Hyperplasia          . . . more
 Hematoma
 Lymphoma
                                 Some possible definitions of
                                       incidentaloma
                                       Imaging study showing
                                      incidental adrenal mass




                                       Patients with cancer
                                     known to metastasize to
                          YES                adrenal                 NO


                  Symptoms and                                        Symptoms and
                     signs of                                            signs of
                   biochemical                                         biochemical
                     activity                                            activity
      YES                           NO                    YES                           NO

    Symptoms and              Symptoms and              Symptoms and              Symptoms and
   signs attributable        signs attributable        signs attributable        signs attributable
  to adrenal disease        to adrenal disease        to adrenal disease        to adrenal disease
YES                 NO YES                    NO YES                     NO YES                       NO

  A                B        C               D        E               F         G               H
      Issues in formulating a question

 Narrow versus broad (for individuals/
  subgroups or entire population)
 Clinically meaningful and useful (based on
  sound biological and epidemiological
  principles)
 Very broadly defined questions may be
  criticized for mixing apples and oranges
 Very narrowly focused questions have
  limited generalizability and sometimes may
  lead to biased interpretations / conclusions
        Benefits of getting the questions right
                      at the start

 Improves clarity of the problem
 Facilitates subsequent steps of the systematic
  review
 Helps select right kind of studies for review
 Anticipates issues, resource needs
 Improves efficiency, reduces needs to revisit
  questions / re-review papers, minimizes
  wasted efforts
                      Summary

 PICO(TS) method is a very useful technique
  to formulate answerable research questions
 Analytic framework can be useful to visualize
  and think about related issues
 Defining criteria
 Biologically meaningful
 Question and criteria guide the entire
  systematic review process

				
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posted:2/19/2010
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