Turning a clinical question into a testable hypothesis Lauren A. Trepanier, DVM, PhD Diplomate ACVIM, Diplomate ACVCP Department of Medical Sciences School of Veterinary Medicine University of Wisconsin-Madison ???
Clinical questions Trust your clinical experience Trust your clinical experience Common diseases Common diseases Clinical controversies Clinical controversies Standards of practice in human patients Standards of practice in human patients
Clinical questions New diagnostic tests New diagnostic tests Better treatment options Better treatment options Characterization of outcomes Characterization of outcomes Prognostic indicators Prognostic indicators Underlying etiology Underlying etiology
Getting ideas Journal club papers Journal club papers Logical follow-ups Logical follow-ups Specialty proceedings Specialty proceedings Knowledge gaps Knowledge gaps Discussions with senior faculty Discussions with senior faculty
Define the state of knowledge Literature search Literature search Multiple search terms Multiple search terms Reference lists from papers Reference lists from papers Read full papers!! Read full papers!! Beware abstracts that never made it to peer reviewed pubs Beware abstracts that never made it to peer reviewed pubs
Define the knowledge gap Major conclusions from each paper Major conclusions from each paper Organize as a logical story Organize as a logical story Why it is important Why it is important What is known in humans What is known in humans What is known in veterinary species of interest What is known in veterinary species of interest
Refining the clinical question What remains to be answered? What remains to be answered? Does your question need revising? Does your question need revising? What do you think you will find (your hypothesis)? What do you think you will find (your hypothesis)?
Framing your research approach Research objectives, or aims, to specifically test your hypothesis Research objectives, or aims, to specifically test your hypothesis To compare To compare To determine To determine To evaluate To evaluate To characterize To characterize
PICOT approach Population Population Intervention Intervention Comparators Comparators Outcomes Outcomes Time frame Time frame
PopulationPopulation Inclusion criteria Inclusion criteria Gold standard for diagnosis Gold standard for diagnosis Validated surrogate marker Validated surrogate marker smallanimal.vethospital.ufl.edu
PopulationPopulation Inclusion criteria Inclusion criteria Specific breed(s) Specific breed(s) Stage of disease Stage of disease Severity of illness Severity of illness Heterogeneity vs. homogeneity Heterogeneity vs. homogeneity
PopulationPopulation Exclusion criteria Exclusion criteria Prior treatments allowed? Prior treatments allowed? Washout Washout Patient size vs. blood drawn Patient size vs. blood drawn Exclude fractious animals? Exclude fractious animals? Owner consent Owner consent
InterventionIntervention Drug treatment Drug treatment Surgical procedure Surgical procedure Diagnostic assay Diagnostic assay What other care is allowed? What other care is allowed? Avoid “clinician discretion” without guidelines Avoid “clinician discretion” without guidelines
InterventionIntervention Blinded vs. double blinded Blinded vs. double blinded Applies to all evaluators Applies to all evaluators Owners Owners Managing clinicians Managing clinicians Techs administering questionnaires Techs administering questionnaires Radiologists Radiologists Pathologists Pathologists
ComparatorsComparators Clinically relevant Clinically relevant Normal or suspected of disease? Normal or suspected of disease? Placebo or standard of care? Placebo or standard of care? Concurrent Concurrent Randomized Randomized
RandomizationRandomization Random numbers Random numbers Evaluators should be blinded to scheme Evaluators should be blinded to scheme Random Numbers
OutcomesOutcomes Define a primary outcome Define a primary outcome Objective Objective Easily measured Easily measured Clinically available Clinically available Validated for your species Validated for your species Relevant to clinical response Relevant to clinical response Dr. Noel Moens, Guelph
OutcomesOutcomes Subjective primary outcomes Subjective primary outcomes Validated scoring system Validated scoring system Complement with objective outcomes whenever possible Complement with objective outcomes whenever possible Blinded evaluators!! Blinded evaluators!! Dr. Duncan Lascelles, NCState
OutcomesOutcomes Secondary outcomes Secondary outcomes Less important? Less important? May be harder to prove May be harder to prove Can generate further hypotheses Can generate further hypotheses Add depth Add depth
Sample size and power Both prospective and retrospective designs Both prospective and retrospective designs Need enough cases to overcome variability within groups to show a difference between groups Need enough cases to overcome variability within groups to show a difference between groups P = Viviano et al. J Vet Intern Med. 2009
Sample size calculation Type I error: finding a difference when it is actually due to chance Type I error: finding a difference when it is actually due to chance Type II error: missing a difference that is actually present Type II error: missing a difference that is actually present With too few cases, you can have either type With too few cases, you can have either type
PowerPower Type I error: P = 0.05 Type I error: P = 0.05 Type II error: often set at 10-20% Type II error: often set at 10-20% Power = 100 -Type II error Power = 100 -Type II error Power = ability to detect a true difference Power = ability to detect a true difference Power often set at 80-90% Power often set at 80-90%
Sample size (or power) calculation Two approaches: Two approaches: Start with known sample size and calculate the power to find a difference Start with known sample size and calculate the power to find a difference Set a minimum power and calculate needed sample size Set a minimum power and calculate needed sample size
Sample size (or power) calculation Choose your stats test based on type of data Choose your stats test based on type of data Define the variability in your control population (SD) Define the variability in your control population (SD) Define the difference you need to detect Define the difference you need to detect
Sample size Consider drop-out Consider drop-out
Time frame Recruitment period Recruitment period Timing of intervention Timing of intervention Duration of intervention Duration of intervention Time points for evaluation Time points for evaluation
Time frame Consider seasonal variables Consider seasonal variables Follow-up Follow-up Complicated? Complicated? Prolonged? Prolonged?
Finalized PICOT research plan Still addresses the hypothesis Still addresses the hypothesis Still relevant Still relevant Feasible! Feasible! Clinical expertise Clinical expertise Caseload Caseload Support staff Support staff Funds Funds Career time frame Career time frame
Finalized PICOT research plan Question is of interest to pet owners Question is of interest to pet owners Intervention is low risk Intervention is low risk Follow-up is convenient Follow-up is convenient Incentives are considered Incentives are considered
Common roadblocks Disease is uncommon Disease is uncommon Studied outcome is rare Studied outcome is rare Data collection too labor intensive Data collection too labor intensive
Common roadblocks Samples banked without validated assays (!) Samples banked without validated assays (!) Case identification out of your control Case identification out of your control Collaborators unmotivated Collaborators unmotivated
Key points Study what you know Study what you know Choose straight-forward aims using available assays/procedures Choose straight-forward aims using available assays/procedures Define the approach using PICOT Define the approach using PICOT
Key points Make sure you would volunteer your own pet to participate Make sure you would volunteer your own pet to participate Results should be publishable no matter what the outcome Results should be publishable no matter what the outcome
Questions or comments?