Evidence Based Laboratory Medicine Notes

Evidence Based Laboratory Medicine

The Principles

  • Definition: Evidence-Based (Laboratory) Medicine (EBLM) is a new term that embodies current best practice. It is defined as:
    • "The conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individuals" (Sackett et al., 1996).
  • Background:
    • Developed in the 1990s.
    • Widely accepted by health systems worldwide.
    • Principles employed in laboratory medicine.
    • Ensures a well-informed medical standard, resulting in optimal patient care (Guyatt, G et al., 1992, JAMA 268(17):2420-5).
  • Integration necessities:
    • Determining where laboratory medicine fits into the care pathway.
    • Determining when testing is appropriate.
    • Assessing the type and quality of evidence required to demonstrate the test's clinical utility.
    • Understanding how the test impacts clinical actions.
    • Identifying where changes in the care pathway will occur.
    • Determining where benefit/value can be achieved.
  • Goal: To provide the best laboratory procedures that benefit health care.
  • Principles:
    • Formulating the question.
    • Searching for the evidence.
    • Appraising the evidence.
    • Applying the evidence.
    • Assessing (auditing) the practice.
    • Modifying the practice.

The Process

  • Principles Diagram:
    • Identify the question → Search for evidence → Critically appraise evidence → Apply to practice → Audit practice → Modify practice.

Why EBLM is Needed

  • A request for a diagnostic test is part of clinical decision-making.
  • Relevance of the test to the clinical situation is crucial.
  • Critical appraisal of evidence is necessary in terms of quality.
  • Evidence is continually evolving, especially for new tests.
  • Quality in clinical practice is a political agenda item.

Diagnostic Test Considerations

  • A diagnostic test is considered an intervention.
  • It should be requested only when a question is being asked, and the result will provide an answer.
  • The best evidence for the value of a test is improved outcome.

Contrasting Perspectives on Medical Testing

  • Too much testing vs. Insufficient testing:
    • Expensive testing vs. Laboratories expected to generate income.
    • Tests have little impact on outcomes vs. Test results are essential for clinical decision making.

Emphasis on Outcomes

  • The result of an intervention:
    • Health outcome.
    • Economic outcome.
  • Differing expectations:
    • Patient:
      • Promptness.
      • Effective treatment.
      • Symptom relief.
    • Service provider:
      • Promptness.
      • Delivery of effective care.
      • Workload.
      • Economic factors.

Why Focus on Outcomes?

  • Increasing concerns about the quality of health care.
  • Cost concerns.
  • Increasing patient expectations.
  • New delivery models (e.g., point of care testing).
  • Continual availability of new evidence.
  • Discovery of new technologies.
  • Resource allocation is an increasing problem.

EBLM's Central Role

  • EBLM is at the heart of what we do.
  • Quality assurance.
  • Audit.
  • Research & Development.
  • Education & training.

Factors to Achieve Quality in Health Care

  • Safe – avoiding harm, minimization of risk.
  • Patient-centered – respecting individual needs and values.
  • Timely – minimizing delays; performance targets.
  • Efficient – avoiding waste.
  • Equitable – equal quality, guidelines.
  • Effective – evidence-based, maximization of benefit.
  • Reasonable cost (Institute of Medicine, 2001).

Findings from a Review of Health Care in the US

  • Medical errors:
    • Accounted for approximately 100,000 deaths per year.
    • Costing approximately $$2 billion per year.
  • Costs of poor quality: Approximately 30-40% of total health care spending.
  • Conclusion: The health service was fragmented, dangerous, and wasteful (Institute of Medicine, 2000).

Laboratory Medicine Point of View

  • Test repertoire is increasing.
  • Workload is increasing.
  • There is uncontrollable demand.
  • Unnecessary testing occurs.
  • Utilization of tests is varied.
  • Continually new evidence needs consideration.
  • Translation of evidence to practice is slow.
  • There is a perception of limited investment.

Clinical Outcomes from Medical Testing

  • Clinical outcomes:
    • Death.
    • Disease.
    • Disability.
    • Discomfort.
    • Dissatisfaction.
  • Testing outcomes:
    • Faster decision making.
    • Earlier treatment.
    • Improved compliance/standardization.
    • Reduced complications.
    • Reduced empirical/unnecessary treatment.
    • Reduced re-admission.
    • Improved survival.
    • Improved patient satisfaction.

Economic Outcomes

  • Cost to the patient.
  • Cost to the provider.
  • Cost to society.
  • Surrogates:
    • Number of clinic visits.
    • Length of stay.
    • Re-admission rate.
    • Intervention rate.
    • Working days lost.
    • Productive years gained.

Outcomes of Testing

  • Impact of the test on clinical outcome.
  • Analytical performance and impact on outcomes.
  • Modality of testing and impact on outcomes.
  • Health economics of testing.

Decision Making

  • The pyramid of evidence includes:
    • Investment decision.
    • Cost-effectiveness.
    • Technical performance.
    • Organizational impact.
    • Clinical impact.
      • Diagnosis.
      • Treatment.
      • Health outcome.
    • Diagnostic performance.

Implementation of EBLM

  • EBLM Principles:
    1. Define the Question.
    2. Search for the Evidence.
    3. Appraise that Evidence.
    4. Apply the Evidence.
    5. Audit the Practice.
    6. Modify the Practice.
  • Process Diagram:
    • Identify the question → Search for evidence → Critically appraise evidence → Apply to practice → Audit practice → Modify practice.

Step 1: Importance of Good Questions

  • Articulates the problem in a clear and structured way.
  • Central to reviewing the literature.
  • Key to future study design.

Things to Consider

  • Patient and disease:
    • Background to a condition.
    • Aetiology.
    • Risk factors.
    • Patient-specific factors.
  • Test:
    • Availability.
    • Screening.
    • Diagnosis.
    • Prognosis.
    • Accuracy.
    • Clinical outcome.

Formulate an Answerable Question - The PICO System

  • P - patient problem or population being addressed.
  • I - test or treatment intervention (aka indicator).
  • C - comparator or control – to which intervention is compared.
  • O - outcome – depends upon the nature of the question.
P - Patient Problem or Population
  • Primary problem.
  • Patient group.
  • Disease or health status.
  • Age, race, sex, previous ailments, current medications.
I - Test or Treatment Intervention
  • What you plan to do for that patient.
  • Specific diagnostic test, treatment, medication.
  • Recommend a procedure.
  • This is the main consideration for the patient.
C - Comparator or Control
  • The alternative.
  • Can be omitted.
O - Outcome
  • What you plan to accomplish/improve/effect.
  • Should be measurable (e.g., eliminate/relieve symptoms, improve function, improve prognosis).

Type of Question

  • Therapy/Prevention.
  • Diagnosis.
  • Aetiology (cause).
  • Prognosis.
  • Analytical.
  • Operational.
  • Economic.

PICO Variants

  • PPICO
    • Population
    • Previous tests
    • Intervention
    • Comparator
    • Outcome
  • PICOT
    • Population
    • Intervention
    • Comparator
    • Outcome
    • Time
  • PICCO
    • Population
    • Intervention
    • Comparator
    • Change management
    • Outcome

Examples of Questions in each Category

Q1: Aetiology, Risk Factors and Prevalence
  • Case 1: A 34-year-old woman runs 5 miles every day, collapses after 6 weeks with chest pains. Troponin level is 0.02 ng/L (upper reference interval 0.01 ng/L).
  • Question: Does sustained physical exercise lead to increased serum troponin level?
  • PICO Breakdown:
    • P: Women
    • I: Sustained physical exercise
    • C: Normal lifestyle exercise
    • O: Serum troponin level
  • Full Question: In women ~35 years old, will sustained physical exercise increase serum troponin levels compared to women with normal lifestyle exercise?
Q2: Diagnosis
  • Case 2: Microbiologist concerned about the number of urines sent from primary care for suspected UTI, believes dipstick test might help.
  • PICO Breakdown:
    • P: Patients presenting to GPs with symptoms suggestive of UTI
    • I: Dipstick urinalysis for leucocyte esterase and nitrite
    • C: Lab tests for microscopy, culture, and sensitivity
    • O: Correct diagnosis of urinary tract infection
  • Full Question: In patients presenting to GP with UTI symptoms, can dipstick urinalysis for LE and nitrite be used to rule in/out a UTI diagnosis, reducing the number of urines sent to the lab?
Q3: Prognosis
  • Case 3: Oncologist reads about a new gene panel test to predict breast cancer recurrence and consults a pathologist.
  • PICO Breakdown:
    • P: Women diagnosed with breast cancer
    • I: Tissue expression of a panel of genes
    • C: Grading of cancer based on histology, tumor size, biomarkers, etc.
    • O: Recurrence of disease
    • T: 5-year follow-up period
  • Full Question: How well can the expression of a panel of genes in primary tumor at diagnosis in women with breast cancer predict the likelihood of recurrence?
Q4: Treatment: Guiding Therapy
  • Case 4: Primary care physician questions self-monitoring of blood glucose in type 2 diabetes management and consults a clinical biochemist.
  • PICO Breakdown:
    • P: Patients with type 2 diabetes
    • I: Self-monitoring of blood glucose (SMBG) as part of an integrated package
    • C: No self-monitoring of blood glucose
    • C: Change management: Adjust dosage according to blood glucose
    • O: Control of blood glucose concentration (reduction in complications)
  • Full Question: Does including SMBG as part of an integrated package in managing type 2 diabetes lead to better glycemic control and a reduction in complications?
Q5: Analytical Performance
  • Case 5: A prostate risk management program advocates using a PSA assay meeting specific quality criteria. The current assay doesn't meet the criteria.
  • PICO Breakdown:
    • P: Men receiving PSA tests as part of a prostate cancer risk management program
    • I: Serum PSA testing meeting the agreed quality criteria with respect to accuracy
    • C: Serum PSA testing not meeting the agreed quality criteria with respect to accuracy
    • O: Unnecessary biopsies avoided and cancers detected
  • Full Question: Does the use of a PSA test that meets agreed quality criteria with respect to accuracy lead to improved test performance (through avoidance of unnecessary biopsies) as well as detecting more cancers?
Q6: Operational
  • Case 6: The health management organization wants to investigate the costs and benefits of transferring more diabetes management into the community setting and wants to assess point-of-care HbA1c testing.
  • PICO Breakdown:
    • P: Patients with diabetes
    • I: Point of care testing (POCT) for HbA1C
    • C: Laboratory testing for HbA1c
    • C: Clinical decision on result at the time of intervention
    • O: Glycaemic control
  • Question: Will the use of POCT for HbA1C as part of an integrated package of care for the management of diabetes improve glycaemic control?
Q7: Economic
  • Case 7: The clinical biochemist wants to introduce brain natriuretic peptide (BNP) testing to rule out heart failure and reduce the need for echocardiography.
  • PICO Breakdown:
    • P: Patients presenting to GPs with symptoms suggestive of heart failure
    • I: BNP testing
    • C: No BNP testing
    • O: Total cost of diagnosing heart failure
    • T: Over a period of one year
  • Question: Does the introduction of BNP as a first-line test in the diagnostic triage pathway for patients with suspected heart failure attending their GP reduce the total cost involved in making the diagnosis of heart failure?

Step 2: Searching for the Evidence

  • Internet (good websites).
  • PubMed.
  • Literature:
    • Peer-reviewed journals.
      • Journal quality.
      • Study quality.
    • Clinical trials.
    • Research.

Searching Tips

  • OR: One of a choice of words.
  • AND: All words requested.
  • NOT: Excludes certain words.
  • ADJ or NEAR: Words must be next to each other or within about 5 words.
  • *: Truncate words with variable endings.
  • (): Group words.
  • Limits: Restrict language, publication date, humans, etc.
  • [ti] or :ti: The word must be in the title.
  • MeSH: Medical Subject Headings (controlled vocabulary in PubMed or Cochrane).

Systematic Review + Meta-analysis

  • Presenting critically appraised data.
  • Systematic review: A summary of the literature that uses defined methods for the performance of a comprehensive literature search and critical appraisal of the studies identified from the search.
  • Meta-analysis: A set of statistical techniques for combining similar information from different studies to derive an overall estimate of a treatment effect or characteristics of a test.

Hierarchy of Strength of Evidence

  • EBM Levels of Evidence Pyramid (from top to bottom):
    Meta-analysis → Systematic Reviews → Randomized Controlled Trials → Cohort Studies → Case Control Studies → Case Series & Case Reports → Animal Studies/Laboratory Studies (Guyatt et al. 2000).
  • RCTs and controlled clinical trials: help answer treatment and diagnosis questions.
  • Cohort Studies: help answer prognosis and etiology/harm questions.
  • Case Control Studies.
  • Case Series & Case Reports.
  • Animal Studies/Laboratory Studies.

Step 3: Appraisal of the Evidence

  • Critical Appraisal: The process of carefully and systematically examining research to judge its trustworthiness and its value and relevance in a particular context.
  • 'Weighing up the evidence to assess its validity (closeness to the truth) and usefulness (clinical applicability)' (Buris A. What is critical appraisal? http://www.medicine.ox.ac.uk).
  • Sackett DL, Haynes RB. On the need for evidence-based medicine. Evid Based Med 1995;1:4-5.

Appraisal of the Evidence: Key Questions

  • Was there a clear question for the study to address (PICO)?
  • Are the results valid?
  • Was there a comparison with an appropriate reference standard?
  • Did all patients get the diagnostic test and the reference standard (bias)?
  • Could the results of the test of interest have been influenced by the results of the reference standard (bias)?
  • Is the disease status of the tested population clearly described?
  • Were the methods for performing the test described in sufficient detail?
  • What are the results?
  • How sure are we about these results? (statistical analyses).
  • Can the results be applied to your patients/ the population of interest?
  • Can the test be applied to your patient or population of interest?
  • Were all outcomes important to the individual or population considered?
  • What would be the impact of using this test on your patients/population?

What is Critical Appraisal? - Considerations

  • Not a negative dismissal of any piece of research; but a balanced assessment of benefits and strengths of research against its flaws and weaknesses.
  • Not assessment of results alone; but assessment of research process and results.
  • Considers both quantitative and qualitative aspects of research.
  • To be undertaken by all health professionals as part of their work, not just expert researchers/statisticians.

Why Should We Critically Appraise?

  • Published research is not always reliable – incorrect conclusions can be drawn from poor evidence.
  • Published research is not always relevant.
  • We need a systematic framework to interpret research.

Confidence in Results: Key Questions

  • Could they have occurred by chance?
  • Confidence intervals?
  • Statistical significance?
  • Adequate description of the data collection methods?
  • Appropriate, clearly described, and justified methods of analysis?

Published Research Findings - May Be False (Ioannidis 2005)

Scenario% Time Eventually True
Confirmatory meta-analysis of good quality RCTs85 %
Adequately powered RCT with little bias and pre-study 50 % chance effective85 %
Meta-analysis of small inconclusive studies41 %
Underpowered but well-performed phase I/II RCT23 %
Underpowered, but poorly performed phase I/II RCT17 %

Step 4: Apply the Evidence

  • Can follow the PICO framework again:
    • P: Does the evidence apply to the patient/population and setting in the original question?
    • I: Does my method have the required performance, and am I using the right decision (cut-off) values?
    • C: Is the current standard of care similar to the control groups featured in the evidence?
    • C: What is the change in practice required, and is it achievable?
    • O: What were the outcomes shown in the evidence, and are they appropriate and achievable?

Can the Test Be Applied to Your Patient or Population of Interest?

  • Age, sex, ethnicity, and spectrum bias.
  • Equipment, reagent, and staff resources.
  • Level and availability of expertise required to interpret the tests.
  • Current practice and availability of services.
  • Timings of blood collection and test measurement.
  • Training requirements.

What Would Be the Impact of Using This Test on Your Patients/Population?

  • Benefits vs. cost / harm.
  • Consider clinical needs.
  • Quality specifications.
  • Does the laboratory service meet the established standard of care?
  • Is the process of care optimal and make best use of the laboratory service, including process change?
  • Are the best health outcomes being achieved?
  • Economic criteria.

Step 5: Audit the Practice

  • The audit assesses whether the application of new evidence and the introduction of a new test has led to improved outcome.
  • Also serves purposes of:
    • Training.
    • Effective management.
    • (Continuous) quality improvement.
    • Maintenance of good practice.

Step 6: Modify the Practice

  • EBLM is a continual process.
  • Changes in technology.
  • Research discoveries.
  • Changes in health priorities.
  • Comparison (validation) of a new diagnostic test to current gold standard –
    • Specificity, sensitivity, cost, turn-around time, intervention, sample type.

Evidence Based Laboratory Medicine - Summary

  • Identify the question → Search for evidence → Critically appraise evidence → Apply to practice → Audit practice → Modify practice.

Guidelines for the Process of EBLM

  • There is a need for guidelines.
  • Summarized in Oosterhuis et al. 2004