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    Establishment of Reference Intervals

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    Reference intervals are defined as the range of test results that are expected for a given analyte in a reference population. They are established using a reference sample group that represents the reference population. Reference intervals are important for clinical decision making and laboratories must establish or verify reference intervals for each analyte using their methodology. Reference intervals must also be periodically evaluated and updated as needed based on changes to the patient population or testing methodology.

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    Establishment of Reference Intervals

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    Sparrow
    48 views42 pages
    Reference intervals are defined as the range of test results that are expected for a given analyte in a reference population. They are established using a reference sample group that represents the reference population. Reference intervals are important for clinical decision making and laboratories must establish or verify reference intervals for each analyte using their methodology. Reference intervals must also be periodically evaluated and updated as needed based on changes to the patient population or testing methodology.

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    ESTABLISHMENT OF REFERENCE INTERVALS

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    Reference intervals are defined as the range of test results that are expected for a given analyte in a reference population. They are established using a reference sample group that represents the reference population. Reference intervals are important for clinical decision making and laboratories must establish or verify reference intervals for each analyte using their methodology. Reference intervals must also be periodically evaluated and updated as needed based on changes to the patient population or testing methodology.

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    Download as pptx, pdf, or txt
    48 views42 pages

    Establishment of Reference Intervals

    Uploaded by

    Sparrow
    Reference intervals are defined as the range of test results that are expected for a given analyte in a reference population. They are established using a reference sample group that represents the reference population. Reference intervals are important for clinical decision making and laboratories must establish or verify reference intervals for each analyte using their methodology. Reference intervals must also be periodically evaluated and updated as needed based on changes to the patient population or testing methodology.

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    ESTABLISHMENT OF

    REFERENCE INTERVALS
    Reference interval:
     A pair of medical decision points that span the limits of
    results expected for a given condition.
     The upper and lower reference limits are set to
    define a specified percentage (usually 95%) of the values
    for a population.
     This means that a percentage (usually 5%) of patients will
    fall outside of the reference interval in the absence of any
    condition or disease.
     Reference intervals are sometimes referred to as
    reference ranges.
     The preferred term is reference interval
    because range implies the absolute maximum and
    minimum values.
     Reference interval are required by professional
    accreditation and regulatory standards.
     In most cases, a normal range is used as the reference
    interval.
     The term ‘normal’ has been replaced by the term
    ‘reference’.
    Who will establish reference interval?
     Reference intervals are usually established by the
    scientific community or the manufacturers of reagents and
    new methodologies.
    REFERENCE INTERVAL STUDIES
    1. Establishing a reference interval:
     A new reference interval is established when there is no
    existing analyte or methodology in the clinical or reference laboratory
    with which to conduct comparative studies.

     It is a costly and labor-intensive study that will involve laboratory


    resources at all levels and may require from 120 to as many as 700
    study individuals.
    REFERENCE INTERVAL STUDIES

    2. Verifying a reference interval (transference):


     This is done to confirm the validity of an existing reference interval
    for an analyte using the same (identical) type of analytic system
    (method or instrument).
     These are the most common reference interval studies performed
    in the clinical laboratory and can require as few as 20 study individuals.
    TERMINOLOGY RECOMMENDED BY IFCC

    Reference individual
    Reference population
    Reference sample group
    Reference value
    Reference distribution
    Reference limit
    Reference interval
    Observed value
     Reference individual:
     An individual selected for comparison using defined criteria.
    eg: age,sex,health status.
     Reference population:
     consists of all possible reference individuals. It usually has
    an unknown number and is therefore a hypothetical entity.
     presence of health is not implied, allowing the construction of
    reference intervals for both the healthy and the sick.
     Defining the reference population is fundamental for the
    preparation of effective reference intervals.
     Reference sample group:
     an adequate number of reference individuals taken to
    represent the reference population.
     Ideally they should be randomly drawn from the reference
    population.
     Reference value:
     value (test result) obtained by observation or
    measurement of a particular quantity on an individual
    belonging to a reference sample group.
     Not to be confused with reference limit
     Reference distribution
     The statistical distribution of reference values.
     Hypotheses regarding reference distribution obtained from a reference
    population can be tested using the reference distribution of the
    sample group and adequate statistical methods.
     The parameters of the hypothetical distribution of the reference
    population may be estimated using the reference distribution of the
    reference sample group and adequate statistical methods.
     Reference limit:
     derived from the reference distribution and is used for descriptive
    purposes.
     It is common practice to define a reference limit so that
    a stated fraction of the reference values is less than or equal to, or
    more than or equal to the respective upper or lower limit.
     A reference limit is descriptive only of reference values and should
    not be confused with the term “decision limit.
     Observed value
     (patient test result) is the value of a particular type of
    quantity obtained by either observation or measurement
    and produced to make a medical decision.
     It can be compared with reference values, reference
    distributions, reference limits or reference intervals.
    Types of reference interval

    1.Medical decision level:


    Value for an analyte that represents the boundary between
    different therapeutic approaches.
    2.Normal range:
    Range of results between two medical decision points that
    correspond to the central 95% of results from a healthy patient
    population.Of the results, 2.5% will be above the upper limit and 2.5%
    will be below the lower limit of the normal range.
    3. Therapeutic Range:
     Reference interval applied to a therapeutic drug.
     Reference intervals are needed for all tests in the clinical
    laboratory.
     The provision of reliable reference intervals is an important task
    for clinical laboratories and test manufacturers.
     The dynamic review of existing reference intervals by the
    health care team (scientific community, manufacturers, and
    clinical laboratory) is crucial to meeting the challenges of
    providing optimal laboratory data for patient care.
    Reference interval use can be grouped into 3 main
    categories:
     Diagnosis of a disease or condition
     Monitoring of a physiologic condition
     Therapeutic management
     PICTURE
    QUESTIONS REGARDING REFERENCE INTERVALS FOR
    LABORATORY
    Has the laboratory established or verified its reference intervals ?

     Reference intervals are important to allow a clinician to assess patient


    results against an appropriate population.
     The reference range must be established or verified for each analyte
    and specimen source (e.g., blood,urine,CSF, when appropriate.
     For many analytes (e.g., therapeutic drugs and CSF total protein )
    literature references or a manufacturer’s package insert information may
    be appropriate.
    QUESTIONS REGARDING REFERENCE INTERVALS FOR
    LABORATORY
    Does the laboratory evaluate the appropriateness of its reference
    intervals,and take corrective action if necessary?
    Criteria for evaluation of reference intervals include
     Introduction of a new analyte to the test repertoire
     Change in analytic methodology
     Change in patient population
    If it is determined that the range is no longer appropriate for the
    patient population, corrective action must be taken.
    Steps to establish a reference interval
     Define an appropriate list of biological variation and
    analytic interferences from medical literature.

     Choose selection and partition criteria.

     Complete a written consent form and questionnaire to


    capture selection criteria
    Categorize the potential reference individuals based on the
    questionnaire findings

    •Exclude individuals from the reference sample group based


    on exclusion criteria
    Define the number of reference individuals in consideration
    of desired confidence limits and statistical accuracy
    Standardize collection and analysis of reference specimens
    for the measurement of a given analyte consistent with the
    routine practice of patients

    Inspect the reference value data and prepare a histogram to


    evaluate the distribution of data

    Identify possible data errors and/or outliers and then analyze


    the reference values
    Selection of reference individual

     All group of reference individuals should be defined.


     Condition under which reference specimen were obtained
    and processed should be known and condition should be
    same for all patient specimen.
     The analyte of interest should be same for patient and
    reference individuals.
     Results produced using adequate standardized methods
    under sufficient analytical quality control.
     For detailed approach stages in pathogenesis or disease
    should be demarcated for diagnosis.
     It is important to distinguish selection and partitioning criteria.
     Selection criteria applied to obtain a group of reference
    individuals. This group is subdivided into subgroups using
    partitioning criteria. Whether specific gender is a selection or
    partitioning criteria depends on the purpose of the actual
    project.
    Pre analytic and analytic considerations for reference interval

    Pre analytic factors Analytic factors


     Subject preparation  Precision
     Prescription medications  Accuracy
     Collection time  Linearity
     Sample storage  Interference
     Stress  lot to lot reagents
     Food / beverage ingestion  Recovery
    Analysis of reference values
    Non parametric method Parametric method

    statistical test that makes no specific  Statisticaltest that assumes
    assumption about distribution of data. the observed values or some
     Non parametric methods rank the mathematical transformation
    reference data in order of increasing of those values, follows a
    size. (normal) gaussian
     Majority of analytes are not normally distribution
    distributed, non parametric tests are
    recommended analysis for most
    reference range intervals
    Data analysis to verify a reference interval
    ( transference)
     When possible, clinical laboratories rely on assay manufacturers or on

    published primary literature to determine reference intervals.


     This avoids the expensive and lengthy process of establishing a
    reference range interval on a minimum of 120 healthy people.
     The CLSI allows less vigorous studies to verify a reference interval
    with as few as 20 subject specimens.
     Method verification studies can be used if the test method and study
    subjects are similar to the vendor’s reference data and package insert
    information.
     The main assumption in using transference studies is that
    the reference method is of high quality and the subject
    populations are similar.
     The manufacturer’s reported 95% reference limits may be
    considered valid if no more than 10% of the tested subjects
    fall outside the original reported limit.
    Diagnostic efficiency
     Diagnostic sensitivity

    Ability of a test to detect a given disease or condition.
     Diagnostic specificity
     Ability of a test to correctly identify the absence of a given
    disease or condition.
     Positive predictive value:

    chance of an individual having a given disease or condition


    if the test is abnormal.
     Negative predictive value:

    chance of an individual does not have a given disease or


    condition if the test is within the reference interval.
    COMMON PROBLEMS ENCOUNTERED WHEN
    MONITORING
    REFERENCE INTERVALS
     Changes in reagent formulations by the vendor
    (e.g., new antibody)
     Erroneous initial reference interval either by the vendor or
    laboratory
     Minor changes in reagents due to lot-to-lot variations
     Differences between reference interval and test populations
    THANK YOU

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