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What is TQM? What does it consist of (w/ brief explanation of each)?
- Total Quality Management: management process for continuous quality improvement
- Q planning/processes: processes are designed (or selected) to be error "minimal" ("preventative")
- Q control: On-going monitoring of testing process for accuracy ("right now")
- Q assessment: review of system to determine system problems ("overall")
- Q improvement: re-design of processes using findings of Q assessment ("reaction/prevent")
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Highest error frequency times for clinical care? Lowest?
- Highest: test choice, result use
- Lowest: analytical
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What is method validation and what does it consist of?
- Verification/Establishment of the analytical performance of a method
- consists of - Accuracy, Precision, Reportable range, Reference intervals
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What must be completed before reporting patient results for an FDA-cleared test system? An uncleared test system?
- Cleared: demonstrate that it is comparable to mfgr established specs (Accuracy, Precision, Reportable range)
- Verify that the mfgr reference values are appropriate for your pt pop
- Uncleared: determine Accuracy, Precision, Analytical sensitivity, Analytical specificity, Reportable range, Reference intervals, Any other characteristic required for test performance
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What were the key issues that CLIA-88 introduced?
- Test complexity (mod, high, waived, PPM)
- PT
- Personnel Standards
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What is "bias"?
- Another term for systematic error
- Could refer to proportional or constant variation
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How can one assess the accuracy of a test method?
- Calibrators: referenced to the definitive method
- External Standards: NIST, CAP, pure materials
- Recovery experiment: assess matrix effects
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What are the three method comparisons? Give details about the method most used for CLS.
- Definitive method: "gold standard"
- Reference method: traceable to definitive method
- Comparable method: compare to another lab (or another assay within your own lab)
- Analyze both methods over 5-20 days and plot on scattergram (X=reference, Y=candidate)
- Visually evaluate data
- Calculate linear regression, r, and Sy.x
- *note - proportional error affects slope, constant error affects intercept
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Define correlation coefficient, standard error of estimate, coefficient of variation,
- Correlation coefficient (r): is there a relationship? (1=perfect)
- Std Error... (Sy.x): basically a stddev around a regression line (95% of points within ±2 Sy.x)
- Coefficient of var (C.V.): relative standard deviation (
 ) - puts the stddev raw # into context
- *all are used during method comparison
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What is a Gaussian Distribution of data?
- "bell shaped curve"
- ~2/3 data within ± 1SD
- ~95% data within ± 2SD
- 99.7% data within ± 3SD
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Repeatability vs reproducability
- Both are measurements of precision
- Repeatability: successive results with no changes (reagent, calibration, analyst, etc)
- Reproducability: similar results after changes are made
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What is the F-test and how do we use it?
- Statistical test to compare variance (var=stdev2)
- F = var1/var2 where var1>var2 (F is always >1)
- Compare to a table to determine if variances are unequal
- Used during precision testing (method comparison)
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Define analytical measuring range
AMR: range that can be directly reported by instrument without dilution
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How do you determine LOD/LOQ? What is functional sensitivity?
- run sample w/o analyte 10-20 times, calc mean and SD
- Limit of detection (LOD): mean + 3sd
- Limit of quantitation (LOQ): mean + 10sd
- *results below LOD/LOQ reported as <nn
- Functional sensitivity: lowest concentration that can be measured with C.V. of 20% (or 10%)
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Potential interferents w/ types of interference and if they typically result in pos or neg results. How is this tested?
- Hemolysis: spectral+, chemical-, addition+(artificial increase)
- Turbidity: light scatter+/-, volume displacement-
- Bilirubin: spectral+, chemical-
- Interference testing is similar to accuracy recovery experiment (compare same sample w/ and w/o interferent)
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Determining reference interval CLSI C28
- Very involved
- 120 subjects per partition (age, sex, etc when appropriate)
- includes questionnaire
- Transference more common (verify validity of existing range to your assay and population)
- 20-60 pts
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Bayesian Statistics - Sensitivity, Specificity, Predictive value+, Predictive value-, Efficiency, Prevalence
- Sensitivity: fraction of pts w/ disease detected
- Specificity: fraction of pts w/o disease that test neg
- PV+: proportion of pos tests that represent disease
- PV-: proportion of neg tests that represent lack of disease
- Efficiency: proportion of tests that correctly classify pt
- Prevalence: proportion of tested popn with disease (TP+FN/TP+FP+TN+FN)
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What are ROC plots?
- Receiver Operating Characteristic plots
- Plot true negatives (TN) (1-specificity) vs true positives (TP) (sensitivity) for varying cutoff values
- the point closest to the upper left corner is best cutoff (maximum efficiency)
- Area under curve of 1 (no lines visible) is perfect
- Area under curve of .5 (y=x) is 50/50
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Assayed vs unassayed QC
- Assayed: mfgr provides values (conc, var)
- Unassayed: user determined values
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Levy-Jennings method and its flaws
- Run controls 20 times (during appropriate times)
- Calc mean and SD, create chart
- Plot controls on chart and reject if outside limit (2SD)
- Problems: False rejection (4.5% 1 ctrl, 9% 2 ctrls), No warning capability, No ID of error TYPE
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How do various types of errors affect gausian distribution of a control? What are these types of errors typically related to?
- random error: widening of curve
- instrument problems (pipetting, mixing, washing, electronics, etc)
- systematic error (shift): abrupt move in running mean
- physical event (maint, rgt change, calibration, etc)
- systematic error (trend): gradual, continuous change in running mean
- degradation of component (QC material, aging lamp, reagant, etc)
- mixed errors: systematic type error that occurs randomly (leaking pipetter, sample evaporation)
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Describe each of the Westgard Multi-rules (including alternative rules)
- 1-2s: one control exceeds 2SD limit.
- Warning rule, failure does not reject assay, initiates determination of other rule set
- 1-3s: one control excees 3SD limit.
- Implies random error (only one point)
- 2-2s: two simultaneous (or consecutive) values exceed the SAME limit of 2SD (both + or both -)
- Implies systematic error
- *can be across run or within run
- R-4s: range between two observations within a run exceeds 4SD
- Implies random error
- 4-1s: four consecutive observations exceed the same control limit (+1SD or -1SD)
- Implies systematic error
- *can be across run (last 4) or within run (last 2 for 2 ctls)
- 10x: ten consecutive observations fall on the same side of the mean
- Implies long-standing systematic error
- *can be across run (last 10) or within run (last 5 for 2 ctls)
- across controls = within run = both controls
- within controls = across run = one control
- alternative rules: for assays with 3 control materials
- 9x or 12x rule
- 3-1s
- 2 of 3: 2 out of last 3 ctls exceed same 2SD limit
- can be within or across runs
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What are the modified Westgard multi-rules? What are they for?
- Use 1-3s, 2-2s, and R-4s rules to reject run
- Use 4-1s and 10x as warnings for preventative maintenance (accept run)
- These tests are statistically relevant, but may not be medically relevant
- For tests with long intervals between calibrations
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What are a few alternate approaches to the Westgard multi-rules?
- Westgard EZ rules: software that uses your inputted CV and quality goals to determine the best rules
- examples include 1-5s, etc (personalized)
- Multi-stage QC: different rules based on likelihood of error
- Start-up (any changes) - more sensitive rules (more likelihood of error)
- Monitoring (during run) - single limit rules (less likelihood of error)
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What is the appropriate response (steps) to QC failure
- 1. Determine type of error (R or S)
- 2. Relate type of error to likely causes
- *Consider factors in common on multi-test systems
- 3. Relate causes to any recent changes/actions
- 4. Verify solution. Document remedy.
- *NOTE - repeating controls is statistically likely to bring them into QC range, even if the true reading is outside of the acceptable value (doubled SD, shifted SD)
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Three types of External Quality Control w/ brief explanation
- Internal QC: daily assay of control materials
- Peer comparison: send QC results to central body (vendor?) for comparison with others
- Proficiency testing: assay of unknown samples provided by external body. Mandated.
- must meet peer-group consensus +/- abs value, percent value, or statistical range (depends on the analyte)
- 3 sets of 5 samples per year. 4/5 is passing. Must pass 2/3 consecutive.
- *note - if test isn't in CLIA you must 'verify accuracy' twice per year (usually send to reference lab)
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Give 5 examples of patient-based QC w/ detail
- Serum indices: spectro est of hemolysis, icterus, and lipemia
- Test inter-relationships: T. protein always > albumin, etc
- Physiological limits: "absurd values"
- may indicate clot, bubble, or IV dilution
- Delta checks: comparison of current to previous results (absolute, relative, or rate)
- Insensitive, many false positives
- Average of normals: monitor running avg of selected patient results (in real time)
- equivalent to X bar on DxH
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What are the physiological limits (absurd values) for the following analytes: Albumin, bili, creatinine, CK, cholesterol, Ca + K
- Albumin: <1.5 or >6.0 mg/dL
- Bilirulin: <0.2 mg/dL
- Creatinine: < 0.3 mg/dL
- CK: <5 U/L
- Cholesterol: <50 mg/dL
- Ca + K: Ca <2.0 mg/dL, K >10.0mmol/L (EDTA)
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What are the 3 ways that IV Fluid might interfere with the values for various chemistry tests?
- Normal saline (0.9% NaCl): increased Na and Cl
- Dextrose 5% in water (D5W): Glucose 5,000mg/dL (absurd value)
- Lactated Ringer's: lactate 28mmol/L (absurd value)
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