A Discrepant Confirmatory Result: Laboratory Stewardship and Quality When a Referral Lab and Your Lab Disagree
Your biochemical genetics laboratory performs plasma amino acid analysis by ion-exchange chromatography with ninhydrin detection. A 3-year-old with developmental delay and seizures had a plasma amino acid profile at an outside reference laboratory reported as 'elevated serine, suggestive of a serine biosynthesis defect.' The outside lab used a different method (LC-MS/MS with derivatization). Your lab repeats the plasma amino acids on a fresh sample and finds serine within the reference interval, with no other abnormality. The clinician is confused and asks which result to believe; the family has already been told the child may have a treatable disorder and has started serine supplementation. Your laboratory director is asked to review.
1. What are the possible explanations for the discrepancy, and how would you systematically investigate it before deciding which result is correct?
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Possible explanations:
- Pre-analytic differences: sample handling/time to processing, hemolysis (red cells are rich in some amino acids), fasting status, diet/supplementation, and timing relative to seizures or treatment. Serine can be affected by hemolysis and by delayed separation.
- Methodologic differences: ion-exchange/ninhydrin vs. LC-MS/MS with derivatization have different specificities, interferences, and reference intervals. Co-eluting compounds or derivatization artifacts can cause false elevations on one platform.
- Reference interval mismatch: the outside lab may use age-appropriate or method-specific cutoffs that differ from yours; 'elevated' may be marginal.
- True biologic variability: serine is influenced by diet and clinical state; a single sample may not be representative.
- Reporting/transcription error: wrong patient, units, or a mislabeled result.
Systematic investigation:
- Obtain the original report, method, reference interval, and any flags from the outside lab; confirm patient identity and specimen dates.
- Review pre-analytic details for both samples (hemolysis index, time to processing, fasting, medications/supplements).
- Re-run the fresh sample on your platform and, if possible, send an aliquot to a third method or a second reference lab for concordance.
- Check internal quality control and proficiency testing performance for serine on your platform; review calibration and any recent method changes.
- Compare with clinical context and other analytes (e.g., other amino acids, urine serine, CSF if a serine biosynthesis defect is seriously considered).
Only after this review should you decide which result to act on.
2. The serine supplementation was started based on the outside result. What are the stewardship and communication responsibilities of the laboratory and care team now?
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Laboratory stewardship responsibilities:
- Do not simply declare your result 'correct.' Communicate the discrepancy transparently to the clinician, including the methodologic basis and the limits of a single sample.
- Document the investigation, the QC review, and the recommendation in the laboratory record; if an error is found on either side, follow the laboratory's nonconforming-event/corrective-action process and notify the outside lab as appropriate.
- Recommend confirmatory testing (repeat sample, alternate method, and - if a serine biosynthesis defect is seriously considered - CSF serine and molecular testing of PHGDH/PSAT1/PSPH), because plasma alone is insufficient for that diagnosis.
Care-team communication:
- The clinician should re-discuss with the family that the initial result is being re-evaluated and that supplementation may not be indicated; avoid abandoning a treatable diagnosis prematurely, but also avoid unnecessary treatment.
- Serine supplementation is generally well tolerated, but ongoing treatment without confirmation should be reassessed; decisions should be made with the metabolic specialist.
- Provide the family with a clear, plain-language explanation and a plan for confirmatory testing.
Quality improvement: review whether the outside lab's reference intervals and your lab's are harmonized, and whether the report clearly states method and limitations.
3. What quality metrics and safeguards would you put in place to reduce the chance of a similar discrepancy causing harm in the future?
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Safeguards and metrics:
- Report clarity: every amino acid report states the method, specimen type, reference interval source, and interpretative caveats (e.g., hemolysis, fasting, supplementation).
- Critical/actionable result policy: define which results require direct clinician notification and a recommended confirmatory pathway; document the notification.
- Discrepancy review process: a formal pathway for reconciling discordant results between laboratories, with root-cause analysis and corrective action, tracked as a quality metric.
- QC and proficiency testing: monitor performance for key analytes (including serine) on each platform; review calibration and lot changes; participate in external quality assessment.
- Reference interval harmonization: periodically compare intervals with referral labs and with age-specific data; document any differences.
- Communication and education: educate clinicians that a single abnormal amino acid is a screening signal, not a diagnosis, and that confirmatory testing (repeat, alternate method, CSF, molecular) is required for treatable disorders.
- Metrics to track: rate of discordant confirmatory results, time to clinician notification of critical results, rate of corrected reports, and turnaround time for add-on/confirmatory testing.
Culture: encourage clinicians to call the lab when results don't fit the clinical picture; a discrepancy is a signal to investigate, not a reason to dismiss either result.