Introduction

The Molecular Genetics discipline supplies a variety of report styes that provide a direct comparison of individual participant results with all results received. Participants’ results are compared to a calculated median from all method classifications for a particular test and within the main variable of the method system for the measurand. Survey reports are issued after the scheduled closing date.

All Molecular Genetics reports are structured to provide:

• Summary and overall participant performance
• Result review
• Method comparison (if applicable)
• Commentary
• Cumulative summary of the last three year’s performance.

Assessment of results

The RCPAQAP Molecular Genetics programs are designed to assess laboratory’s performance in the detection of genetic abnormalities across a variety of disorders. Overall participant performance is based on consensus results returned for qualitative measurands. Quantitative results are illustrated in scatterplots including the median value and an indicator of the upper and lower (+/- 3 standard deviations) range.

Analysis of Qualitative results

The expected results for all qualitative survey results (i.e. detection, genotype and clinical interpretation) are determined from reference testing and/or consensus of all results, regardless of method used.

Reference testing result:

• Validation of a genotype is performed by a NATA-accredited reference testing laboratory.
• This applies to the Sanger DNA Sequencing module, where PCR products are generated by member(s) of the Molecular Genetics advisory committee.

Survey result consensus:

• If a test achieves ≥80% consensus/agreement from 6 or more results, this is then listed as the expected value. Participants who return the expected result are assessed as “Concordant”.  Minor discordance will also be provided as an assessment grade, implying that a result is not considered a critical error (acceptable) but warrants a review to ensure accuracy.  These values are included to achieve 80% consensus.
• If a test achieves ≤80% consensus from 6 or more results, participants in the minority group are assessed as inconsistent from the consensus and their results are graded as “Discordant”.
• When <80% or < 6 labs agree, results will be reviewed by the appropriate advisory committee for consideration to void assessment (graded as “Not Assessed”) or deem the sample for educational purposes only with an assessment against a target value. Review outcomes will be recorded in the Survey Report.

Genotyping

Genotyping results are assessed against an expected value determined by the reference testing laboratory, or survey result consensus. The assessment of genotyping results takes into consideration the clinical context, nature of an error and clinical relevance of an error (i.e. diagnosis, treatment, counselling).

Listed below are the general considerations for the assessment of genotyping results.

Considerations for a “Concordant” genotype:

• Correct variant
• Incorrect amino acid change when only protein variant is reported

Considerations for a “Minor discordance” genotype:

• Genotype mis-positioned
• No or incorrect zygosity (only applies in cases where zygosity status has implications on clinical interpretation e.g. diagnosis, reproductive planning)

 Considerations for a “Discordant” genotype:

• Incorrect variant
• False negative/positive result where an expected variant is covered by scope of assay performed (also applies if scope of assay not stated)
• Variant not reported due to assay limitations i.e. not included in laboratory’s standard testing panel, or below limit of detection. Depending on the clinical relevance of the variant, the advisory committee will recommend if a missed variant should be graded as “Discordant”, “Minor discordance” or “Not assessed”.

A discordant genotype highlights the need for further investigation into the accuracy of genotyping processes e.g. sample handling, assay performance, and data analysis.

Clinical Interpretation

Clinical interpretation of genotyping results is assessed against survey result consensus. Listed below are the general considerations for the assessment of clinical interpretation.

Considerations for a “Concordant” interpretation:

• Correctly interprets genetic variant in the context of clinical history provided
  • Correct diagnosis provided for the expected genotype
  • Correct recommendation of treatment option

Considerations for a “Minor discordance” interpretation:

• Misdiagnosis that does not have adverse effects on patient care or outcomes

Considerations for a “Discordant” interpretation:

• Discordant genotype
• Incorrectly interprets genetic variant in the context of clinical history provided i.e. misdiagnosis or incorrect treatment options

Analysis of Quantitative Results

Quantitative analysis is performed on all tests where a numerical result is provided. Results are illustrated in a scatterplot for all methods. The scatterplot illustrates the median value and an indicator of the upper and lower (+/- 3SD) range. Assessment of quantitative measurands is based on an APS score or z-score. Refer to Analytic Performance Specification – Quantitative Analysis.

Refer to the table below for the assessment categories of each module.