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The FT4L method is an in vitro diagnostic test for the quantitative measurement of Free Thyroxine in human serum and plasma on the Dimension® EXL™ integrated chemistry system with LOCI® Module. Measurements of free thyroxine are used in the diagnosis and monitoring of thyroid disease.

The TSH method is an in vitro diagnostic test for the quantitative measurement of Thyroid Stimulating Hormone in human serum and plasma on the Dimension Vista® System. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

The submission describes the Dimension® Vista Free Thyroxine Flex® reagent cartridge, FT4 and the Dimension Vista® Thyroid Stimulating Hormone Flex® reagent cartridge, TSH. These are in vitro diagnostic tests for the quantitative measurement of Free Thyroxine and Thyroid Stimulating Hormone in human serum and plasma, respectively, on the Dimension Vista® System. The submission is for the inclusion of pediatric reference intervals to the labeling (Package Inserts) of these assays. No changes were made to the reagents, device design, or manufacturing process.

The document describes the establishment of pediatric reference intervals for the Dimension Vista® Free Thyroxine (FT4) and Thyroid Stimulating Hormone (TSH) Flex® reagent cartridges. It does not contain an acceptance criteria table related to the device's performance against specific metrics of accuracy or precision in the traditional sense, but rather focuses on establishing biological reference intervals. The study's primary goal was to define these pediatric reference intervals.

Here's an analysis of the provided information:

1. Table of Acceptance Criteria and Reported Device Performance

As noted, the document doesn't provide a table of discrete acceptance criteria for device performance (e.g., sensitivity, specificity, accuracy against a gold standard). Instead, the acceptance in this context relates to the establishment and statistical validation of reference intervals for pediatric populations.

The reported "performance" for the Dimension Vista® FT4 and TSH assays, in the context of this submission, is the established pediatric reference intervals. These are compared against adult reference intervals and the assay's analytical measuring range to demonstrate suitability for pediatric use.

Justification of Suitability for Pediatric Use (Acceptance Criteria Implicitly Met):

The document states two key rationales for accepting the pediatric reference intervals, implicitly acting as "acceptance criteria" for the device's application in this population:

• 1. Alignment with Indications for Use: "Testing of pediatric patients is within the established indications for use in the diagnosis and treatment of thyroid disease..."
• 2. Analytical Compatibility: "The newly-established pediatric reference intervals are either within or are above the previously-established reference intervals for euthyroid (normal thyroid) adult populations and they are within the analytical measuring ranges of the Dimension Vista® FT4 and TSH assays. Therefore, the Dimension Vista® FT4 and TSH assays have appropriate analytical performance to test pediatric patients."

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size: A total of 421 patients were analyzed to establish the pediatric reference intervals:
  • Infants (01 - 23 months): 82
  • Children (02 - 12 years): 191
  • Adolescents (13 – 20 years): 148
• Data Provenance: The document does not explicitly state the country of origin or if the data was retrospective or prospective. It implies the samples were collected specifically for this study ("Data from a total of 421 patients... were analyzed to establish..."). Given the context of establishing reference intervals, it is likely prospective collection from healthy individuals within the specified age groups, though this is not explicitly stated.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This type of information is not applicable to this study. The "ground truth" here is the biological variation of FT4 and TSH levels in healthy pediatric populations. Reference intervals are established statistically from a cohort of presumably healthy individuals, not through expert consensus on individual cases.

4. Adjudication Method for the Test Set

This is not applicable. There was no need for adjudication as the study focused on quantitative measurements and statistical analysis of those measurements to define reference ranges.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

This is not applicable. The device is an in-vitro diagnostic test for quantitative measurement, not an imaging device or a diagnostic aid requiring human interpretation that benefits from AI assistance. Therefore, an MRMC study and effect size for human improvement are not relevant.

6. Standalone Performance

Yes, this study inherently focuses on the standalone performance of the Dimension Vista® FT4 and TSH assays. The goal was to determine the measured analyte levels in a specific population (pediatrics) using the device alone, to establish reference intervals. There is no human-in-the-loop component for the determination of the numeric values.

7. Type of Ground Truth Used

The ground truth used to establish the reference intervals is biological reference data from a population of presumably healthy subjects within specified age groups. This involves statistical methods (non-parametric for children/adolescents, robust symmetric for infants, sometimes after log transformation for skewed data) to determine the central 95% of values.

8. Sample Size for the Training Set

This study is not framed in terms of a "training set" for an algorithm. The samples of 421 pediatric patients (82 infants, 191 children, 148 adolescents) directly served as the dataset from which the reference intervals were derived using statistical methods, which could be considered the "training" for the reference interval definition.

9. How the Ground Truth for the Training Set Was Established

The "ground truth" (i.e., the reference intervals) for the pediatric populations was established through statistical analysis of quantitative measurements of FT4 and TSH in serum/plasma samples from the 421 pediatric subjects.

• CLSI C28-A3c Guideline: The study followed the "Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline -- Third Edition (CLSI C28-A3c)" standard.
• Non-parametric approach: Used for children and adolescents, where the 2.5th and 97.5th percentiles of the distribution of values were calculated. This technique is typically used when the sample size is sufficient (usually >120).
• Robust symmetrical method (Horn and Pesce, CLSI EP28-A3c): Used for infants due to a sample size of less than 120 (82 patients).
• Log transformation: For the TSH assay in infants, the data was highly positively skewed, so a natural log transformation was applied to achieve a normal distribution before applying the robust symmetric method.
• Confirmation with Simulated Reference Intervals: Both methods were confirmed with two simulated reference intervals (non-parametric and robust symmetric) estimated as the means of the 95% upper and lower bounds from 1000 data sets.

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