Search Results

The Thyretain ™ TSI Reporter BioAssay is intended for the qualitative detection in serum of thyroid stimulating autoantibodies to the thyroid stimulating hormone (TSH) receptors (TSHRs) on the thyroid. The detection of these stimulating autoantibodies, in conjunction with other clinical and laboratory findings, may be useful as an aid in the differential diagnosis of patients with Graves' disease (GD).

The Thyretain ™ TSI Reporter BioAssay (TSI Reporter) utilizes a patented bioassay technology to detect thyroid stimulating immunoglobulin (TSI) in human serum. Genetically engineered Chinese hamster ovary (CHO) cells, expressing a chimeric form' of the human thyroid stimulating hormone receptor (TSHR) and a cyclic adenosine monophosphate (cAMP) induced luciferase reporter gene, are cryogenically preserved and provided in measured aliquots. The CHO Mc4 cell line has a nucleic acid sequence encoding a chimeric human TSH receptor, designed for reduced response to thyroid blocking immunoglobulin (TBI) activity. Thus, the hTSH receptor, comprised of 730 amino acids, has amino acid residues 262 to 335 replaced by the equivalently located 73 amino acid residues of the rat Luteinizing Hormone receptor to form the chimeric TSHR. This chimeric receptor is linked to a firefly luciferase reporter gene in operable combination with a glycoprotein hormone a-subunit promoter. The cells are seeded and grown for 15 to 18 hours to confluent monolayers in a 96-well plate. Patient sera, reference control, positive and normal controls and are diluted with a proprietary reaction buffer (RB), added to the cell monolayers and allowed to react with the cells for 3 hours. During this induction period TSI, if present in the patient serum, bind to the chimeric human TSHR on the cell surface. This binding event induces a signaling cascade resulting in increased production of intra-cellular cAMP. This increased production of cAMP is evidenced by increased production of luciferase. At the conclusion of the 3 hour induction period the cells are lysed. Luciferase levels are then measured using a luminometer. A significant increase in luminescence over the Reference Control indicates the presence of TSI antibodies in the sample.

Here's a summary of the acceptance criteria and the studies that prove the device meets them, based on the provided text:

Thyretain™ TSI Reporter BioAssay: Acceptance Criteria and Study Summary

The provided document describes the Thyretain™ TSI Reporter BioAssay as an in-vitro diagnostic device intended for the qualitative detection of thyroid stimulating autoantibodies (TSI) in human serum, to aid in the differential diagnosis of Graves' disease (GD). The performance was assessed through non-clinical and clinical studies, primarily comparing it to a legally marketed predicate device, the KRONUS TSH Receptor Antibody (TRAb) Coated Tube (CT) Assay Kit.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for clinical performance in a numerical format that would typically precede a study. Instead, it presents the results of comparative studies against a predicate device and clinical sensitivity/specificity. The implied acceptance is that the device demonstrates comparable performance to the predicate and acceptable clinical utility (sensitivity and specificity).

• Positive Percent Agreement (PPA): 93.8% (95% CI: 88.2% to 96.8%)
• Negative Percent Agreement (NPA): 89.5% (95% CI: 84.0% to 93.2%)

Site 3-NC (n=231 valid specimens):

• Positive Percent Agreement: 74.6% (95% CI: 63.5% to 83.3%)
• Negative Percent Agreement: 97.5% (95% CI: 93.8% to 99.0%)
  Post-hoc analysis removing hypothyroid patients at Site 3-NC increased PPA to 81.5% (95% CI: 70.4% to 89.1%). |
  | Clinical Sensitivity/Specificity | Not explicitly stated as a numerical criterion for acceptance, but demonstrated to provide useful diagnostic information. | Study with 249 characterized specimens:
• Clinical Sensitivity: 92.0% (46/50 Graves Disease positive)
• Clinical Specificity: 99.5% (198/199 Other autoimmune diseases and healthy controls negative) |

2. Sample Sizes and Data Provenance

• Non-Clinical Studies:
  • Assay Cutoff:
    • "Training set": 30 subjects with diagnosed Graves' disease and 44 normal subjects.
    • "Testing-set" (pre-clinical verification): 50 GD positive sera, 140 normal sera.
  • Precision (Intra-assay, Inter-assay, Inter-Day): Varies per test; for Inter-Day, n=120 for high, medium, low TSI serum, n=40 for normal serum, n=80 for controls.
  • Reproducibility:
    • Panel 1: 4 specimens tested at multiple sites (3 sites, with one having 2 technicians). Each site/technician performed testing twice a day over 8 days, leading to 180 total tests for each sample (3 sites x 2 tests/day x 8 days x 4 samples = 192, or 3 sites x 2 techs x 2 tests/day x 8 days = 96 for specific site/tech data, actual calculation seems to be 180 total for "positive ratio").
    • Panel 2: 3 samples tested at 2 sites twice a day for 5 days, totaling 60 tests for each sample (2 sites x 2 tests/day x 5 days x 3 samples = 60).
• Clinical Performance Studies:
  • Comparative Study:
    • Combined Sites 1-COH and 2-MN: 312 specimens initially, 299 analyzed (1 excluded for insufficient quantity, 12 excluded due to indeterminate results on comparator).
    • Site 3-NC: 247 specimens initially, 231 analyzed (16 excluded due to indeterminate results on comparator).
  • Clinical Sensitivity and Specificity: 249 characterized specimens.
• Data Provenance: The document implies the data is retrospective/archived samples, as it refers to "patients with diagnosed Graves' disease," "normal subjects with no known or clinically diagnosed thyroid disease," and "sera obtained from physicians with diagnostic information." The multi-site nature (COH, MN, NC) suggests geographical diversity within the US. There is no explicit mention of the country of origin for all samples.

3. Number of Experts and Qualifications for Ground Truth

• Non-Clinical Studies (Assay Cutoff): Ground truth was established based on "diagnosed Graves' disease" and "normal subjects with no known or clinically diagnosed thyroid disease," implied to be clinical diagnosis by physicians. No specific number or qualifications of experts are provided.
• Clinical Performance Studies (Comparative Study, Clinical Sensitivity/Specificity):
  • The "ground truth" for the comparative study was the results from the KRONUS TSH Receptor Antibody (TRAb) Coated Tube (CT) Assay Kit (the predicate device). This implies that the predicate device's results were accepted as the reference for comparison against the subject device.
  • For the Clinical Sensitivity and Specificity study, specimens were "249 characterized specimens" categorized as "Graves Disease" and "Other autoimmune diseases and healthy controls." This categorization itself acts as the ground truth. The method of characterization (e.g., expert clinical diagnosis, pathology) is not explicitly detailed, but it is implied to be based on clinical diagnosis ("Diagnosis"). No specific number of experts or their qualifications are provided for establishing these fundamental diagnoses.

4. Adjudication Method

• The document does not describe an adjudication method for establishing ground truth using multiple experts.
• For the comparative study, discordant results between the subject device and the predicate device were analyzed, especially at Site 3-NC. The analysis focused on patient TSH results and ATA guidelines for hypothyroidism to explain the discrepancies, rather than an expert adjudication of the initial diagnosis. No multi-reader, observer, or expert consensus adjudication is described for the ground truth of the patient samples.

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

• No MRMC comparative effectiveness study is described where human readers' performance with and without AI assistance is evaluated. The device is an in-vitro diagnostic assay read by a luminometer, not an AI interpreting images for human readers.

6. Standalone Performance

• Yes, the clinical performance studies (both the comparative study and the clinical sensitivity/specificity study) describe the standalone performance of the Thyretain™ TSI Reporter BioAssay. The device produced its own results (positive/negative) which were then compared to either the predicate device's results or defined clinical diagnoses.

7. Type of Ground Truth Used

• Non-Clinical (Assay Cutoff): Clinical diagnosis of Graves' disease or no known thyroid disease.
• Clinical Performance (Comparative Study): The results of the predicate device (KRONUS TSH Receptor Antibody (TRAb) Coated Tube (CT) Assay Kit) were used as the reference for comparison.
• Clinical Performance (Clinical Sensitivity and Specificity): Clinical diagnosis ("Graves Disease", "Other autoimmune diseases and healthy controls"). This would typically be established based on a combination of clinical signs/symptoms, other laboratory tests, and possibly imaging, by a physician.

8. Sample Size for the Training Set

• For establishing the preliminary assay cutoff:
  • 30 subjects with diagnosed Graves' disease.
  • 44 normal subjects with no known or clinically diagnosed thyroid disease.
  • (An additional "testing-set" of 50 GD positive sera and 140 normal sera was used for verification).

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

• The ground truth for the training set (for assay cutoff determination) was established through clinical diagnosis: "subjects with diagnosed Graves' disease" and "normal subjects with no known or clinically diagnosed thyroid disease." This implies traditional clinical assessment by physicians.

Ask a specific question about this device