(248 days)
The Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge is an in vitro diagnostic test for the quantitative measurement of total testosterone in human serum and plasma on the Dimension Vista® System. Measurements of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, delayed or precocious puberty, impotence in males, and in females, hirsutism (excessive hair), and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.
The Dimension Vista® Testosterone Calibrator is an in vitro diagnostic product for the calibration of the Total Testosterone (TTST) assay on the Dimension Vista® System.
The Dimension Vista® LOCI Total Testosterone Flex® Reagent Cartridge (TTST) method is a homogeneous, competitive chemiluminescent immunoassay based on LOCI® technology. LOCI reagents include two synthetic bead reagents and labeled testosterone antibody. The first bead reagent (Chemibeads) is coated with a testosterone analog and contains a chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains photosensitive dye. Chemibeads and labeled testosterone antibody are added sequentially to the reaction vessel. Testosterone from the patient sample competes with the testosterone-analog-chemibead for a limited amount of labeled testosterone antibody. Sensibeads are then added and bind to the biotinylated portion of the labeled testosterone antibody to form bead pair immunocomplexes. Illumination of the complex by light at 680 nm generates singlet oxygen from the Sensibeads which diffuses to the Chemibeads triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is an inverse function of the concentration of total testosterone in the sample.
Dimension Vista® LOCI Total Testosterone reagents are liquid and contained in reagent wells of a Flex® reagent cartridge. There are twelve (12) wells in each Flex® reagent cartridge. A barcode label on the Flex® reagent cartridge identifies the test method, lot number, expiration date, and fixed number of tests for which the Flex® reagent cartridge can supply reagent. There are eighty (80) tests per Flex® reagent cartridge and four (4) Flex® reagent cartridges per carton.
The Dimension Vista® Testosterone Calibrator (TTST CAL) is a lyophilized human serum based calibrator set containing testosterone and preservatives. Within each set of twelve (12) vials there are two (2) 1.0 mL amber glass vials for each calibrator level. There are six (6) calibrator levels labeled A, B, C, D, E, and F, which span the assay range. Each glass vial is closed with a plug and a color coded plastic cap. Vials are stored at 2-8°C. Lyophilized calibrators are reconstituted with reagent grade water using the steps listed in the instructions for use (IFU).
The provided document describes the Siemens Healthcare Diagnostics Inc. Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge and its associated calibrator, seeking substantial equivalence to predicate devices. The study focuses on the performance characteristics of the new device.
Here's an analysis of the acceptance criteria and study details based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined "acceptance criteria" in a quantitative, pass/fail format for each performance characteristic. Instead, it presents the results of various performance studies and implies that these results demonstrate substantial equivalence to the predicate device. The predicate device itself and recognized CLSI guidelines serve as implicit benchmarks for acceptable performance.
However, based on the provided data, we can infer some targets or observed ranges that indicate acceptable performance. The "Reported Device Performance" column reflects the results of the studies described.
| Performance Characteristic | Implicit Acceptance Criteria (Inferred from CLSI Guidelines & Predicate) | Reported Device Performance (Dimension Vista® LOCI Total Testosterone Flex®) |
|---|---|---|
| Method Comparison (vs. CDC ID/LC-MS/MS) | High correlation (e.g., r > 0.95), slope near 1, y-intercept near 0, 95% Confidence Interval for slope encompassing 1, for intercept encompassing 0. | N=113 samples. Range: 7.3 - 1033 ng/dL (CDC), 8-949 ng/dL (Vista TTST). |
| Slope: 0.93 | ||
| y-intercept: 4.0 | ||
| Correlation coefficient (r): 0.994 | ||
| 95% CI Slope: 0.92 to 0.95 | ||
| 95% CI Intercept: 0.4 to 5.7 | ||
| Precision (Repeatability %CV) | (Based on CLSI EP05-A2 and typical immunoassay performance expectations, generally 0.05 from polynomial regression, high correlation coefficient). | Statistically linear across 8 to 1,000 ng/dL for serum, lithium heparin, sodium heparin, and EDTA plasma. p-values > 0.05. |
| Serum: $0.97x + 0.1$, r=0.999 | ||
| Sodium Heparin: $0.98x + 0.1$, r=0.998 | ||
| Lithium Heparin: $0.98x + 0.0$, r=0.999 | ||
| EDTA: $0.96x + 0.1$, r=0.999 | ||
| Limit of Blank (LoB) | Stated as 4 ng/dL | 4 ng/dL |
| Limit of Detection (LoD) | Stated as 5 ng/dL | 5 ng/dL |
| Limit of Quantitation (LoQ) | Reproducible measurement with total precision ≤20% (as per CLSI EP05-A2). | 8 ng/dL (with total precision ≤20%) |
| Interferences (Hemoglobin, Bilirubin, Lipemia Bias) | Low bias (e.g., 0.95), slope near 1, intercept near 0. | Li Hep Plasma: Slope 0.98, Intercept -1.6 ng/dL, r=0.998 |
| Na Hep Plasma: Slope 0.99, Intercept -1.4 ng/dL, r=0.996 | ||
| K2 EDTA Plasma: Slope 1.00, Intercept -1.1 ng/dL, r=0.995 |
2. Sample Size Used for the Test Set and Data Provenance
- Method Comparison: 120 serum samples were initially measured. After removing 7 samples (6 below range, 1 above range), 113 samples were used for regression analysis.
- Data Provenance: Not explicitly stated but clinical samples were used, likely from a patient population within the US given the submission to the FDA. The study was performed at Siemens Healthcare Diagnostics' Newark, DE site. This is a retrospective analysis in the sense that samples were collected and then tested.
- Precision: Serum pools, a plasma pool, and commercial controls were used.
- Sample Size: Tested in singlicate from two independent cups twice a day for 20 days. This implies 40 measurements per sample type.
- Data Provenance: Not specified, but likely proprietary pools or commercial controls. Study performed at Siemens Healthcare Diagnostics' Newark, DE site.
- Analytical Measuring Range/Linearity: High and low pools for serum, lithium heparin, sodium heparin, and EDTA samples.
- Sample Size: Each level was assayed N=5 replicates. The number of distinct pools (high/low) is not specified for each sample type, but implied to be sufficient to cover the range.
- Data Provenance: Not specified, likely internal laboratory prepared pools. Study performed at Siemens Healthcare Diagnostics' Newark, DE site.
- Limits of Detection and Quantitation: Testosterone free serum samples and low testosterone serum samples.
- Sample Size: Not explicitly stated for LoB/LoD, but LoQ was determined based on precision data (implied 40 measurements).
- Data Provenance: Not specified, likely internal laboratory prepared samples.
- Interferences: Serum samples with various interfering substances spiked in.
- Sample Size: Not specified per substance, typically multiple replicates at each concentration.
- Data Provenance: Not specified, likely internal laboratory prepared samples.
- Heterophilic Antibody Interference: Individual human serum samples with low and high endogenous HAMA.
- Sample Size: Not specified, but implied individual samples were tested.
- Data Provenance: Not specified.
- Cross-reactivity: Spiked test samples.
- Sample Size: Not specified per cross-reactant, typically multiple replicates at each concentration and testosterone level.
- Data Provenance: Not specified, likely internal laboratory prepared samples.
- Serum and Plasma Equivalency: Sixty (60) matched sets of fresh draws.
- Sample Size: 60 matched sets. One sample removed, so 59 sets for regression analysis.
- Data Provenance: Not explicitly stated, but implies prospectively collected clinical samples.
- Expected Values (Reference Interval):
- Adult Males ≤50 years old: 174 samples
- Adult Males >50 years old: 174 samples
- Pre-menopausal females: 174 samples
- Post-menopausal females: 174 samples
- Pediatric (various age/gender/Tanner stages): Ranges from 20 to 125 samples per group.
- Data Provenance: Not specified, but likely from healthy volunteers (prospective) or carefully selected retrospective samples to establish reference ranges for different demographics.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
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Ground Truth for Method Comparison: The reference method was the CDC Isotope dilution/liquid chromatographic-tandem mass spectrometry (CDC ID/LC-MS/MS). This is a highly accurate and precise analytical method that by its nature serves as its own "expert" or gold standard. It does not rely on human interpretation or consensus for ground truth.
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Ground Truth for Reference Intervals: The reference intervals were established using the "robust" method or non-parametric methods described in CLSI EP28-A3c, applied to samples from healthy individuals. The "ground truth" here is the biological range observed in these populations, rather than an expert interpretation of the result from a single patient. The selection of "healthy" individuals likely involves criteria established by medical professionals, but this is not detailed as a panel of experts.
4. Adjudication Method for the Test Set
This type of in-vitro diagnostic device (immunoassay for a quantitative measurement) does not typically involve an adjudication method in the way medical imaging AI devices do (e.g., 2+1 radiologist review). The output is a quantitative value. Agreement is assessed statistically against a reference method or through precision studies, not through expert consensus on the device's output for individual cases.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic devices where human readers interpret results, and the AI system acts as an aid to improve their performance. This document concerns a fully automated in-vitro diagnostic immunoassay which provides a numerical result directly, rather than an image or complex data needing human interpretation.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
Yes, the entire submission and the performance studies detailed (Method Comparison, Precision, Linearity, Limits of Detection/Quantitation, Interferences, Cross-reactivity, Serum/Plasma Equivalency, Reference Intervals) effectively describe the standalone performance of the algorithm, as it's an automated device that provides quantitative results without human interpretation in the determination of the final value. The performance evaluation focuses on the analytical performance of the Dimension Vista® LOCI Total Testosterone Flex® reagent cartridge and system itself.
7. Type of Ground Truth Used
- Method Comparison: CDC Isotope dilution/liquid chromatographic-tandem mass spectrometry (CDC ID/LC-MS/MS) (a highly accurate reference analytical method, considered a gold standard).
- Precision, Linearity, LoD/LoQ, Interferences, Cross-reactivity, Serum/Plasma Equivalency: These studies rely on known concentrations (e.g., spiked samples, control materials, or reference method values from the method comparison) to establish the accuracy and reliability of the device's measurements.
- Expected Values (Reference Interval): Data from well-defined populations of healthy individuals, analyzed using statistical methods (non-parametric or "Robust" method).
8. Sample Size for the Training Set
The provided document does not mention a training set in the context of machine learning or AI algorithms as the primary development method for the immunoassay. This device is based on a "homogeneous, competitive chemiluminescent immunoassay based on LOCI® technology" (a biochemical detection method), not a software algorithm that learns from a training dataset in the typical AI sense. The development of such an assay involves extensive biochemical optimization, reagent formulation, and analytical validation.
9. How the Ground Truth for the Training Set Was Established
As no training set (in the AI/ML context) is discussed, this question is not applicable. The "ground truth" for developing this type of immunoassay would involve precise chemical standards and assays to characterize reagent performance and assay kinetics during R&D.
§ 862.1680 Testosterone test system.
(a)
Identification. A testosterone test system is a device intended to measure testosterone (a male sex hormone) in serum, plasma, and urine. Measurement of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, delayed or precocious puberty, impotence in males and, in females hirsutism (excessive hair) and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.(b)
Classification. Class I.