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The T2Biothreat Panel is a qualitative, multiplexed, nucleic acid-based in vitro diagnostic test intended for use with the T2Dx Instrument. The T2Biothreat Panel detects nucleic acids from the following organisms directly from K2EDTA whole blood samples:

1. Bacillus anthracis (plasmids pXO1 and pXO2)
2. Francisella tularensis
3. Burkholderia spp. (B. mallei/B. pseudomallei)
4. Yersinia pestis
5. Rickettsia prowazekii

The T2Biothreat Panel will not distinguish between detection of Burkholderia mallei and Burkholderia pseudomallei but will present valid detections as a positive detection of Burkholderia species.

The T2Biothreat Panel is intended to test individuals with signs and symptoms of infection from biothreat agents and/or individuals who are at risk for exposure or may have been exposed to these agents. The T2Biothreat Panel is indicated as an aid in the diagnosis of anthrax, tularemia, melioidosis, glanders, typhus fever and plague in response to suspected or confirmed bioterrorism events or outbreaks. Diagnosis of infection must be made in conjunction with clinical, epidemiologic and other laboratory data. Results are for the presumptive identification of Bacillus anthracis, Francisella tularensis, Burkholderia spp. (B. mallei), Yersinia pestis and Rickettsia prowazekii. Results are meant to be used in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidel by the relevant public health authorities. The definitive identification of Bacillus anthracis, Francisella tularensis, Burkholderia mallei, Burkholderia pseudomallei, Yersinia pestis or Rickettsia prowazekii requires additional testing and confirmation procedures in consultation with the appropriate public health authorities for whom reports may be required. Positive results do not rule out co-infections with pathogens not included on the T2Biothreat Panel. Negative results do not preclude infection with the biothreat microbial agents targeted by the device and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

The T2Biothreat Panel is indicated for use in laboratories that have the appropriate biosafety equipment, personal protective equipment (PPE), containment facilities, and personnel trained in the safe handling of clinical specimens potentially containing biothreat organisms.

The T2Biothreat Panel is indicated for use in laboratories that follow public health guidelines that address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities.

This assay is not FDA-cleared or approved for testing blood or plasma donors.

The T2Biothreat Panel is a qualitative, multiplexed, nucleic acid-based in vitro diagnostic test intended for use with the T2Dx Instrument. The T2Biothreat Panel detects nucleic acids from the following organisms directly from K2EDTA whole blood samples: Bacillus anthracis (plasmids pXO1 and pXO2), Francisella tularensis, Burkholderia spp. (B. mallei/B. pseudomallei), Yersinia pestis, and Rickettsia prowazekii. The T2Biothreat Panel is run on the T2Dx, a fully automated, benchtop instrument. During processing on the T2Dx, intact pathogen cells are concentrated directly in whole blood, then lysed to release the target DNA. After amplification, target amplicon is hybridized with superparamagnetic particles and then detected by T2MR. The Internal Control on the T2Biothreat Panel monitors performance for each sample. The T2Biothreat Panel is a qualitative molecular diagnostic assay that employs whole blood compatible PCR amplification followed by T2 Magnetic Resonance (T2MR) detection. The T2Biothreat Panel is performed on the T2Dx Instrument, which executes all steps after specimen loading, with the capability of loading up to seven blood specimens at the same time. Individually, a KeEDTA whole blood specimen containing a minimum of 3 mL is loaded directly onto the T2Biothreat Sample Inlet, which is then placed on the T2Biothreat Cartridge along with the T2Biothreat Reagent Tray. The Cartidge and Reagent Tray contain the lysis reagent, internal control, primers, enzyme, buffer and probe-coupled superparamagnetic particles for each detected tarqet. After loading into the T2Dx. the blood specimen is mixed with the red blood cell lysing reagent and the bacterial cells and human cellular debris are concentrated by centrifygation. The internal control is added to the concentrated pellet and a bead-beating process lyses the bacterial cells. The supernatant containing the DNA from the lysed bacterial cells and the internal control is amplified using the target and internal control-specific primers. The generated amplified product is aliquoted into individual tubes containing target-specific probe conjugated particles for each detected target and the internal control. The amplified to target-specific probes attached to superparamagnetic particles causing clustering of the particles. The hybridization occurring in individual tubes is analyzed in the T2MR reader and a signal for each target is generated, which indicates the presence of the target organism(s). This automated process is the same process followed by the FDA cleared T2Candida and T2Bacteria Panels performed on the T2Dx Instrument system. When running a single specimens simultaneously, the first specimen will be reported in approximately 4 hours from the specimen is loaded onto the instrument. The results are interpreted by the device software as valid or invalid (based on the result of the internal control or target detections), and if valid, results are reported as "Positive" or "Target not Detected" for each specific target.

Here's a breakdown of the acceptance criteria and study information for the T2Biothreat Panel, based on the provided text:

Acceptance Criteria and Device Performance

Study Information

The provided document describes standalone performance studies for the T2Biothreat Panel. It does not mention any multi-reader multi-case (MRMC) comparative effectiveness study.

2. Sample Sizes and Data Provenance

• Test Set (Clinical Performance):

  • Negative Arm: Undisclosed number of K2EDTA whole blood samples from healthy donors (no signs/symptoms of infection) and febrile donors (fever ≥ 100.4 °F).
  • Positive Arm: Sequence-verified clinical bacterial strains spiked into whole blood collected from febrile donors. The sample sizes for the positive arm are listed as:
    • B. anthracis (pXO1 & pXO2): 6 (< LoD), 32 (1-3x LoD), 12 (3-5x LoD) = 50 samples
    • Burkholderia spp.: 17 (< LoD), 77 (1-3x LoD), 6 (3-5x LoD) = 100 samples
    • F. tularensis: 7 (< LoD), 35 (1-3x LoD), 8 (3-5x LoD) = 50 samples
    • R. prowazekii: Undisclosed (< LoD), 10 (1-3x LoD), 40 (3-5x LoD) = 50 samples
    • Y. pestis: 26 (< LoD), 24 (1-3x LoD), undisclosed (3-5x LoD) = 50 samples
  • Data Provenance: Not explicitly stated regarding country of origin, but implies clinical samples from "7 geographically diverse sites" and "healthy and febrile donors." The study appears to be prospective in its design, using collected samples for testing.

• Test Set (Analytical Performance - Reproducibility): Sample types consisted of negative K2EDTA-treated whole blood and various positive K2EDTA-treated whole blood samples (single, dual, and triple species spikes) at 1-1.5x LoD or 2-3x LoD. The total number of replicates for each condition varied but was sufficient to achieve the stated agreements (e.g., 128 replicates for B. anthracis at 1-1.5x LoD, 379 for negatives).

3. Number of Experts and Qualifications for Ground Truth

• Not Applicable: For this in vitro diagnostic device, ground truth for the clinical performance study was established by spiking sequence-verified clinical bacterial strains into whole blood samples at specific concentrations, meaning the "truth" was known by controlled experimental design rather than expert human interpretation of results. No external "experts" were used to establish ground truth for the test set.

4. Adjudication Method for the Test Set

• Not Applicable: As the clinical performance study involved spiking known concentrations of sequence-verified bacterial strains into samples, the ground truth was inherently known. There was no need for an adjudication method as the results are compared directly against the known composition of the spiked samples.

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

• No: The document does not mention a multi-reader multi-case (MRMC) comparative effectiveness study or any assessment of how human readers improve with or without AI assistance. This device is an automated in vitro diagnostic panel, not an AI-assisted diagnostic tool for human interpretation.

6. Standalone Performance (Algorithm Only)

• Yes: The entire set of analytical and clinical performance studies presented (Limit of Detection, Analytical Reactivity, Analytical Specificity, Reproducibility, Interfering Substances, Competitive Inhibition, Clinical Performance Characteristics) represents the standalone performance of the T2Biothreat Panel without human-in-the-loop for interpretation or decision-making. The device is fully automated, and results are interpreted by the device software.

7. Type of Ground Truth Used

• Known Spiked Concentrations / Sequence-Verified Strains: For both analytical and clinical performance, the ground truth was established by carefully spiking known concentrations of sequence-verified clinical bacterial strains into K2EDTA whole blood samples. This provides a definitive "true positive" or "true negative" status against which the device's performance is measured.
• For the negative arm of the clinical study, the ground truth was based on samples from "healthy donors" (presumed negative) and "febrile donors" (presumed negative for the target biothreat agents unless proven otherwise through the spiking).

8. Sample Size for the Training Set

• Not provided/Applicable in the sense of ML training data: The document does not explicitly mention a "training set" in the context of machine learning model training data. This is an in vitro diagnostic device that uses a pre-defined algorithm (nucleic acid amplification followed by T2 magnetic resonance detection) rather than a machine learning model that requires a distinct training phase with labeled data. The development of the assay (primers, probes, algorithm parameters) would have involved extensive R&D and optimization, but this wouldn't be referred to as a "training set" in the same way as for AI/ML.

9. How Ground Truth for the Training Set Was Established

• Not Applicable (for ML training data): As noted above, the concept of a separate "training set" for an AI/ML model with established ground truth is not explicitly addressed or relevant in the provided text for this in vitro diagnostic device. The "ground truth" during device development and optimization would come from standard microbiological and molecular biology techniques to confirm the presence, identity, and concentration of target organisms.

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