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T2Candida® 1.1 Panel and T2Dx® Instrument is a qualitative T2 Magnetic Resonance (T2MR®) assy for the direct detection of Candida species in K₂EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida 1.1 Panel identifies five species of Candida and categorizes them into the following three species groups:

• 1. Candida albicans and/or Candida tropicalis
• 2. Candida parapsilosis
• Candida glabrata and/or Candida krusei 3.

The T2Candida 1.1 Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida 1.1 Panel does not distinguish between C. glabrata and C. krusei.

The T2Candida 1.1 Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida 1.1 Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification.

The T2Candida positive and negative External Controls (T2Candida QCheck Positive Kit and the T2Dx QCheck Negative Kit) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems.

The T2Candida 1.1 Panel and T2Dx Instrument is comprised of the T2Candida 1.1 Panel performed on the T2Dx Instrument. The T2Candida 1.1 Panel is a qualitative molecular diagnostic assay that employs a whole blood compatible PCR amplification followed by T2 magnetic resonance (T2MR) detection. The T2Candida 1.1 Panel is performed on the T2Dx Instrument which executes all steps after specimen loading. A K₂EDTA whole blood specimen is loaded onto the T2Candida 1.1 Sample Inlet, which is then placed on the T2Candida 1.1 Cartridge along with the T2Candida 1.1 Reagent Tray. The Reagent Tray contains the internal control, amplification reagent, enzyme and the probe-coupled superparamagnetic particles for each Candida target. Two milliliters of the blood specimen is transferred to the T2Dx Instrument where lysis of the red blood cells, concentration and lysis of the Candida cells and amplification of the Candida DNA takes place. Amplification products are detected by T2MR detection using species-specific probes which are attached to the superparamagnetic particles. The assay identifies Candida albicans and/or Candida tropicalis, Candida parapsilosis, and Candida glabrata and/or Candida krusei. The test does not distinguish between C. albicans and C. tropicalis. The test does not distinguish between C. glabrata and C. krusei

The provided text describes a 510(k) premarket notification for the T2Candida 1.1 Panel, aimed at amending labeling to include pediatric patients. The information focuses on analytical and clinical performance to demonstrate substantial equivalence to a previously cleared device.

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. A table of acceptance criteria and the reported device performance:

The document primarily focuses on demonstrating substantial equivalence by relying on previously obtained performance data and additional tests for pediatric populations and cross-reactivity. Explicit acceptance criteria for clinical performance are not directly stated in percentages (e.g., minimum sensitivity/specificity), but the summary indicates "acceptable performance" was demonstrated. The analytical acceptance criteria for cross-reactivity are defined for the new tests.

Table of Acceptance Criteria and Reported Device Performance

2. Sample sizes used for the test set and the data provenance:

• Clinical Performance (Pediatric):
  • Sample Size: A total of 246 pediatric samples were evaluated across two peer-reviewed publications.
  • Data Provenance: The data came from existing studies (peer-reviewed publications) where the T2Candida 1.1 Panel was utilized. The document does not specify the country of origin, but generally, such studies supporting FDA submissions would often include data from the US or other regions with comparable clinical practices. The studies were retrospective in the sense that they were "existing studies" identified and utilized for this submission, although the original data collection within those studies might have been prospective.
• Analytical Cross-Reactivity:
  • Sample Size:
    • Initial testing: 3 replicates per organism at 10^6 CFU/mL.
    • For organisms showing initial cross-reactivity: Additional 6 replicates (from two additional sample preparations) at 10^6 CFU/mL, and 3 replicates at lower concentrations (1000 CFU/mL, 100 CFU/mL, 33 CFU/mL).
  • Data Provenance: This appears to be prospective laboratory testing conducted specifically for this submission, as it's described as "Additional cross-reactivity testing was performed in this submission."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• Clinical Performance (Pediatric): The ground truth for this segment of the study was primarily established by blood culture results. The document does not mention the use of experts (e.g., radiologists) for establishing this ground truth, as it's a molecular diagnostic device measuring specific microbial presence. Blood culture is a laboratory-based gold standard for candidemia diagnosis.
• Analytical Cross-Reactivity: Ground truth for this was based on known spiked concentrations of the organisms and the inherent characteristics of the T2Candida 1.1 Panel's detection mechanism (T2 signal cutoff). No external human experts are mentioned for ground truth establishment here.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

• Clinical Performance (Pediatric): Not applicable. The ground truth was based on blood cultures.
• Analytical Cross-Reactivity: A form of adjudication was applied for cross-reactivity. If an organism demonstrated cross-reactivity at 10^6 CFU/mL, it was "further evaluated with additional replicates from two additional sample preparations." Furthermore, the rule for confirming cross-reactivity was: "Results were not considered cross-reactive if only one replicate demonstrated cross-reactivity." This implies a majority rule or consistency requirement rather than a specific expert consensus adjudication.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• Not applicable. This device is a molecular diagnostic test for detecting Candida species directly from blood, not an imaging-based AI diagnostic. Therefore, a multi-reader multi-case study involving human readers and AI assistance is not relevant to this type of device.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

• Yes, this is effectively a standalone device. The T2Candida 1.1 Panel (and T2Dx Instrument) runs the assay and provides results (positive/negative for specific Candida groups, or invalid). Its performance is evaluated intrinsically through its ability to detect the target organisms (clinical sensitivity/specificity) and avoid false positives/negatives (analytical cross-reactivity). While a clinician interprets the results, the device's diagnostic output itself (e.g., "Candida albicans/tropicalis detected") is generated by the algorithm/system without human intervention in the diagnostic process of reading the T2MR signals.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

• Clinical Performance (Pediatric): Primarily blood culture results.
• Analytical Cross-Reactivity: Known concentrations of spiked organisms in blood, with the "ground truth" for cross-reactivity being the absence or presence of specific amplification and detection events as defined by the assay's cutoffs.

8. The sample size for the training set:

• The document does not explicitly mention a "training set" in the context of machine learning, as this is a molecular diagnostic device with a defined mechanism (T2MR technology, PCR amplification) rather than a machine learning algorithm that learns from data. Its "training" is inherent in its design and optimization during development, validated by analytical and clinical studies. No specific sample size for "training" is provided in the submission summary.

9. How the ground truth for the training set was established:

• As above, "training set" and its associated ground truth establishment methods (e.g., expert labels for images) are not applicable in the typical AI/ML sense for this device. The development process for such molecular diagnostics involves extensive analytical characterization (e.g., limit of detection, inclusivity, exclusivity, precision studies) to define performance parameters and establish expected results, which serves a similar function to providing "ground truth" for the device's operational parameters.

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T2Candida 1.1 Panel and T2Dx Instrument is a qualitative T2 Magnetic Resonance (T2MR) assay for the direct detection of Candida species in K2EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida 1.1 Panel identifies five species of Candida and categorizes them into the following three species groups:

1. Candida albicans and/or Candida tropicalis
2. Candida parapsilosis
3. Candida glabrata and/or Candida krusei
   The T2Candida 1.1 Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida 1.1 Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. The T2Candida QCheck Positive and T2Dx QCheck Negative External Controls are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems.

The T2Candida 1.1 Panel run on the T2Dx® Instrument is a qualitative T2 Magnetic Resonance (T2MR®) assay for the direct detection of Candida species in EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida Panel identifies five species of Candida and categorizes them into the following three groups:

• 1. Candida albicans and/or Candida tropicalis,
• 2. Candida parapsilosis
• 3. Candida qlabrata and/or Candida krusei
     The T2Candida 1.1 Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida 1.1 Panel does not distinguish between C. glabrata and C. krusei. The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification. The T2Candida positive (T2Candida QCheck) and negative External Controls (T2Dx QCheck) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems. The T2Candida 1.1 Panel utilizes magnetic resonance-based detection (T2®MR technology) to qualitatively detect the same five species of Candida direct from K2EDTA-treated human whole blood. The T2Candida 1.1 Panel, run on the T2Dx instrument, performs sample concentration and Candida target DNA amplification for direct detection of species-specific amplicon. The test incorporates an Internal Control (IC) for monitoring test performance. The workflow for T2Candida 1.1 Panel is the same as the original cleared test and can only be performed on the T2Dx instrument, a bench-top, automated sample-to-result system, which performs all steps in the test after specimen loading. A design change was made to remove two foil-sealed tubes containing calcium hypochlorite ("bleach tubes") from the T2Candida Cartridge configuration and modify the software to remove the bleach transfer steps from the T2Dx workflow.

Here's an analysis of the acceptance criteria and study findings for the T2Candida 1.1 Panel, based on the provided text:

1. Acceptance Criteria and Reported Device Performance

• A/T Channel: 100.0 (97.1-100.0)
• P Channel: 99.2 (95.7-99.9)
• K/G Channel: 99.2 (95.7-99.9)
• Overall: 99.5 (98.1-99.9)
  Compared favorably to the predicate (T2Candida Panel DEN140019) specificity. |
  | Improved Product Stability (ability to achieve acceptable shelf-life) | Product shelf-life demonstrated at 8 months, with studies ongoing to extend it. Stability issues observed with the predicate panel due to bleach byproducts were mitigated. |

2. Sample Size and Data Provenance

• Test Set Sample Size: Not explicitly stated as a single number. Two specificity studies were conducted, each involving:
  • Human whole blood pooled from healthy donors.
  • Samples triple-spiked with high titer (100 CFU or 1000 CFU) of Candida species (C. albicans, C. parapsilosis, C. glabrata or C. tropicalis, C. parapsilosis, C. krusei).
  • Negative samples were human whole blood from the same pool without spiking.
  • Samples were loaded such that Negative Samples and Positive APG or TPK were positioned in adjacent drawers.
• Data Provenance: The studies appear to be conducted internally by the manufacturer (T2 Biosystems, Inc.) in a controlled laboratory setting. The origin of the healthy donor whole blood is not specified (e.g., country of origin). The studies are retrospective modifications to an existing device, validating the changes.

3. Number of Experts and Qualifications

This information is not provided in the text. The study focuses on laboratory performance metrics (specificity, stability) rather than human interpretation or expert-adjudicated ground truth.

4. Adjudication Method

This information is not applicable/provided in the text. The device is a qualitative diagnostic assay, and the study evaluates its direct detection performance against known spiked concentrations. There's no mention of human adjudication of results.

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

• No MRMC study was done. The device is a standalone diagnostic panel, not one designed for human-in-the-loop assistance. The study focuses on the device's technical performance.

6. Standalone Performance

• Yes, a standalone performance study was done. The specificity studies described directly evaluate the T2Candida 1.1 Panel's ability to accurately detect Candida species (or their absence) in blood samples, without human intervention in the diagnostic process beyond sample loading and result interpretation.

7. Type of Ground Truth Used

• Known Spiked Samples: The ground truth for the specificity studies was established by preparing blood samples with known concentrations (high titer: 100 CFU or 1000 CFU) of specific Candida species or known negative (unspiked) blood samples. This is a form of controlled laboratory spiking to simulate infection.

8. Sample Size for Training Set

• Not explicitly provided. The document describes a Special 510(k) submission for a modified version (1.1) of an already cleared device. It states the fundamental scientific technology and principle of operation are equivalent to the original T2Candida Panel (cleared as DEN140019). Information regarding the training set for the original algorithm or the 1.1 update is not presented in this document.

9. How Ground Truth for Training Set Was Established

• Not explicitly provided. As with the training set size, this document focuses on the validation of the modified device. Details on how the ground truth was established for the original algorithm's development (training) are not included.

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The T2Candida Panel and T2Dx® Instrument is a qualitative T2 Magnetic Resonance (T2MR®) assay for the direct detection of Candida species in EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida Panel identifies five species of Candida and categorizes them into the following three species groups:

1. Candida albicans and/or Candida tropicalis,
2. Candida parapsilosis
3. Candida glabrata and/or Candida krusei

The T2Candida Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida Panel does not distinguish between C. glabrata and C. krusei.

The T2Candida Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification.

The T2Candida positive and negative External Controls are intended to be used as quality control samples with the T2Candida Panel when run on the T2Dx® instrument system. These controls are not intended for use with other assays or systems.

The T2Candida panel and T2Dx® Instrument is comprised of the T2Candida Panel performed on the T2Dx® Instrument. The T2Candida Panel is a qualitative molecular diagnostic assay that employs a whole blood compatible PCR amplification followed by T2 magnetic resonance (T2MR) detection. The T2Candida Panel is performed on the T2Dx Instrument which executes all steps after specimen loading. A K2 EDTA whole blood specimen is loaded onto the T2Candida Sample Inlet, which is then placed on the T2Candida Base along with the T2Candida Reagent Pack. The Reagent Pack contains the internal control, amplification reagent, enzyme and the probe-coupled superparamagnetic particles for each Candida target. Three milliliters of the blood specimen is transferred to the T2Dx® Instrument where lysis of the red blood cells, concentration and lysis of the Candida cells and amplification of the Candida DNA takes place. Amplification products are detected by T2MR detection using species-specific probes which are attached to the superparamagnetic particles. At the end of each assay, the T2Dx® Instrument uses a bleach solution to neutralize all liquids on the cartridge to mitigate the risk of amplicon contamination. The assay provides an identification of Candida albicans and/or Candida tropicalis, Candida parapsilosis, and Candida glabrata and/or Candida krusei. The test does not distinguish between C. albicans and C. tropicalis. The test does not distinguish between C. glabrata and C. krusei.

Acceptance Criteria and Device Performance Study for T2Candida Panel and T2Dx® Instrument

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly present a table of acceptance criteria in numerical values for clinical performance metrics (like minimum desired PPA/NPA). Instead, it describes various studies and their results, implying that these results were deemed acceptable for market clearance. For the purpose of this response, I will interpret "acceptance criteria" as the performance metrics that were reported and considered satisfactory by the FDA for the device to be classified.

2. Sample sizes used for the test set and data provenance

• Test Set (Clinical Study - Contrived Samples):

  • Sample Size: 250 positive contrived samples (50 isolates for each of the five Candida targets, spiked at specific concentrations) + 50 negative unspiked blood specimens = 300 total samples.
  • Data Provenance: The human blood specimens were collected from patients at three clinical sites in K2EDTA tubes. These specimens were then transported to T2 Biosystems for preparation of contrived samples. The prepared samples were de-identified and shipped to testing sites. The data is thus a mix of prospective (blood collection) and contrived (spiking) for the positive samples, and prospective for the negative samples. The isolates used for spiking were obtained from a reference laboratory and a clinical laboratory (US, implicitly).

• Test Set (Clinical Study - Prospective Samples):

  • Sample Size: 1501 blood specimens from adult patients.
  • Data Provenance: Prospective. Specimens were collected at nine geographically diverse sites.

3. Number of experts used to establish the ground truth for the test set and their qualifications

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.

• For the Contrived Samples: The "ground truth" (presence and concentration of Candida species) was established through controlled laboratory spiking (colony count testing) and sequencing of isolates. This is an analytical determination, not typically requiring expert consensus on diagnosis.
• For the Prospective Samples: The "ground truth" for candida presence/absence was primarily established by blood culture results, which is a standard laboratory reference method. The identification of isolates was confirmed by sequence analysis of the ITS2 region. While a clinical microbiologist or pathologist would interpret these results, the document does not specify a panel of experts for adjudication.

4. Adjudication method for the test set

• For the Contrived Samples: No formal adjudication method involving multiple human readers is described for the contrived samples. The ground truth was based on the known spiking composition and verified colony counts. Discrepancies (e.g., initial LoD not validated) led to retesting.
• For the Prospective Samples: The "gold standard" was blood culture. For false positive T2Candida results (where blood culture was negative), a chart and case history review was conducted. This review process itself can be seen as a form of clinical adjudication, attempting to find clinical evidence supporting or refuting the T2Candida result when the primary reference method (blood culture) disagreed. However, the document does not specify an "adjudication method" in the sense of a consensus panel (e.g., 2+1, 3+1).

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No. A multi-reader multi-case (MRMC) comparative effectiveness study involving human readers or AI assistance was not conducted or described. The T2Candida Panel and T2Dx® Instrument is a molecular diagnostic assay that provides a direct result for Candida species; it is not an image-based AI device that would typically involve human readers interpreting AI output.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes. The studies described for the T2Candida Panel and T2Dx® Instrument represent standalone (algorithm only) performance. The device fully automates the processing and analysis steps after manual specimen loading, and "the T2Dx® Instrument reports a positive or negative result for each detection channel." The performance metrics (sensitivity, specificity, PPA, NPA, precision, LoD, etc.) are all indicative of the device's inherent capability to detect Candida species from whole blood without real-time human interpretation or modification of its direct output.

7. The type of ground truth used

• For Analytical Studies (Precision, LoD, Analytical Sensitivity, Co-infection, Analytical Specificity): The ground truth was established by controlled laboratory preparation of samples with known Candida species and concentrations, verified by colony count testing and sequence analysis of isolates. Negative controls were known to be free of Candida.
• For Clinical Studies (Contrived Samples): The ground truth was established by controlled laboratory spiking of blood specimens with specific, verified Candida isolates at known concentrations. Negative samples were unspiked blood.
• For Clinical Studies (Prospective Samples): The ground truth for the presence or absence of Candida infection was primarily based on blood culture results, which is a widely accepted laboratory reference standard for candidemia. For "false positives" by T2Candida where blood culture was negative, chart and case history review was used to provide further context.

8. The sample size for the training set

The document does not explicitly specify a "training set" in the context of machine learning model development. For molecular diagnostic assays like the T2Candida Panel, the development process typically involves extensive analytical studies to establish assay design, primer/probe specificity, cutoff values, and performance characteristics, rather than training a machine learning algorithm on a distinct dataset.

However, the assay cut-off values (Table 12) for the T2MR signal were established using a "limit of blank study" with negative blood specimens from 113 healthy and 39 unhealthy patients (total 152 samples), tested with two different reagent lots. This serves a similar purpose to training data for setting a threshold.

9. How the ground truth for the training set was established

As noted above, there isn't a "training set" in the traditional machine learning sense. However, the ground truth for establishing the assay cut-off (analogous to a threshold used in training) was:

• Negative blood specimens: Confirmed to be negative for Candida (implied by sourcing from healthy/unhealthy patients and used to determine the upper limit of T2 signal distribution for negative measurements).
• Positive internal control measurements: Used to determine the lower limit of T2 signal for positive internal controls. The internal control itself is a known DNA sequence amplified and detected within each sample.

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