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Bladder EpiCheck Kit is intended for the qualitative detection of DNA methylation patterns of 15 loci in human DNA that are associated with transitional cell carcinoma of the bladder. The test is performed on voided urine samples and run on the ABI® 7500 Fast Dx Real-Time PCR system.

Bladder EpiCheck Kit is indicated for use as a non-invasive method to monitor for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with Non-Muscle Invasive Bladder Cancer.

The Bladder EpiCheck Test is a real-time PCR-based in vitro diagnostic assay intended for the qualitative detection of DNA methylation patterns associated with transitional cell carcinoma of the bladder to monitor for tumor recurrence (in conjunction with cystoscopy) in patients previously diagnosed with non-muscle invasive bladder cancer (NMIBC).

The assay consists of a panel of 15 novel DNA methylation (covalent addition of methyl (CH3) groups to the C5 position of the pyrimidine ring of cytosines, typically in a CpG dinucleotide) biomarkers that were found to distinguish between patients with bladder cancer and patients without bladder cancer. The Bladder EpiCheck Test differentiates between methylated and non-methylated DNA, creating a unique platform for methylation profiling of urine specimens towards the detection of bladder cancer recurrence in patients previously diagnosed with the disease. The test is comprised of reagents for end-to-end (sample-to-answer) processing of urine samples (reagents for DNA extraction, DNA digestion, PCR amplification, and analysis software), and is performed using the Applied Biosystems® 7500 Fast Dx Real-Time PCR system.

A voided urine specimen is centrifuged, and the cells (both normal and cancerous if present) are separated from the urine supernatant. DNA is then extracted from the cell pellet using the Bladder EpiCheck Extraction kit (P/N NX899090-01C). The extracted DNA is digested using a methylation-sensitive restriction enzyme mix. which cleaves DNA at specific recognition sequences if they are unmethylated. Methylated DNA is protected from enzymatic digestion and therefore remains intact.

Here's a breakdown of the acceptance criteria and study details for the Bladder EpiCheck Kit, based on the provided FDA 510(k) summary:

Device: Bladder EpiCheck Kit
Intended Use: Qualitative detection of DNA methylation patterns of 15 loci in human DNA associated with transitional cell carcinoma of the bladder, used as a non-invasive method to monitor for tumor recurrence in conjunction with cystoscopy in patients previously diagnosed with Non-Muscle Invasive Bladder Cancer.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in a dedicated table format. However, performance metrics are reported. Based on the "Method Comparison" section (9.2 Clinical), the de facto acceptance criteria appear to be tied to non-inferiority against the predicate device (UroVysion Bladder Cancer Kit) and sufficient performance against a Gold Standard.

2. Sample Size and Data Provenance for Test Set (Clinical Performance Study)

• Sample Size:
  • Against Gold Standard: 583 subjects (total voided urine specimens collected from 583 subjects). Valid Bladder EpiCheck and GS results were obtained from 449 subjects.
  • Against Predicate Device (Matched Cases): Valid Bladder EpiCheck, UroVysion, and GS results were obtained from 352 samples.
  • Specificity in Urology Patients without Bladder Cancer: 147 subjects.
  • Clinical Specificity - Cross Reactivity with Other Cancers: 147 urine samples.
• Data Provenance:
  • Country of Origin: U.S. and Canada (from 11 academic and urology specialty medical centers).
  • Retrospective or Prospective: The main clinical study (Method Comparison) was a multi-center, prospective, IRB-approved longitudinal study. The specificity study in urology patients without bladder cancer was also multi-center, prospective. The cross-reactivity study utilized banked remnant de-identified urine samples, which would generally be considered retrospective.

3. Number of Experts and their Qualifications for Establishing Ground Truth for the Test Set

The document does not specify the number of experts or their qualifications for establishing the ground truth. It states that positive cases were confirmed by "cystoscopy and pathology." This implies that the ground truth was established by clinical diagnoses and pathological examination of tissue, presumably performed by trained urologists and pathologists, which are standard practices. No "experts" are explicitly described as reviewing cases for the purpose of establishing a "ground truth" consensus for the study, beyond the routine clinical workflow.

4. Adjudication Method for the Test Set

The adjudication method is implicitly described for the Gold Standard (GS) definition:

• "a subject was considered 'positive' if the interpretation for either cytology or the combined cystoscopy/pathology results were positive"
• "and a subject was considered 'negative' if both cytology and the combined cystoscopy/pathology results were negative."

This indicates a hierarchical or "any positive result makes it positive" adjudication for the ground truth definition. There is no explicit mention of an adjudication panel (e.g., 2+1, 3+1) for cases of disagreement between cytology and pathology results, or for disagreements among multiple readers of the ground truth modalities.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This device is a molecular diagnostic test (in-vitro diagnostic) and not an imaging AI device that assists human readers. Therefore, the concept of human readers improving with AI vs. without AI assistance does not apply in this context. The comparison was between the Bladder EpiCheck test result and clinical ground truth (cytology/pathology), and between Bladder EpiCheck test results and the predicate device's test results.

6. Standalone (Algorithm Only Without Human-in-the-Loop) Performance Study

Yes, the device's performance, as reported in the "Method Comparison" section, is a standalone (algorithm only without human-in-the-loop) performance. The Bladder EpiCheck Kit provides a qualitative result (positive/negative) based on its algorithm (EpiScore), and this result is compared directly to the established Gold Standard.

7. Type of Ground Truth Used

The primary ground truth used for the clinical performance study consisted of:

• Combined Cystoscopy/Pathology data: This is the gold standard for definitive diagnosis of bladder cancer recurrence.
• Clinical Cytology: Urine cytology was also part of the Gold Standard definition.

Therefore, the ground truth is a combination of pathology (histopathological examination of biopsy/resection specimens) and outcomes data (clinical diagnosis via cystoscopy, supplemented by cytology).

8. Sample Size for the Training Set

The document refers to "Clinical Cutoff (Training and Feasibility Data)" in section 9.1.

• Total for software algorithm development: 178 samples.
• First set (for cut-off definition): 109 samples (40 control, 69 UCC positive).
• Second set (for cut-off validation): 67 samples (51 control, 16 UCC positive).

It's important to note that this "training" refers to the development and validation of the EpiScore algorithm's cutoff, not necessarily a machine learning training set in the AI sense.

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

For the "training" set (used for algorithm development and cutoff definition, section 9.1), the ground truth was established by:

• "urine samples collected from control patients with a history of bladder cancer and bladder cancer positive patients confirmed by cystoscopy and pathology."
• "Urothelial Cell Carcinoma (UCC) positive patients confirmed by pathology."

Similar to the test set, the ground truth for algorithm development was based on definitive clinical diagnosis and pathological confirmation.

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The Applied Biosystems Bacillus anthracis Detection Kit is a real-time polymerase chain reaction (PCR) test kit intended for the qualitative in vitro diagnostic (IVD) detection of target DNA sequences for Bacillus anthracis, or BA). The Applied Biosystems Bacillus anthracis Detection Kit is intended to test human whole blood (EDTA) specimens and blood culture specimens with growth detected by a continuous monitoring blood culture system. Blood culture specimens must be determined to contain gram-positive bacilli by Gram stain prior to testing of whole blood specimens must be performed concomitantly with standard of care blood culture.

The Applied Biosystems Bacillus anthracis Detection Kit is indicated for use in CLIA-certified high-complexity laboratories in response to a confirmed Bacillus anthracis event only in accordance with the guidelines provided by public health authorities prior to or during a public health emergency. Testing with the Applied Biosystems Bacillus anthracis Detection Kit must only be performed when public health authorities have determined the need for this test must only be used with specimens from individuals with clinical signs and symptoms of B. anthracis infection and who have either been exposed to B. anthracis or may have been exposed to B. anthracis.

The Applied Biosystems Bacillus anthracis Detection Kit is intended for use as an aid in the diagnosis of anthrax infection and results are for the presumptive identification of Bacillus anthracis. The diagnosis of B. anthracis infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence, in addition to the identification of B. anthracis from cultures or directly from clinical specimens. The definitive identification of B. anthracis requires additional testing and confirmation procedures in consultation with the appropriate public health authorities for whom reports may be required.

The Applied Biosystems Bacillus anthracis Detection Kit has not been clinically evaluated with specimens collected from individuals with B. anthracis infection or those presumed to B. anthracis. 'B. anthracis Not detected' results do not preclude infection with Bacillus anthracis and should not be used as for diagnosis, treatment, or other patient management decisions.

Laboratories implementing this test must have the appropriate biosafety equipment, personal protective equipment (PPE), containment facilities and personnel trained in the safe handling of diagnostic clinical specimens potentially containing B. anthracis. Anthrax is a nationally notifiable disease caused by a biothreat microbial agent and must be reported to public health authorities.

The distribution of in vitro diagnostic devices for Bacillus spp. detection is limited to laboratories that follow public health guidelines that address appropriate biosafety conditions, interpretation of test results, and coordination of findings with public health authorities.

The Applied Biosystems Bacillus anthracis Detection Kit is intended for use with the AB1 7500 Fast Dx Real-Time PCR Instrument with analysis using the Applied Biosystems Bacillus anthracis Interpretive Software (BaIS).

The Applied Biosystems™ Bacillus anthracis Detection Kit is a multiplexed real-time polymerase chain reaction (PCR) test kit intended for the qualitative in vitro diagnostic (IVD) detection of target DNA sequences for B. anthracis. Reagents are lyophilized in a 96-well plate format as a fully formulated Mastermix and are stable at room temperature for up to one year. The kit is specifically designed for performing real-time PCR using the Applied Biosystems (ABI) 7500 Fast Dx instrument and software, with nucleic acids extracted from clinical specimens using a Qiagen manual extraction method or Roche MagNA Pure automated extraction methods. An automated interpretative software component (BalS) is included in the kit but supplied separately and operates on a computer(s) that is separate from the ABI 7500 Fast Dx computer.

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

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly present a formal "Acceptance Criteria" table with pass/fail thresholds for all aspects. Instead, it describes performance studies and their outcomes. Based on the performance data provided, we can infer the de facto acceptance associated with demonstrating strong performance indicators.

• Whole Blood: 150 CFU/mL
• Blood Culture, Aerobic: 10,000 CFU/mL
• Blood Culture, Anaerobic: 10,000 CFU/mL
  Roche MagNA Pure:
• Whole Blood: 50 CFU/mL
• Blood Culture, Aerobic: 2270 CFU/mL
• Blood Culture, Anaerobic: 3040 CFU/mL
  (All values are presumptively "met" the >95% detection criteria given they are reported as LODs). |
  | Analytical Inclusivity| 100% detection rate for B. anthracis strains carrying both plasmid targets. Correctly identify 'Bacillus anthracis suspected' for strains with only one plasmid target. | 100% detection rate for B. anthracis strains that carry both plasmid targets. For three strains known to carry only one plasmid target, the assay generated 'Bacillus anthracis suspected' results as expected. |
  | Analytical Exclusivity| High no detection rate (close to 100%) for non-target organisms. No false positives. | Initial no detection rate for exclusivity testing was 95.68%. Repeat testing was conducted, resulting in a final no detection rate of 100%. Some known Bacillus cereus strains (BAG1X1-1, 03BB102, and G-9241) that contain a pXO1-like plasmid were correctly identified as 'Bacillus anthracis suspected'. |
  | Interfering Substances| No significant interference from common substances unless noted with appropriate labeling limitations. | Identified specific technique-specific substances that interfere (e.g., MagNA Pure Wash Buffer, 10% Bleach, Ethanol >5%). Appropriate limitations were added to product labeling. |
  | Microbial Interference| 100% detection rate of B. anthracis in the presence of other clinically-relevant organisms. | 100% detection rate of B. anthracis in the presence of potentially interfering organisms in whole blood and blood culture. |
  | Reproducibility | Consistent results across operators, instruments, and reagent lots. Limited false negatives/positives in control samples. Positive percent agreement metrics indicate reproducibility. | One low positive sample returned negative. One high positive sample returned 'Bacillus anthracis suspected' due to pXO1 assay failure, but returned 'Bacillus anthracis detected' on repeat. No false positive events out of 270 negative PCR tests. 24 sample replicates (across all three lots) returned initial indeterminate results, all determined negative by supervisor review. No invalid results. |
  | Carry-Over/Cross-contamination| Minimal to no false positive events due to carry-over/cross-contamination. | Automated Method (MagNA Pure): 2 false positive events out of 135 negative samples (Specificity: 98.5%).
  Manual Method (Qiagen DSP): No false positive events out of 139 negative samples (Specificity: 100%).
  Contamination events identified on surfaces during testing, highlighting areas of risk. |
  | Clinical Specificity | 100% Negative Percent Agreement (NPA) for B. anthracis negative samples. | For 401 blood culture specimens and 439 whole blood specimens: 100% Negative Percent Agreement (NPA) when compared to the expected negative result. |
  | Clinical Sensitivity | High Positive Percent Agreement (PPA) for B. anthracis positive samples. | 96% Positive Percent Agreement (PPA) (CI: 90.4-96.5%) for 87 low-positive whole blood specimens. Three specimens initially generated 'Bacillus anthracis suspected' results. |

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

• Limit of Detection (LOD): 1612 technical replicates were tested. Data provenance is not specified by country, but it's analytical data likely generated in-house at MRIGlobal (developer). Prospective (controlled spike-in experiments).
• Analytical Inclusivity: 24 different Bacillus anthracis strains tested in triplicate (24 strains * 2 extraction methods * 3 replicates = 144 technical replicates)
• Analytical Exclusivity: 154 non-target organisms tested in wet lab.
• Interfering Substances: 50 potentially interfering substances. Each substance tested in triplicate-paired samples (with and without B. anthracis). 50 * 2 * 3 = 300 samples (assuming paired means 3 concentrations per, and triplicate-paired means 3 replicates per substance per condition).
• Reproducibility: 7 panel members tested twice a day by three teams on five non-consecutive days. Details not fully specified for total sample count, but likely included multiple replicates for each panel member/condition. (e.g., 7 panel members * 2 times/day * 3 teams * 5 days = 210 runs, each run likely involving multiple replicates). "No false positive events occurred out of the 270 PCR tests of negative samples."
• Carry-Over/Cross-contamination:
  • Automated method (MagNA Pure): 9 runs, each with 31 samples, for a total of 279 samples. 135 negative samples.
  • Manual method (Qiagen DSP): 12 batches, total of 279 samples. 139 negative samples.
• Clinical Specificity: 401 blood culture specimens and 439 whole blood specimens. Samples were "left-over fresh and frozen blood culture samples," "randomly accessed, residual blood," and "febrile whole blood samples." Collected prospectively and serially from three point-of-care collection sites within the US.
• Clinical Sensitivity: 87 low-positive whole blood specimens (simulated/contrived). Each aliquot was spiked with 1 of 18 Bacillus anthracis strains. "Febrile whole blood specimens ... determined to be negative for Bacillus anthracis" were used as the matrix for spiking. Samples were contrived (prospective experimental design using collected negative clinical matrix). Clinical performance testing was conducted at three laboratories within the US.

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 ground truth.

• For analytical studies (LOD, Inclusivity, Exclusivity, Interference, Reproducibility, Carry-Over), ground truth is established by the known concentration/presence of cultured organisms or purified DNA, or by the known absence of the target.
• For clinical specificity, samples were "assumed to be negative for Bacillus anthracis" based on their collection context (e.g., routine CBC, fever of unknown origin that would not indicate B. anthracis exposure, or confirmed to be positive for other bacterial species but not B. anthracis). No independent expert assessment or gold standard positive confirmation was used for these negative samples.
• For clinical sensitivity, the ground truth was established by artificial spiking of known concentrations of Bacillus anthracis into negative clinical samples.

4. Adjudication Method for the Test Set

The document mentions adjudication in two instances:

• Reproducibility: "24 sample replicates (across all three reagent lots) that returned initial indeterminate results. All were determined to be negative by supervisor review." This suggests a form of expert review for indeterminate results.
• Analytical Exclusivity: "Some known Bacillus cereus strains... Detection of these strains was indicated by a test result of ‘Bacillus anthracis suspected’ with amplification of the plasmid manually confirmed by the supervisor." This also indicates supervisor review for specific expected "suspected" results.

No broad 2+1 or 3+1 adjudication method for clinical test sets is described. For the clinical performance, the results are directly compared to the assumed/contrived ground truth.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic (IVD) PCR test kit, not an imaging AI designed to assist human readers. Its performance is assessed as a standalone diagnostic tool.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done

Yes, the studies presented (Analytical Sensitivity, Inclusivity, Exclusivity, Interference, Microbial Interference, Reproducibility, Carry-Over/Cross-contamination, Clinical Specificity, Clinical Sensitivity) represent the standalone performance of the "Applied Biosystems™ Bacillus anthracis Detection Kit" which includes the AB1 7500 Fast Dx Real-Time PCR Instrument and the Applied Biosystems Bacillus anthracis Interpretive Software (BaIS). It is an automated test with automated interpretation and report generation, so its performance is inherently a "standalone" or "algorithm only" type of assessment.

7. The Type of Ground Truth Used

The ground truth varied by study type:

• Analytical Studies (LOD, Inclusivity, Exclusivity, Interference, Microbial Interference, Reproducibility, Carry-Over): Controlled laboratory settings with known concentrations of purified DNA or cultured organisms. For negative controls, known absence of target.
• Clinical Specificity: "Assumed to be negative for Bacillus anthracis" for clinical samples collected from individuals not suspected of anthrax, or confirmed to have other bacteria. This is a clinical "expected negative" based on the patient population and standard clinical practice, rather than an independent gold standard for B. anthracis negativity.
• Clinical Sensitivity: Contrived samples where known concentrations of Bacillus anthracis were spiked into clinical samples previously determined to be negative for B. anthracis. This is a simulated positive ground truth.

8. The Sample Size for the Training Set

The document describes premarket validation studies for a diagnostic kit. It does not provide information about a "training set" size for model development, as this device is a PCR assay with interpretive software, not a machine learning model that undergoes a separate training phase with a distinct dataset of this nature. The "training" in this context refers to the development and optimization process, which is not typically quantified in terms of a "training dataset size" in the same way as for AI/ML algorithms.

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

As above, the concept of a "training set" and its ground truth establishment, as it applies to AI/ML, is not directly applicable to this PCR diagnostic kit. The "ground truth" during the development phase would have involved known positive and negative controls, spiked samples, and characterized bacterial strains, similar to the analytical studies performed for validation.

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SeptiCyte™ LAB is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in the PAXgene™ Blood RNA Tube. SeptiCyte™ LAB is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infection-negative systemic in patients suspected of sepsis on their first day of ICU admission. The test generates a score (SeptiSCORE™) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infection-positive systemic inflammation. SeptiCyte™ LAB is in-vitro diagnostic use.

SeptiCyte™ LAB is an in vitro diagnostic test to be used when prescribed by a clinician in professional settings such as central hospital laboratories. SeptiCyte™ LAB is a reverse transcription quantitative polymerase chain reaction (RT-gPCR)-based laboratory test that quantifies the relative expression levels of four host response genes (CEACAM4, LAMP1, PLA2G7, PLAC8) using RNA extracted from the whole blood of critically ill patients suspected of sepsis. It is a kit developed specifically for the Applied Biosystems® 7500 Fast Dx Real-Time PCR System. SeptiCyte™ LAB serves as an indicator of the host response to infection in systemically inflamed patients by measuring the expression of specific genes with roles in immune function, and infection. More specifically it aids in differentiating infection-positive systemic inflammation (IPSI) from infection-negative systemic inflammation (INSI).

SeptiCyte™ LAB measures the relative expression levels of the four genes by threshold cycle (Ct) in RT-qPCR. Ct values are linearly combined in a SeptiSCORE™ ranging from 0 to 10 by SeptiCyte™ Analysis software. The higher the SeptiSCORE™ value, the greater the likelihood of IPSI; the lower the SeptiSCORE™, the less likely the condition is caused by infection (INSI).

The provided text describes the SeptiCyte™ LAB device, an in vitro diagnostic test for aiding in the differentiation of infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis.

Here's the breakdown of the acceptance criteria and study details:

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

The document does not explicitly state "acceptance criteria" with specific numerical thresholds for performance metrics. Instead, it describes "Primary Endpoint" and "Secondary Endpoint" which the clinical study "met." I will use these endpoints as the de facto acceptance criteria.

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

• Sample Size: 447 adult patients
• Data Provenance: Observational, prospective clinical trials conducted across eight clinical sites in the US and Europe.

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

• Number of Experts: Three medical experts.
• Qualifications of Experts: Assumed to be medical professionals with expertise in critically ill patients and sepsis diagnosis, as they were referred to as an "RPD panel" and "medical experts" providing "independent clinical case review." Specific experience duration (e.g., "10 years experience") is not provided.

4. Adjudication method for the test set

The adjudication method involved a "majority opinion of three medical experts."

• Consensus RPD: Subjects were stratified by diagnosis (SIRS, Sepsis, or Indeterminate) according to the majority opinion. Indeterminate cases (n=37) were excluded from the analysis.
• Forced RPD: Subjects were stratified by diagnosis (SIRS or Sepsis) according to the majority opinion, with no Indeterminate category allowed, forcing all patients into either SIRS or sepsis categories.

This closely resembles a 3+1 or simply majority consensus method, where at least two out of three experts had to agree for a definitive diagnosis.

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 focusing on human readers' improvement with AI assistance was not done. The study evaluated the standalone performance of the SeptiCyte™ LAB device in relation to a retrospective physician diagnosis, and its contribution to logistic regression models alongside other clinical variables. There is no mention of human readers interpreting images or data with and without AI assistance.

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

Yes, the primary and secondary endpoints evaluate the performance of the SeptiSCORE™ (generated by the device's algorithm) as a standalone diagnostic aid. The SeptiSCORE™ was compared against a ground truth established by medical experts (RPD). The logistic regression models also assessed the SeptiSCORE's contribution amongst other variables, indicating its standalone diagnostic utility.

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

The ground truth used was expert consensus (Retrospective Physician Diagnosis or RPD), established by a panel of three medical experts. This diagnosis was made after the patient was discharged from the hospital and after all clinical information was available at discharge, and the experts were blinded to the SeptiCyte™ LAB test results.

8. The sample size for the training set

The document does not specify the sample size for a training set. The clinical study described involved 447 patients, which served as the evaluation (test) set for the device's performance. Information about a separate training set used to develop the SeptiSCORE™ algorithm is not provided in this document.

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

Since the document does not mention a specific training set or its sample size, it does not describe how ground truth for a training set was established.

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The Lyra Direct Strep Assay is a Real-Time PCR in vitro diagnostic test for the qualitative detection and differentiation of Group A ß-hemolytic Streptococcus (Streptococcus pvogenes) and pyogenic Group C and G B-hemolytic Streptococcus nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharvngitis, such as sore throat. The assay does not differentiate between pyogenic Groups C and G ß-hemolytic Streptococcus.

All negative test results should be confirmed by bacterial culture, because negative results do not preclude Group A, C or G Strep infection and should not be used as the sole basis for treatment.

The assay is intended for use in hospital, reference, or state laboratory settings. The device is not intended for point-of-care use.

The Lyra Direct Strep Assay detects nucleic acids isolated from throat swab specimens obtained from patients with signs and symptoms of pharyngitis. A multiplex Real-time PCR reaction is carried out under optimized conditions in a single tube generating amplicons for Group A B-hemolytic Streptococcus (Streptococcus pyogenes) and pyogenic Group C and G B-hemolytic Streptococcus, and the Process Control (PRC). Identification of Group A, pyogenic Group C/G, and the PRC occurs by the use of target-specific primers and fluorescent-labeled probes that hybridize to conserved regions in the genomes of Group A, pyogenic Group C/G, and the PRC. The assay does not differentiate between Group C and Group G streptococci.

A specimen from a patient's throat swab is transferred to the Process Buffer then heated to lyse the bacteria and expose the DNA. The lysed specimen is then added to a rehydrated Master Mix of targeted oligonucleotide primers, fluorophore and quencher-labeled probes is added to each plate. The plate is placed into the Applied Biosystems® 7500 Fast Dx instrument and the Quidel Molecular Direct Streptococci Assay protocol is initiated.

This assay is based on Taqman® chemistry, and uses an enzyme with DNA polymerase, and 5'-3' exonuclease activities. During DNA amplification, this enzyme cleaves the probe bound to the conserved complementary DNA sequence, separating the quencher dye from the reporter dye. This step generates an increase in fluorescent signal upon excitation by a light source of the appropriate wavelength. With each cycle, additional dye molecules are separated from their quenchers resulting in an increase in the fluorescent signal. If sufficient fluorescence is achieved, the sample is reported as positive for the detected nucleic acid.

{
  "acceptance_criteria_and_study": {
    "acceptance_criteria_table": {
      "headers": [
        "Performance Metric",
        "Acceptance Criteria (Implicit)",
        "Reported Device Performance"
      ],
      "data": [
        [
          "Precision/Repeatability (Group A Strep, High Negative)",
          "Acceptable detection rates",
          "45.8% Detection"
        ],
        [
          "Precision/Repeatability (Group A Strep, Low Positive)",
          "Acceptable detection rates",
          "100% Detection"
        ],
        [
          "Precision/Repeatability (Group A Strep, Moderate Positive)",
          "Acceptable detection rates",
          "100% Detection"
        ],
        [
          "Precision/Repeatability (Group A Strep, Negative)",
          "Acceptable detection rates",
          "0% Detection"
        ],
        [
          "Precision/Repeatability (Pyogenic Group C Strep, High Negative)",
          "Acceptable detection rates",
          "75% Detection"
        ],
        [
          "Precision/Repeatability (Pyogenic Group C Strep, Low Positive)",
          "Acceptable detection rates",
          "100% Detection"
        ],
        [
          "Precision/Repeatability (Pyogenic Group C Strep, Moderate Positive)",
          "Acceptable detection rates",
          "100% Detection"
        ],
        [
          "Precision/Repeatability (Pyogenic Group C Strep, Negative)",
          "Acceptable detection rates",
          "0% Detection"
        ],
        [
          "Reproducibility (Group A Strep, Low Pos, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "99% (89/89)"
        ],
        [
          "Reproducibility (Group A Strep, Mod Pos, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "100% (90/90)"
        ],
        [
          "Reproducibility (Group A Strep, Neg, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "0% (0/90)"
        ],
        [
          "Reproducibility (Pyo Group C Strep, Low Pos, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "100% (89/90)"
        ],
        [
          "Reproducibility (Pyo Group C Strep, Mod Pos, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "100% (90/90)"
        ],
        [
          "Reproducibility (Pyo Group C Strep, Neg, Combined)",
          "Acceptable detection rates (e.g., close to 100% for positive and 0% for negative)",
          "0% (0/90)"
        ],
        [
          "Analytical Specificity (Cross-reactivity)",
          "No cross-reactivity with common throat microorganisms",
          "None of the forty-four (44) microorganisms tested cross-react with the assay."
        ],
        [
          "Clinical Sensitivity (Group A Strep, All Sites)",
          "High sensitivity (no explicit numerical criteria, but implied to be high for regulatory acceptance)",
          "96.5% (95% CI: 91.3%-98.6%)"
        ],
        [
          "Clinical Specificity (Group A Strep, All Sites)",
          "High specificity (no explicit numerical criteria, but implied to be high for regulatory acceptance)",
          "98.0% (95% CI: 97.0%-98.6%)"
        ],
        [
          "Clinical Sensitivity (Pyogenic Group C and G Strep, All Sites)",
          "High sensitivity (no explicit numerical criteria, but implied to be high for regulatory acceptance)",
          "95.7% (95% CI: 88.1%-98.5%)"
        ],
        [
          "Clinical Specificity (Pyogenic Group C and G Strep, All Sites)",
          "High specificity (no explicit numerical criteria, but implied to be high for regulatory acceptance)",
          "98.3% (95% CI: 97.4%-98.9%)"
        ]
      ]
    },
    "test_set_sample_size": "1293 prospectively collected fresh throat specimens.",
    "test_set_data_provenance": "United States, prospective.",
    "number_of_experts_ground_truth": "The document does not explicitly state the number of experts used to establish ground truth for the clinical study. However, the ground truth was established by microbiological culture, which typically involves trained laboratory personnel but not necessarily an 'expert consensus' in the sense of multiple independent clinical expert opinions on each case.",
    "qualifications_of_experts": "Not explicitly stated for the clinical ground truth. For culture methods, typically microbiologists or trained laboratory technologists perform and interpret the results.",
    "adjudication_method": "Not applicable in the context of expert consensus. The ground truth was based on a composite culture method: a specimen was considered positive if culture from either the directly plated swab or the transport fluid material was positive for the target streptococci. This is a laboratory-based reference standard, not an adjudication of expert opinions.",
    "mrmc_comparative_effectiveness_study": "No, a multi-reader multi-case (MRMC) comparative effectiveness study was not explicitly mentioned. The study compares the device performance to a reference standard (culture), not to human readers with and without AI assistance.",
    "standalone_performance_study": "Yes, the clinical sensitivity and specificity results 'vs. Composite Cultures' (Tables X and XI) represent the standalone performance of the algorithm/device without human-in-the-loop assistance for interpretation of primary results.",
    "type_of_ground_truth": "Expert reference standard based on **composite bacterial culture** (directly plated throat swabs and culture of transport fluid material). Cultured isolates were typed by latex agglutination, and beta-hemolytic isolates were speciated using MALDI TOF.",
    "training_set_sample_size": "The document does not explicitly state the sample size for a 'training set'. The data presented are for analytical and clinical validation. While the device developers would have utilized data during development, specific training set sizes are not provided in this regulatory submission for a diagnostic device.",
    "ground_truth_for_training_set": "Not explicitly stated. For PCR-based assays, 'training' typically involves optimizing assay parameters (primers, probes, cut-offs) using characterized bacterial strains and spiked samples (e.g., as described in the Analytical Sensitivity and LoD sections), rather than a large clinical training set with expert ground truth in the same way an AI model might be trained."
  }
}

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The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in real-time RT-PCR (rRT-PCR) assays on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument in conjunction with clinical and epidemiological information:

• For qualitative detection of influenza virus type A or B viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]) and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
• For determination of the subtype of seasonal human influenza A virus as seasonal A/H1, A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture.
• For the presumptive identification of virus in patients who may be infected with influenza A subtype A/H5 (Asian Lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors.
• To provide epidemiologic information for surveillance of circulating influenza viruses.

The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR assays (rRT-PCR) on the ABI 7500 Fast Dx Real-Time PCR Instrument. The CDC Human Influenza Virus Real-time RT-PCR Diagnostic Panel is a panel of oligonucleotide primers and dual-labeled hydrolysis (TaqMan®) probes to be used in rRT-PCR for the in vitro qualitative detection and characterization of human influenza viruses from viral RNA in respiratory specimens from patients presenting with influenza-like illness (ILI). Detection of viral RNA not only aids in the diagnosis of illness caused by seasonal and novel influenza viruses in patients with ILI, but also provides epidemiological information on influenza and aids in the presumptive laboratory identification of specific novel influenza A viruses. The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is based on technology which is used in many molecular diagnostic assays. rRT-PCR assays are one-tube assays that first reverse-transcribe specific regions of RNA into cDNA copies. The cDNA then serves as a template for a polymerase chain reaction that utilizes a thermocyclic heating and cooling of the reaction to logarithmically amplify a specific region of DNA. The probe anneals to a specific internal target sequence located between the target loci of the forward and reverse primers. During the extension phase of the PCR cycle, the 5' nuclease activity of Tag polymerase degrades any probe molecules hybridized to amplified target sequence, causing the reporter dye to separate from the quencher dye, and generating a fluorescent signal. With each cycle, additional reporter dye molecules are cleaved from their respective probes, increasing the fluorescence intensity. Fluorescence intensity is monitored at each PCR cycle. Amplification of targets is reflected by logarithmic increase in fluorescence over time in comparison to background signal.

The provided text does not contain specific acceptance criteria with numerical thresholds that the device must meet, nor does it detail a dedicated pivotal study with a defined sample size and ground truth establishment methodology for this specific device (K111507) to demonstrate its performance against those criteria.

Instead, the submission for K111507 relies on the "substantial equivalence comparison" to two previously FDA-cleared predicate devices (K080570 and K101564). The performance data cited for K111507 directs the reader to the performance characteristics established for these predicate devices. The document also includes additional performance data collected during the 2010-2011 influenza season to show that recent circulating strains can be detected.

Therefore, the following information is extracted and presented based on the available text:

1. Table of Acceptance Criteria and Reported Device Performance

As specific, quantified acceptance criteria for K111507 are not explicitly stated in the provided text, a direct comparison table cannot be created in the traditional sense. The submission for K111507 primarily relies on the equivalency to predicate devices and additional data showing detection of recent circulating strains.

Reported Device Performance (for K111507, based on additional data for recent circulating strains):

2. Sample Size and Data Provenance for Test Set

• Sample Size for Test Set:
  • For detection of recent seasonal influenza A/H3 and B: 49 original specimens.
  • For detection in lower respiratory tract specimens: 18 original specimens.
• Data Provenance: Retrospective, from US public health laboratories (identified as "original specimens received from US public health laboratories").

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. Given the nature of a PCR diagnostic panel, the ground truth would typically be established through a reference method, often a combination of viral culture and/or additional molecular testing performed by qualified laboratory personnel, rather than expert interpretation of images or clinical assessments.

4. Adjudication Method for Test Set

The document does not describe any adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of the test set.

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

• No MRMC study was done. This device is a real-time RT-PCR diagnostic panel, not an AI-assisted diagnostic tool for human readers. Therefore, the concept of human readers improving with AI vs. without AI assistance is not applicable.

6. Standalone Performance Study (Algorithm Only)

• Yes, a standalone study was implicitly done. The performance data presented (detection of influenza A/H3 and B in specimens) represents the algorithm's (the PCR panel's) performance independent of human-in-the-loop diagnostic interpretation beyond standard laboratory procedures. The detection is based on the fluorescent signal generated by the rRT-PCR assay.

7. Type of Ground Truth Used

• The ground truth type is implied to be a reference method for influenza detection and characterization, likely viral culture and/or a validated molecular method accepted as the standard for influenza diagnosis. The text states "Performance characteristics for influenza were established...as demonstrated by analytical testing of the 49 original specimens...". For the lower respiratory specimens, it states the panel "detected influenza A/H3, A/H1pdm09, and influenza B," implying comparison to an established truth.

8. Sample Size for Training Set

• The document does not explicitly mention a "training set" in the context of this diagnostic panel. As a PCR diagnostic kit, its development involves designing primers and probes that target specific viral genetic sequences. This process typically involves bioinformatics analysis and wet-lab analytical validation using known positive and negative controls, rather than a machine learning "training set" in the conventional sense. The "performance characteristics" data mentioned (from predicate devices and the additional 2010-2011 season data) serve as validation or evaluation data.

9. How Ground Truth for Training Set Was Established

• Not applicable, as a discrete "training set" with established ground truth in the context of machine learning is not described or relevant for this type of PCR diagnostic device. The design and analytical validation of PCR primers and probes rely on known viral sequences and synthetic or cultured viral samples with confirmed identities, not a "ground truth" derived from human experts interpreting a diagnostic outcome.

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