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The Aptima Herpes Simplex Viruses 1 & 2 assay (Aptima HSV 1 & 2 assay) is an in vitro diagnostic nucleic acid amplification test (NAAT), using real time transcription-mediated amplification (TMA), for the qualitative detection and differentiation of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) messenger RNA (mRNA) in clinician-collected swab specimens from anogenital skin lesions. The assay is intended for use with swab specimens placed in Aptima specimen transport medium (STM) or in viral transport media (VTM) that is immediately diluted into STM.

The Aptima HSV 1 & 2 assay is intended for use as an aid in the diagnosis of HSV-1 and/or HSV-2 infections in symptomatic male and female patients. The Aptima HSV 1 & 2 assay is indicated for use on the Panther® system.

The Aptima Herpes Simplex Virus 1 & 2 assay (Aptima HSV assay) is a nucleic acid amplification test (NAAT) developed for use on the fully automated Panther system that utilizes target capture, transcription mediated amplification (TMA), and real-time detection of HSV-1, HSV-2, and an internal control (IC). The Aptima HSV assay amplifies and detects mRNAs for HSV-1 and HSV-2. These RNAs are expressed from the viral genome during the infection cycle, and are packaged inside HSV-1 and HSV-2 viral particles prior to virus release from infected cells. The Aptima HSV assay therefore detects virus-infected cells and the mature virus particles themselves.

The Aptima HSV assay involves three main steps, which all take place in a single tube on the Panther® system: target capture, target amplification by TMA, and detection of the amplification products (amplicon) by the fluorescent labeled probes (torches). The assay incorporates an IC in every test to monitor targeted nucleic acid capture, amplification and detection.

When the Aptima HSV assay is performed, the targeted viral mRNA and IC are isolated using magnetic microparticles and target-specific capture oligomers, in a process called target capture. The capture oligomers contain sequences complementary to specific regions of the targeted RNA (HSV mRNA or IC) as well as a string of deoxyadenosine residues. During the hybridization step, the sequence-specific regions of the capture oligomers bind to specific regions of the RNA target molecules. The microparticles, including the captured RNA target molecules bound to them, are pulled to the side of the reaction tube using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification inhibitors. After target capture steps are completed, the specimens are ready for amplification.

Target amplification occurs via TMA, which is a transcription-based nucleic acid amplification method that utilizes two enzymes, MMLV (Moloney murine leukemia virus) reverse transcriptase and T7 RNA polymerase. The reverse transcriptase is used to generate a DNA copy (containing a promoter sequence for T7 RNA polymerase) of the target sequence. T7 RNA polymerase produces multiple copies of RNA amplicon from the DNA copy template. Detection is achieved using single-stranded nucleic acid torches that are present during the amplification of the target and hybridize specifically to the amplicon in real time. Each torch has a fluorophore and a quencher. The quencher suppresses the fluorescence of the fluorophore as it is designed to be in close proximity when not hybridized to the amplicon. When the torch binds to the amplicon, the quencher is moved farther away from the fluorophore and it will emit a signal at a specific wavelength when excited by a light source. More torch hybridizes when more amplicon is present. The increase in fluorescent signal from progressive amplification is detected by fluorometers within the Panther system. The Panther system can detect and discriminate between the three fluorescent signals corresponding to HSV-1, HSV-2 and IC amplification products. The fluorescence (measured in relative fluorescence units [RFU]) is monitored over time to produce a real-time fluorescence emergence curve for each reporter dye. The Panther system software compares the fluorescence emergence curves to fixed cut off times to report results (TTime) for HSV-1, HSV-2 and IC.

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

Acceptance Criteria and Device Performance for Aptima Herpes Simplex Viruses 1 & 2 Assay

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical performance targets presented in the study. While explicit pre-defined acceptance thresholds (e.g., "Sensitivity must be >90%") are not directly stated as pass/fail criteria, the reported performance metrics demonstrate the device's capability. For this analysis, I will use the clinical performance study results as the reported device performance against generally expected high standards for diagnostic accuracy.

Note: The document does not explicitly state the pre-defined "acceptance criteria" numerical targets. The reported performance below represents the observed results of the clinical study, which presumably met the internal performance requirements for the manufacturer and FDA review.

Table 1: Acceptance Criteria (Implied) and Reported Device Performance

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

• Clinical Test Set Sample Size:
  • Total Subjects: 544 evaluable subjects (195 males and 349 females).
  • Evaluated for HSV-1: 528 VTM specimens and 531 STM specimens.
  • Evaluated for HSV-2: 533 VTM specimens and 535 STM specimens.
• Data Provenance:
  • Country of Origin: United States. The study was conducted at 17 US clinical sites.
  • Retrospective or Prospective: Prospective. The study is described as a "prospective, multicenter clinical study."

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

The document does not specify the number of experts used to establish the ground truth or their specific qualifications (e.g., "radiologist with 10 years of experience").

However, it describes the methods used for the composite reference method:

• ELVIS HSV ID and D3 Typing Test system viral culture
• A validated bidirectional PCR/sequencing procedure
• A third FDA-cleared assay for HSV-1 and HSV-2 was used for final composite reference interpretation when the initial methods disagreed or when PCR/sequencing detected both types.

This suggests that the ground truth was established through a combination of highly reliable laboratory tests, implying a rigorous approach to defining true positive/negative cases, rather than relying solely on individual expert interpretation without further clarification.

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

The document describes an adjudication method for the ground truth:

• "A third FDA-cleared assay for HSV-1 and HSV-2, was used to determine the final composite reference interpretation when the ELVIS D3 culture and PCR/sequencing results did not agree on the type of HSV detected or when PCR/sequencing detected both HSV-1 and HSV-2."

This indicates a hierarchical or tie-breaking system rather than a simple 2+1 or 3+1 consensus among human readers. It relies on a "composite reference method" combining results from multiple validated laboratory tests.

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

This is a diagnostic assay for detecting viral RNA, not an imaging device that involves human readers interpreting images with or without AI assistance. Therefore, no MRMC comparative effectiveness study involving human readers with AI assistance was performed or reported in this submission. The device (Aptima HSV 1 & 2 Assay) is designed to provide a direct qualitative result (positive/negative for HSV-1 and/or HSV-2) from a processed specimen.

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

Yes, a standalone performance study was done in the sense that the Aptima HSV 1 & 2 Assay (the "algorithm" in this context) directly processes specimens and generates results without requiring human interpretation for its output. The clinical performance study directly evaluated the accuracy of the assay's results against a composite reference standard. The "human-in-the-loop" would be the clinician collecting the sample and laboratory technicians running the test and reporting the results, but the analytical output itself is determined by the assay system.

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

The ground truth used was a composite reference method combining:

• ELVIS HSV ID and D3 Typing Test system viral culture
• A validated bidirectional PCR/sequencing procedure
• A third FDA-cleared assay for HSV-1 and HSV-2 (used for tie-breaking/discrepancy resolution)

This is a robust form of ground truth based on multiple established laboratory diagnostic methods.

8. The sample size for the training set

The document does not report a sample size for a training set. This is expected for a diagnostic assay of this type, as it's not a machine learning or AI algorithm that requires a separate "training set" in the conventional sense. The assay's design and optimization (e.g., probe sequences, amplification conditions) would have been developed iteratively, but a distinct "training set" for performance evaluation is not applicable here. The analytical studies (LoD, cross-reactivity, etc.) and the clinical performance study represent the validation of the finalized assay.

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

As there is no explicit "training set" in the context of machine learning, this question is not directly applicable. The assay's components and parameters would have been optimized using internal development processes and validated through analytical studies. For these analytical studies (e.g., LoD, cross-reactivity), the "ground truth" (i.e., known-positive or known-negative samples, specific viral strains/concentrations) would have been established through well-characterized laboratory standards, spiked samples, and reference materials.

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The Abbott RealTime CT/NG (List No. 8L07-91) assay is an in vitro polymerase chain reaction (PCR) assay for the direct, qualitative detection of the plasmid DNA of Chlamydia trachomatis and the genomic DNA of Neisseria gonorrhoeae. The assay may be used to test the following specimens from symptomatic individuals: female endocervical swab, clinician-collected vaginal swab, and patient-collected vaginal swab specimens; male urethral swab specimens; and female and male urine specimens. The assay may be used to test the following specimens from asymptomatic individuals: clinician-collected vaginal swab and patient-collected vaginal swab specimens; female and male urine specimens.

Abbott RealTime CT/NG consists of two reagent kits:

• · Abbott RealTime CT/NG Amplification Reagent Kit (List No. 8L07-91)
• · Abbott RealTime CT/NG Control Kit (List No. 8L07-80)
  The Abbott RealTime CT/NG assay uses PCR technology with homogenous real-time fluorescence detection on the m2000 System. The Abbott m2000 System consists of the Abbott m2000sp and Abbott m2000rt instruments. The Abbott m2000 System integrates sample preparation with nucleic acid amplification and detection to generate assay results. The Abbott m2000sp is used for processing samples and the Abbott m2000rt is used for amplification and detection.

Abbott RealTime CT/NG Assay: Acceptance Criteria and Supporting Study

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Abbott RealTime CT/NG assay are implied by the reported clinical sensitivity and specificity for various specimen types and Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) detection. While explicit numerical acceptance criteria are not stated in the provided text, the reported performance values demonstrate the device's efficacy.

Table 1: Clinical Performance of Abbott RealTime CT/NG Assay

2. Sample Size and Data Provenance (Clinical Study)

• Sample Size for Test Set: A total of 3,832 male and female subjects were enrolled in the multi-center clinical study. For the analysis of the Abbott RealTime CT/NG assay, 6,555 CT results and 6,569 NG results were used.
• Data Provenance: The study was conducted in the United States across 16 geographically diverse sites, including physician private practices, public and private STD clinics, and a hospital emergency room. The study design implies a prospective collection of specimens from enrolled subjects, although it's not explicitly stated as retrospective or prospective in every detail of the summary. The phrase "Specimens were collected from subjects at...sites" supports a prospective approach for the clinical data.

3. Number of Experts and Qualifications (Ground Truth)

The document does not explicitly state the "number of experts" or their specific "qualifications" used to establish the ground truth in the clinical study. Instead, the ground truth was established by comparing the Abbott RealTime CT/NG assay to reference assays.

4. Adjudication Method (Test Set)

The adjudication method for determining the "patient infected status" (ground truth) was based on a combination of reference assay results:

• For CT or NG (Female Subjects): A female was categorized as infected if a minimum of two positive results were reported (at least one from each reference NAAT). A specific condition was also applied for CT: if reference urine specimens were positive and all three reference swab specimens were negative, the subject was considered infected for urine but not swab specimens.
• For CT or NG (Male Subjects): A male was categorized as infected if a minimum of two positive results were reported.
• For NG (All Subjects): If the reference NG culture assay result was positive, the subject was categorized as infected regardless of NAAT results.
• Non-Infected Status: For females, non-infected status was assigned if at least one reference NAAT reported negative results for all sample types AND the NG culture was negative. For males, at least two negative results from reference NAATs AND a negative NG culture result were required for non-infected status.
• Subjects with missing and/or indeterminate results from reference assays were excluded from the analysis (4 subjects for CT and 7 subjects for NG).

This multi-assay, rule-based approach serves as the adjudication method for establishing the ground truth.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned in the provided document. The study is focused on the standalone performance of the Abbott RealTime CT/NG assay against established reference methods, not on comparing human reader performance with and without AI assistance.

6. Standalone Performance (Algorithm Only)

Yes, a standalone performance study was done. The entire clinical study described, measuring the sensitivity and specificity of the Abbott RealTime CT/NG assay against reference methods, represents the standalone performance of the algorithm. The results are summarized in Table 1 above, as well as Tables 3.10-3.13 in the original document.

7. Type of Ground Truth Used

The ground truth used for the clinical study was established by expert consensus using a combination of reference assays:

• Two commercially available Nucleic Acid Amplification Tests (NAATs) for CT and NG.
• Culture for NG.

This is a composite reference standard or adjudicated clinical truth based on multiple established diagnostic methods.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" or "training data" in the context of the Abbott RealTime CT/NG assay development or validation. This is expected given that the device is an in-vitro diagnostic (IVD) PCR assay, which typically relies on analytical validation and clinical performance studies described here, rather than machine learning models that require distinct training and test sets. The presented clinical study serves as the primary validation of the device's performance.

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

As noted above, the document does not refer to a distinct "training set." The Limit of Detection (LOD) and analytical sensitivity studies (Sections 3.14.1), which involve testing known concentrations of CT and NG target DNA and isolates, can be considered part of the analytical validation that informs the assay's performance characteristics. For these analytical studies:

• Known concentrations of CT and NG target DNA were used.
• Dilutions of various CT serovars and NG isolates were tested.

This is a form of defined analytical ground truth based on controlled laboratory preparations of the target organisms. For the clinical performance, the ground truth was established by the composite reference standard from the clinical study as detailed in point 7.

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The Abbott m2000 system is intended for in vitro diagnostic use in performing FDA cleared and approved nucleic acid testing in clinical laboratories. It comprises the Abbott m2000sp and the Abbott m2000rt instruments. The Abbott m2000sp is an automated system for performing sample preparation for nucleic acid testing. The Abbott m2000rt is an automated system for performing fluorescence-based PCR to provide quantitative and qualitative detection of nucleic acid sequences.

The Abbott m2000 System is an instrument platform that automates steps to perform nucleic acid amplification assays from sample processing through amplification, detection, and data reduction. The Abbott m2000 System comprises the m2000sp and m2000rt instruments, which are operated with separate System Control Center (SCC) workstations. Each instrument contains an independent software application; one for the m2000sp and a second for the m2000rt. The m2000sp instrument is a floor standing, automated sample preparation system. The three main components of the m2000sp are the: Instrument, Cabinet, System Control Center (SCC). The m2000rt instrument is a real-time PCR thermal cycler/reader instrument system. The two main components of the m2000rt are the: Instrument, System Control Center (SCC). The Abbott m2000 System software processes sample preparation and amplification/detection protocols based on pre-determined, assay-specific parameters that are contained in individual assay application specification files that are installed on the SCC. The Abbott m2000sp reads and processes bar coded primary sample tubes and processes up to 96 specimens, controls, and calibrators in batch mode. The m2000 System is capable of processing samples from various matrices, depending on the specific assay application, including plasma, serum, endocervical swabs, urethral swabs, vaginal swabs, and urine. At the completion of the automated sample preparation protocol, the operator seals and manually transfers the PCR plate to the Abbott m2000rt for nucleic acid detection. Bar code and m2000sp data is transferred to the m2000rt electronically.

The Abbott m2000 System is an automated instrument platform intended for in vitro diagnostic use in performing FDA-cleared and approved nucleic acid testing in clinical laboratories. This includes the Abbott m2000sp (automated sample preparation) and m2000rt (automated fluorescence-based PCR for quantitative and qualitative detection of nucleic acid sequences). The system was evaluated in conjunction with the Abbott RealTime CT/NG assay.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

While explicit "acceptance criteria" are not presented as a direct table in the provided document, the study aims to demonstrate substantial equivalence to predicate devices and establish performance characteristics. The key performance metrics reported are sensitivity and specificity for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG).

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

• Test Set (Clinical Study):
  • 3,832 male and female, asymptomatic and symptomatic subjects.
  • 3,832 subjects provided urine, endocervical swabs, self-collected vaginal swabs, and clinician-collected vaginal swabs (females) or urine and urethral swabs (males).
  • A total of 6,555 CT results and 6,569 NG results were used in the analysis after excluding subjects for whom patient infected status could not be determined (4 for CT, 7 for NG).
• Data Provenance: Prospective, multi-center clinical study conducted in the United States. Specimens were collected from 16 geographically diverse sites, including physician private practices, public and private STD clinics, and a hospital emergency room.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

The document does not explicitly state the number or qualifications of experts who established the ground truth in the traditional sense (e.g., radiologists interpreting images). Instead, the ground truth was established through a reference standard composed of multiple commercially available nucleic acid amplification tests (NAATs) and culture for NG.

• For CT or NG infection in females: A minimum of two positive results (at least one from each reference NAAT).
• For CT in females (urine/swab discrepancy): Positive urine and negative endocervical swab from both reference assays resulted in categorization as infected for urine but not for swab specimens.
• For CT or NG infection in males: A minimum of two positive results were reported.
• For NG infection (regardless of NAAT) if NG culture positive: If the reference NG culture assay result was positive, the subject was categorized as infected regardless of NAAT results.
• For non-infection in females: At least one of the reference NAATs reported negative results for all sample types AND if the NG culture assay result was negative.
• For non-infection in males: A total of at least two negative results reported by the reference NAATs AND if the NG culture assay result was negative.

Therefore, the "ground truth" was established by a consensus of FDA-cleared diagnostic assays rather than individual expert interpretation.

4. Adjudication Method for the Test Set

The adjudication method for determining "patient infected status" (ground truth) was a composite reference standard based on the results of two commercially available NAATs and culture for NG. It essentially used a "2 out of 2" or "2 out of 3" (for NG cases with culture) positive rule for infection, and a "negative across multiple tests" rule for non-infection. In cases of internal discrepancy, specific rules were applied (e.g., for female CT urine vs. swab).

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, an MRMC comparative effectiveness study involving human readers and AI assistance was not mentioned. This device is an automated in vitro diagnostic system, not an AI-powered diagnostic imaging or interpretation tool designed to assist human readers. Its performance is evaluated as a standalone diagnostic.

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

Yes, the clinical study primarily evaluated the standalone performance of the Abbott RealTime CT/NG assay on the Abbott m2000 System. The reported sensitivity and specificity values are for the assay and system independent of human interpretation beyond typical lab procedures and result reporting.

7. The Type of Ground Truth Used

The ground truth used was a composite reference standard based on the results of:

• Two commercially available nucleic acid amplification tests (NAATs) for CT and NG.
• Culture for NG.

This is a frequently used method for establishing ground truth for infectious disease diagnostics when a single "gold standard" may not always be definitive. It combines multiple reliable diagnostic methods to increase confidence in the true infection status.

8. The Sample Size for the Training Set

The document does not explicitly specify a "training set" size for the Abbott RealTime CT/NG assay and m2000 system. For in vitro diagnostic devices like this, the development process (which would involve data akin to training) is typically extensive and proprietary, focusing on analytical performance and robustness. The clinical study described would be analogous to an independent validation or test set.

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

Since a dedicated "training set" with ground truth establishment in the AI/machine learning sense is not detailed, this question applies less directly. However, the development of the assay would inherently involve:

• Analytical studies: Determining Limit of Detection (LOD), analytical sensitivity (serovars, isolates), cross-reactivity, and interference using well-characterized samples (e.g., quantified pure cultures, spiked samples). The ground truth for these analytical studies is based on known concentrations of targets and the presence/absence of interfering substances or cross-reactants. These studies are detailed in Section 9.0 "Summary of Non-Clinical Testing."

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