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The Aptima Neisseria gonorrhoeae (GC) Assav is an in vitro qualitative nucleic acid amplification (NAAT) the detection of ribosomal RNA (rRNA) from Neisseria gonorrhoeae (GC) to aid in the diagnosis of gonocccal urogenital disease using the Panther System. The assay may be used to test male urine specimens from symptomatic and asymptomatic individuals.

The Aptima GC assay is a target amplification nucleic acid probe test for in vitro qualitative detection of ribosomal RNA (rRNA) from Neisseria gonorrhoeae (GC). The Aptima Neisseria gonorrhoeae Assay combines the technologies of target capture, transcription-mediated amplification (TMA), and hybridization protection assay (HPA). Specimens are collected and transferred into their respective specimen transport tubes. The transport solution in these tubes releases the rRNA target and protects it from degradation during storage. When the Aptima Neisseria gonorrhoeae Assay is performed in the laboratory, the target rRNA molecule is isolated from the specimens by use of a capture oligomer via target capture that utilizes magnetic microparticles. The capture oligomer contains a sequence complementary to a specific region of the target molecule as well as a string of deoxyadenosine residues. During the hybridization step, the sequence specific region of the capture oligomer binds to a specific region of the target molecule. The capture oligomer:target complex is then captured out of solution by decreasing the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the poly-deoxythymidine molecules that are covalently attached to the magnetic particles. The micro particles, including the captured target molecule bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification reaction inhibitors. After the target capture steps are completed, the specimens are ready for amplification. Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Hologic TMA reaction replicates a specific region of the 16S rRNA from GC via DNA intermediates. A unique set of primers is used for the target molecule. Detection of the rRNA amplification product sequences (amplicon) is achieved using nucleic acid hybridization. A single-stranded chemiluminescent DNA probe, which is complementary to a region of the target amplicon, is labeled with an acridinium ester molecule. The labeled DNA probe combines with amplicon to form stable RNA:DNA hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled RNA:DNA hybrids is measured as photon signals in a luminometer, and are reported as Relative Light Units (RLU). The device reagents are identical to the Aptima Neisseria gonorrhoeae Assay reagents for use on the Tigris DTS system but are intended for use on the Panther system with different specimen type indications. The Panther and Tigris DTS systems use the same principles of operation.

Here's a breakdown of the acceptance criteria and study details for the Aptima Neisseria gonorrhoeae Assay, based on the provided FDA 510(k) summary:

This device is an in vitro qualitative nucleic acid amplification test (NAAT) for the detection of Neisseria gonorrhoeae (GC) rRNA to aid in the diagnosis of gonococcal urogenital disease in male urine specimens using the Panther System. It does not appear to involve AI assistance or human reader studies.

1. Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria for clinical performance (sensitivity and specificity) as a set of numerical thresholds. Instead, it states that the study data demonstrate that performance of the Aptima Neisseria gonorrhoeae Assay on the Panther system is substantially equivalent to that of currently FDA-cleared assays for male urine specimens.

However, analytical studies do present performance metrics that implicitly act as acceptance criteria, for example, for Limit of Detection (LoD), precision, and specificity (no interference).

Here's a summary of reported device performance based on the provided text:

Table of Reported Device Performance

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

• Clinical Test Set:
  • Total Enrolled Subjects: 2085 male subjects.
  • Evaluable Subjects: 1959 male subjects (126 subjects not evaluable).
  • Specimens Included in Performance Analysis: 1958 male urine specimens (one specimen with final GC equivocal result was excluded).
  • Data Provenance: Prospective, multi-center clinical study conducted at 11 geographically and ethnically diverse US clinical sites.
    • Sites included obstetrics and gynecology, family planning, and STI clinics.
    • Specimens were collected from symptomatic and asymptomatic men.

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

• The document does not explicitly state the number of experts used to establish ground truth for the clinical test set.
• The ground truth (Patient Infected Status - PIS) was established using up to 3 FDA-cleared NAATs (Nucleic Acid Amplification Tests). This implies that a consensus or reference standard approach using multiple existing, cleared diagnostic methods was used, rather than individual expert review or pathological examination for individual cases.

4. Adjudication Method for the Test Set

• The document states that the Patient Infected Status (PIS) was established using "up to 3 FDA-cleared NAATs". This indicates a composite reference standard approach.
• The specific adjudication rule (e.g., 2/3 positive, 3/3 positive) is not detailed, but the use of multiple FDA-cleared methods implies a robust, multi-test consensus for the ground truth.

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

• No, an MRMC comparative effectiveness study was not done.
• This device is an in vitro diagnostic (IVD) assay (a qualitative nucleic acid amplification test), not an imaging AI device that assists human readers. Therefore, there is no "human-in-the-loop" component or an effect size for human readers improving with AI assistance.

6. Standalone Performance

• Yes, standalone performance was done.
• The described clinical study evaluates the performance of the "Aptima Neisseria gonorrhoeae Assay on the Panther System" directly against a composite reference standard (PIS derived from FDA-cleared NAATs). This is a standalone performance assessment of the algorithm/device itself, without human intervention in the result interpretation.

7. Type of Ground Truth Used

• The ground truth used for the clinical test set was a composite reference standard, referred to as "Patient Infected Status (PIS)".
• PIS was established by testing male urine specimens with "up to 3 FDA-cleared NAATs". This is a highly robust method, relying on multiple well-validated diagnostic tests to determine the true infection status.

8. Sample Size for the Training Set

• The document does not specify the sample size for the training set.
• This document is a 510(k) summary for premarket notification, focusing on the validation of the device for its intended use. Information regarding the development and training of the assay (e.g., specific molecular sequences, probe design) is generally proprietary and not included in this type of submission. The focus is on the performance of the final, locked version of the device.

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

• The document does not specify how the ground truth for any potential training set was established, nor explicitly mention a distinct training set.
• For an IVD such as this, the "training" (or development and optimization) typically involves extensive analytical studies (e.g., primer design, probe specificity, optimization of reaction conditions, LoD determination, cross-reactivity testing) rather than machine learning-style "training data" with a "ground truth" in the same sense as an AI imaging algorithm. The core of the assay relies on well-established molecular biology principles and target identification.

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The Xpert® CT/NG test, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro real-time PCR test for the automated detection and differentiation of genomic DNA from Chlamvdia trachomatis (CT) and/or Neisseria gonorrhoeae (NG) to aid in the diagnosis of chlamydial and gonorrheal disease in the urogenital tract and extragenital sites (pharynx and rectum). The assay may be used to test the following specimens from asymptomatic and symptomatic individuals: female and male urine, patient-collected vaginal swabs (collected in a clinical setting), clinician-collected endocervical swabs, and female and male pharyngeal and rectal swabs.

The Xpert CT/NG test is an automated in vitro diagnostic test for qualitative detection and differentiation of DNA from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (NG). The test is performed on the Cepheid GeneXpert Instrument Systems. The Xpert CT/NG test on the GeneXpert Instrument System automates and integrates sample purification, nucleic acid amplification and detection of the target sequences in simple or complex samples using real-time PCR. The system consists of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The system requires the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, crosscontamination between samples is minimized.

The Xpert CT/NG test includes reagents for the detection and differentiation of CT and NG. A Sample Processing Control (SPC), a Sample Adequacy Control (SAC), and a Probe Check Control (PCC) are also included. The SPC is present to control for adequate processing of the target bacteria and to monitor the presence of inhibitors in the PCR reaction. The SAC reagents detect the presence of a single copy human gene and monitor whether the specimen contains human cells. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems, the GeneXpert Infinity-48 System. GeneXpert Infinity-48s. and the GeneXpert Infinity-80 System, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

The ancillary specimen collection kits for use with the Xpert CT/NG test are the Xpert Vaginal/Endocervical Specimen Collection Kit, Xpert Swab Specimen Collection kit and the Xpert Urine Specimen Collection kit.

This looks like a 510(k) summary for the Cepheid Xpert CT/NG test. The document provides information on analytical and clinical performance studies.

Here's a breakdown of the requested information based on the provided text:

1. Table of acceptance criteria and the reported device performance:

The document doesn't explicitly state "acceptance criteria" with numerical targets for clinical performance (sensitivity, specificity) in the same way it defines LoD for analytical sensitivity. However, based on the presentation and context, the reported sensitivities and specificities from the clinical performance study appear to be the performance demonstrated to justify substantial equivalence.

Since the submission is for a 510(k), the implied "acceptance criteria" for clinical performance is that the device's performance is substantially equivalent to a predicate device. The document states "the Xpert CT/NG test performance is equivalent to the predicate" in the conclusions.

Here's a table summarizing the reported clinical performance:

Analytical Sensitivity (LoD) - (Example of explicit acceptance criteria and performance)

• Acceptance Criteria for LoD: The lowest concentration at which 95% of at least 20 replicates are positive.
• Reported Device Performance (LoD - Pharyngeal Swab Matrix):
  • CT ATCC vr885 serovar D: 161 EB/mL
  • CT ATCC vr879 serovar H: 225 EB/mL
  • NG ATCC 19424: 7.1 CFU/mL
  • NG ATCC 49226: 6.4 CFU/mL
• Reported Device Performance (LoD - Rectal Swab Matrix):
  • CT ATCC vr885 serovar D: 88 EB/mL
  • CT ATCC vr879 serovar H: 161 EB/mL
  • NG ATCC 19424: 4.9 CFU/mL
  • NG ATCC 49226: 5.3 CFU/mL

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

• Sample Size for Test Set:
  • Pharyngeal Swabs: 2577 specimens (eligible for inclusion in data analyses)
  • Rectal Swabs: 2538 specimens (eligible for inclusion in data analyses)
• Data Provenance:
  • Country of Origin: United States ("multi-site prospective investigational study at 9 US institutions").
  • Retrospective or Prospective: Prospective ("multi-site prospective investigational 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 or their qualifications for establishing the ground truth. It states that the ground truth was established using an "anatomic site infected status (ASIS) algorithm based on combined results from two NAAT tests, with a tiebreaker NAAT test if applicable." This suggests a reliance on laboratory test results rather than human expert interpretation of raw data.

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

The adjudication method used for establishing the ASIS (ground truth) was a form of 2+1 rule:

• The anatomic site was considered infected if both primary reference NAAT test results were positive.
• The anatomic site was considered not infected if both primary reference NAAT test results were negative.
• If there was discordance between the two primary reference tests, an additional (tiebreaker) NAAT was performed. In this case, agreement of 2 out of 3 (two primary reference tests + tiebreaker) determined the ASIS result.

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 was not done. This study is an analytical and clinical performance evaluation of an in vitro diagnostic (IVD) nucleic acid amplification test (NAAT), not an AI-assisted diagnostic imaging or interpretation device that would involve human readers.

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

Yes, a standalone performance study was done. The study directly compares the results of the Xpert CT/NG test (algorithm only) to the established ASIS ground truth for each specimen. There is no human-in-the-loop component mentioned for the interpretation of the Xpert CT/NG results themselves.

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

The ground truth used was Anatomic Site Infected Status (ASIS), which was determined by a composite reference method involving multiple nucleic acid amplification tests (NAATs). This is a type of laboratory-based diagnostic ground truth, not pathology, expert consensus on images, or long-term outcomes data.

8. The sample size for the training set:

The document does not provide information on the sample size for a training set. This is typical for traditional in vitro diagnostic (IVD) submissions like this one, as the assay development and validation generally don't utilize "training sets" in the same way machine learning algorithms do. The studies described are for validation of the final device.

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

Not applicable, as a distinct training set and its ground truth establishment are not discussed in this document, which focuses on the validation of the Xpert CT/NG assay.

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The BD ProbeTect™ Neisseria gonorrhoeae (GC) Q* Amplified DNA Assay, when tested with the BD Viper™ System in extracted mode, uses Strand Displacement Amplification (SDA) technology for the direct, qualitative detection of Neisseria gonorrhoeae DNA in cliniciancollected female endocervical and male urethral swabs, patient-collected vaginal swab specimens (in a clinical setting), and female and male urine specimens. The assay is indicated for use with asymptomatic and symptomatic female and male individuals to aid in the diagnosis of gonococcal urogenital disease.

The BD Viper System, when used with the BD ProbeTec amplified nucleic assay(s), is intended for the in vitro detection of targeted organisms from specimens as identified in the assay-specific reagent package insert(s).

The BD ProbeTec GC Q* Amplified DNA Assay is based on the simultaneous amplification and detection of target DNA using amplification primers and a fluorescently-labeled detector probe. The reagents for SDA are dried in two separate disposable microwells: the Priming Microwell contains the amplification primers, fluorescently-labeled detector probe, nucleotides and other reagents necessary for amplification. while the Amplification Microwell contains the two enzymes (a DNA polymerase and a restriction endonuclease) that are required for SDA. The BD Viper "M System pipettes a portion of the purified DNA solution from each Extraction Tube into a Priming Microwell to rehydrate the contents. After a brief incubation, the reaction mixture is transferred to a corresponding, pre-warmed Amplification Microwell which is sealed to prevent contamination and then incubated in one of the two thermally-controlled fluorescent readers. The presence or absence of N. gonorrhoeae DNA is determined by calculating the peak fluorescence (Maximum Relative Fluorescent Units (MaxRFU)) over the course of the amplification process and by comparing this measurement to a predetermined threshold value.

In addition to the fluorescent probe used to detect amplified N. gonorrhoeae target DNA, a second labeled oligonucleotide is incorporated in each reaction. The Extraction Control (EC) oligonucleotide is labeled with a different dye than that used for detection of the N. gonorrhoeae -specific target and is used to confirm the validity of the extraction process. The EC is dried in the Extraction Tubes and is rehydrated upon addition of the specimen and extraction reagents. At the end of the extraction process, the EC fluorescence is monitored by the BD Viper System and an automated algorithm is applied to both the EC and N. gonorrhoeae -specific signals to report results as positive, negative, or EC failure.

Here's an analysis of the acceptance criteria and study detailed in the provided text for the BD ProbeTec™ Neisseria gonorrhoeae (GC) Q* Amplified DNA Assay:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical performance results, where high sensitivity and specificity are demonstrated across various specimen types and patient asymptomatic/symptomatic statuses. While explicit numerical acceptance criteria (e.g., "sensitivity must be >95%") are not explicitly stated as 'acceptance criteria' in the document, we can infer the achieved performance as the criteria met for substantial equivalence.

A = Asymptomatic, S = Symptomatic

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

• Sample Size for Test Set:
  • Female subjects: 994 (eligible)
  • Male subjects: 774 (eligible)
  • Total BD ProbeTec GC Q* assay results used for performance calculations: 6284
• Data Provenance:
  • Country of Origin: North America (seven geographically diverse clinical sites).
  • Retrospective or Prospective: Prospective. The study involved collecting various specimens (endocervical swabs, male urethral swabs, vaginal swabs, and urine) from symptomatic and asymptomatic subjects.

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

Explicit details on the number of experts or their qualifications (e.g., radiologist with 10 years of experience) for establishing ground truth are not provided. The ground truth was established using an algorithm based on results from two commercially available Nucleic Acid Amplification Tests (NAATs) (the BD ProbeTec ET GC/AC assay and another commercially available NAAT). This method relies on the established performance of these reference NAATs rather than individual expert review of each case.

4. Adjudication Method for the Test Set

The adjudication method used to establish the "patient infected status" (PIS) for the ground truth was a 2-out-of-N rule (where N refers to the number of reference tests performed).

• For Female subjects (endocervical swab and urine specimens): Subjects were considered infected if "two of the four endocervical swab and urine specimens (or two of the three or four urethral swab and urine specimens) tested positive in the BD ProbeTec ET GC/AC assay and the other reference NAAT (one specimen testing positive in each NAAT)."
• For Male subjects (urethral swab and urine specimens): Similar algorithm applied.
• Non-infected: Subjects were considered non-infected if "less than two reference NAAT results were positive."

This implies specimens were tested by at least two reference NAATs (BD ProbeTec ET GC/AC and another commercial NAAT).

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study evaluates the performance of an assay (device) directly against a ground truth, not the comparative improvement of human readers with or without AI assistance. The device is for direct detection of N. gonorrhoeae DNA, not for aiding human interpretation of images or other data.

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

Yes, a standalone study was performed. The BD ProbeTec GC Q* Amplified DNA Assay is a fully automated system that detects N. gonorrhoeae DNA and reports results as positive, negative, or EC failure. The performance data presented (sensitivity and specificity) is based on the algorithm's direct output compared to the established patient infected status, without human intervention in result interpretation. The "BD Viper™ System and an automated algorithm is applied to both the EC and N. gonorrhoeae -specific signals to report results."

7. Type of Ground Truth Used

The ground truth used was a composite reference standard or patient infected status (PIS) algorithm, derived from the results of two different commercially available Nucleic Acid Amplification Tests (NAATs): the BD ProbeTec ET GC/AC assay and another commercially available NAAT. It is based on the concordance of these reference molecular tests, rather than pathology (histology), expert consensus of clinical symptoms, or long-term outcomes data.

8. Sample Size for the Training Set

The document does not explicitly state a separate training set size. The clinical performance characteristics are reported from a single clinical study dataset. In diagnostic assay development, initial algorithm development and optimization might occur using internal datasets, but this document describes the validation study for regulatory submission. It's common in IVD submissions for the entire clinical study population to be used for performance evaluation against the ground truth without a separate "training set" as understood in machine learning (where the algorithm learns from the data). If an algorithm's parameters were tuned on this specific dataset, it would be a form of internal validation rather than a truly independent test set. However, the text focuses on the device's performance measurement, implying that the algorithm's parameters were fixed by the time this validation study was conducted.

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

As noted above, a separate "training set" is not explicitly mentioned. For the test set, the ground truth was established by a patient infected status (PIS) algorithm based on the concordance of two distinct commercially available NAATs (BD ProbeTec ET GC/AC assay and another commercially available NAAT) on various patient specimens.

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