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The Solana® RSV+hMPV Assay is a qualitative in vitro diagnostic test for the detection and differentiation of RSV and hMPV viral RNA in nasal and nasopharyngeal swabs from patients with signs and symptoms of respiratory infection. This test is intended for use as an aid in the differential diagnosis of RSV and hMPV viral infections in humans in conjunction with clinical and epidemiological risk factors. This test is not intended to differentiate the two subtypes of RSV or the four genetic sub-lineages of hMPV.

Negative results do not preclude RSV infection and/or hMPV infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Conversely, positive results do not rule-out bacterial infection or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing and clinical presentation must be considered in order to obtain the final diagnosis of respiratory viral infection.

The Solana RSV+hMPV Assay amplifies and detects viral RNA present in viral transport media containing nasopharyngeal or nasal swab specimens obtained from symptomatic patients.

The assay consists of two major steps: 1) specimen preparation, and 2) amplification and detection of target sequences specific to RSV and/or hMPV using isothermal Reverse Transcriptase - Helicase-Dependent Amplification (RT-HDA) in the presence of targetspecific fluorescence probes.

A patient nasal or nasopharyngeal swab specimen in viral transport media is transferred to a Process Buffer Tube, subjected to heat treatment at 95°C for 5 minutes and mixed. The processed sample is transferred to a Reaction Tube. The Reaction Tube contains lyophilized RT-HDA reagents, dNTPs, primers and probes. Once rehydrated with the processed sample, the Reaction Tube is placed in Solana for amplification and detection of RSV and hMPV specific target sequences. In Solana, the target sequences are amplified by RSV and hMPV specific primers and detected by RSV and hMPV specific fluorescence probes, respectively. A process control (PRC) is included in the Process Buffer Tube to monitor sample processing, inhibitory substances in clinical samples, reagent failure or device failure. The PRC target is amplified by RSV and hMPV specific primers and detected by a PRC specific fluorescence probe.

The two target probes and PRC probe are labeled with a quencher on one end and a fluorophore on the other end. In addition, the two target probes and PRC probe incorporate one or more RNA bases. Upon annealing to RSV, hMPV or PRC amplicons, the fluorescence probes are cleaved by RNaseH2 and the fluorescence signal increases due to physical separation of fluorophore from quencher. Solana measures and interprets the fluorescent signal, using on-board method-specific algorithms. Solana then reports the test results to the user on its display screen, and it can print out the results via an attached printer.

Here's an analysis of the provided text, focusing on the acceptance criteria and study that proves the device meets them:

The document describes the Solana RSV+hMPV Assay, a qualitative in vitro diagnostic test for the detection and differentiation of RSV and hMPV viral RNA. The evaluation of this device primarily focuses on its analytical performance (reproducibility, detection limit, analytical specificity) and clinical performance (comparison to an FDA-cleared molecular assay).

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the performance benchmarks achieved in the analytical and clinical studies. While explicit numerical acceptance criteria (e.g., "PPA must be >90%") are not stated as a formalized table, the performance results represent the presented evidence of meeting these criteria.

Here's a table summarizing the reported device performance, which serves as evidence of meeting the implicit acceptance criteria:

• High Negative (0.2x LOD): 71.1% Overall Agreement (95% CI: 56.6 to 82.3)
• Low Positive (1x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
• Moderate Positive (2x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
  RSV B strain Wash/18537/62 (VR-1580):
• High Negative (0.2x LOD): 48.9% Overall Agreement (95% CI: 30.9 to 58.8)
• Low Positive (1x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
• Moderate Positive (2x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
  hMPV 20 Type A2 (IA14-2003 G gene):
• High Negative (0.2x LOD): 77.8% Overall Agreement (95% CI: 63.7 to 87.5)
• Low Positive (1x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
• Moderate Positive (2x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
  hMPV 4 Type B2 (Peru1-2002, B2):
• High Negative (0.2x LOD): 60.0% Overall Agreement (95% CI: 45.5 to 73.0)
• Low Positive (1x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
• Moderate Positive (2x LOD): 100% Overall Agreement (95% CI: 92.1 to 100)
  Negative control and positive control samples showed 100% agreement. The results suggest no significant differences between users, sites, or days. |
  | Analytical Sensitivity (Limit of Detection - LOD): Ability to detect low concentrations of target viruses. | RSV:
• RSV A, A2 (VR-1540): 7.9x10^3 TCID50/mL
• RSV B, Wash/18537/62 (VR-1580): 3.9x10^2 TCID50/mL
  hMPV:
• hMPV 16 Type A1, IA10-2003: 3.7x10^2 TCID50/mL
• hMPV 20 Type A2 IA14-2003 G gene: 1.2x10^4 TCID50/mL
• hMPV 5 Type B1, Peru3-2003: 3.8x10^3 TCID50/mL
• hMPV 4 Type B2, Peru1-2002: 2.3x10^3 TCID50/mL |
  | Analytical Specificity (Cross-Reactivity): No false positives due to other common respiratory microorganisms or interfering substances. | Cross-Reactivity: No cross-reactivity observed with 46 microorganisms (25 bacteria, 1 yeast, 20 viruses) at tested concentrations (10^6 CFU/mL or higher for bacteria/yeast; 10^5 pfu/mL or TCID50/mL or higher for viruses).
  Interference: No evidence of interference from 20 potentially interfering substances (e.g., mucin, blood, nasal sprays, common medications) when tested with RSV and hMPV at 3x LOD concentrations. |
  | Analytical Reactivity (Inclusivity): Ability to detect different strains of the target viruses. | All four additional tested RSV strains (2 RSV A, 2 RSV B) and four additional hMPV strains (1 each of A1, A2, B1, B2) were inclusively detected at concentrations near their LOD. |
  | Clinical Sensitivity/Specificity (Agreement with Comparator): High agreement with an FDA-cleared molecular comparator assay. | RSV (Compared to FDA-cleared molecular assay):
• Positive Percent Agreement (PPA): 95.5% (95% CI: 91.0 to 97.8) for all specimens (Fresh & Frozen)
• Negative Percent Agreement (NPA): 99.9% (95% CI: 91.0 to 97.8) for all specimens (Fresh & Frozen)
  Note: Discrepant results adjudicated using an alternative FDA-cleared molecular device.
  hMPV (Compared to FDA-cleared molecular assay):
• Positive Percent Agreement (PPA): 95.6% (95% CI: 89.1 to 98.3) for all specimens (Fresh & Frozen)
• Negative Percent Agreement (NPA): 99.8% (95% CI: 99.6 to 99.9) for all specimens (Fresh & Frozen)
  Note: Discrepant results adjudicated using an alternative FDA-cleared molecular device. |

Study Details:

The study described is a premarket submission for an in vitro diagnostic device, primarily focused on analytical and clinical performance.

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

   • Analytical Reproducibility Test Set:
     • Four-sample panel (3 levels of combined RSV and hMPV, and a negative sample).
     • Panel run by 2 operators at each of 3 testing sites for 5 non-consecutive days.
     • Each sample tested in 3 replicates.
     • Total of 45 results per level for each virus strain (2 operators * 5 days * 3 sites * 3 replicates).
     • Provenance: In-house laboratory (Athens, Quidel Corp), Lab Alliance, and Medical Center of Wisconsin (US based). The study appears to be prospective for this analytical validation.
   • Analytical Sensitivity (LOD) Test Set:
     • Quantified cultures of 6 virus strains (1 RSV A, 1 RSV B, 1 hMPV A1, 1 hMPV A2, 1 hMPV B1, 1 hMPV B2) serially diluted in negative nasopharyngeal matrix.
     • Each dilution run as 20 replicates.
     • Provenance: This is an analytical study using spiked samples, likely conducted internally or by a contracted lab.
   • Analytical Specificity (Cross-Reactivity/Interference) Test Set:
     • 46 microorganisms (25 bacteria, 1 yeast, 20 viruses) diluted in negative nasal matrix.
     • 20 potentially interfering substances evaluated.
     • Provenance: Analytical study using spiked samples.
   • Analytical Reactivity (Inclusivity) Test Set:
     • 4 additional RSV strains and 4 additional hMPV strains.
     • Provenance: Analytical study using spiked samples.
   • Clinical Studies Test Set:
     • Sample Size: 2064 prospectively collected specimens (nasal or nasopharyngeal swabs) initially included.
     • After exclusions (4 protocol deviations, 14 invalid Solana tests), 2046 specimens were included in the final analysis.
     • Provenance: Collected between January and May 2017 at six sites across the United States. A mix of fresh (769) and frozen (1291) specimens. This is a prospective clinical study.

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

   • For this in vitro diagnostic device, "ground truth" is established through laboratory methods, not human expert interpretation of images.
   • For the analytical studies, the "ground truth" is defined by the known concentrations and identities of the spiked viral material or microorganisms.
   • For the clinical study, the "ground truth" is established by "an FDA-cleared RSV+hMPV molecular assay" (the comparator method). This is a laboratory-based gold standard, not a consensus of human expert readers.
   • There is no mention of experts (e.g., radiologists) in the context of establishing ground truth for this type of diagnostic assay.

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

   • For the clinical study, there was an adjudication for discordant results between the Solana assay and the FDA-cleared molecular comparator.
   • Method: For discordant specimens (Solana Positive/Comparator Negative or Solana Negative/Comparator Positive), an "alternative FDA-cleared molecular device" was used for re-testing. This acts as a tie-breaker or confirmatory test.
   • For RSV: 1 Solana+/Comparator- specimen was positive by an alternative device. 6 of 7 Solana-/Comparator+ specimens were positive by an alternative device.
   • For hMPV: All 3 Solana+/Comparator- specimens were negative by an alternative device. All 4 Solana-/Comparator+ specimens were positive by an alternative device.

4. 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. This is not an imaging-based AI device. It is a molecular diagnostic assay for detecting viral RNA. Therefore, an MRMC study and evaluation of human reader improvement with AI assistance are not applicable. The device's performance is standalone or compared to another laboratory diagnostic method.

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

   • Yes, the performance characteristics (analytical and clinical) presented are for the Solana RSV+hMPV Assay system (device + instrument) operating qualitatively.
   • The "Solana instrument measures and interprets the fluorescent signal, using on-board method-specific algorithms" and "reports the test results to the user on its display screen." This indicates that the results are generated by the algorithm/instrument system itself without real-time human interpretation affecting the qualitative positive/negative result. Humans perform the sample preparation and loading, and read the final result from the instrument.

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

   • Analytical Studies: "Ground truth" was established by spiking known quantities of specific viral strains/microorganisms into negative matrix, representing a controlled laboratory standard.
   • Clinical Studies: "Ground truth" was established by an FDA-cleared RSV+hMPV molecular assay (the comparator device), and for discordant results, a different "alternative FDA-cleared molecular device" was used as a confirmatory ground truth. This is a reference standard based on a previously validated laboratory test.

7. The sample size for the training set:

   • The document describes performance studies (analytical and clinical validation) for a finished device. It does not specify a separate "training set" in the context of machine learning model development. This is typical for traditional in vitro diagnostic device submissions, where the focus is on validation studies rather than the development lifecycle of an "AI" algorithm. The "Solana instrument" has "on-board method-specific algorithms," but how these algorithms were developed or "trained" (if indeed they involve learning from data in a modern ML sense) is not described in this document. Often, such "algorithms" in traditional IVDs are rule-based or statistical models rather than deep learning models.

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

   • As no explicit "training set" (in the machine learning sense) is mentioned, there is no information on how its ground truth would have been established. The document focuses on the validation of the device's performance against established laboratory standards and a clinical comparator.

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