(90 days)
The QIAstat-Dx Meningitis/Encephalitis (ME) Panel is a qualitative multiplexed nucleic acid real-time PCR based in vitro diagnostic test intended for use with the QIAstat-Dx Analyzer 1.0. The QIAstat-Dx ME Panel is capable of simultaneous detection and identification of multiple bacterial, viral, and yeast nucleic acids from cerebrospinal fluid (CSF) specimens obtained via lumbar puncture from individuals with signs and/or symptoms of meningitis and/or encephalitis.
The following organisms are identified using the OlAstat-Dx ME Panel: Enterovirus, Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis (encapsulated), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and Cryptococcus neoformans/gattii*.
The QIAstat-Dx ME Panel is indicated as an aid in the diagnosis of meningitis and/or encephalitis and results must be used in conjunction with other clinical, endemiological, and laboratory data. Results from the OlAstat-Dx ME Panel are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with organisms not included in the QIAstat-Dx ME Panel. The agents detected may not be the definite cause of the disease. Negative results do not preclude central nervous system infection.
Not all agents of central nervous system infection are detected by this test and sensitivity in clinical use may differ from that described in the instructions for use.
The QIAstat-Dx ME Panel is not intended for testing specimens collected from indwelling central nervous system medical devices.
The QIAstat-Dx ME Panel is intended to be used in conjunction with standard of care culture for organism recovery, serotyping, and antimicrobial susceptibility testing.
*Cryptococcus neoformans and Cryptococcus gattii are not differentiated.
The QIAstat-Dx® Meningitis/Encephalitis (ME) Panel is part of the QIAstat-Dx Meningitis/Encephalitis system and works with the OIAstat-Dx Analyzer 1.0.
The QIAstat-Dx ME Panel is intended to be used with cerebrospinal fluid (CSF) specimens.
Once the cartridge has been inserted into the instrument, the test starts automatically and runs for approximately 80 minutes. When the test is finished, the cartridge is removed by the user and discarded. The OIAstat-Dx Analyzer 1.0 automatically interprets test results and displays a summary on the analyzer display screen. The results can be printed using a connected printer, if needed. The detected analytes are displayed in red. For other analytes tested, they are displayed in green if not detected or in gray if not applicable or invalid. The analyzer will report if an error occurs during processing, in which case the test will fail and no results will be provided (screen will show "FAIL").
QIAstat-Dx consists of single-test cartridges with pre-packaged reagents including both wet and dry chemistry necessary to perform the sample preparation, nucleic acid amplification and detection to be used in conjunction with the QIAstat-Dx Analyzer 1.0. All sample preparation and assay steps are performed within the cartridge, so the user does not need to manipulate any reagent during the test. This eliminates exposure of the user or the Analyzer to chemicals contained in the cartridge during the test and up to the disposal of used cartridges.
Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer the sample and fluids via the Transfer Chamber (TC) to their intended destinations. Following the introduction of the sample from a disposable transfer pipette, the following assay steps occur automatically and sequentially:
- Resuspension of air-dried internal control and Proteinase K (ProtK) enzyme using . provided buffer and mixing with the liquid sample (IC Cavity and ProtK Cavity);
- Cell lysis using mechanical (rotation) and chemical (chaotropic and isotonic) ● means (lysis chamber):
- Membrane-based nucleic acid purification from Lysate by: ●
- Mixing lysate with binding buffer and capturing on the membrane -(purification chamber);
- First washing of membrane to remove bound proteins (purification chamber and waste chamber);
- Second washing of membrane to leave only bound nucleic acids -(purification chamber and waste chamber);
- Rinsing of Transfer Chamber (TC) using the rinsing buffer before introduction of the eluate (Transfer Chamber);
- Drying of membrane with bound nucleic acids with an air flow generated by a high flow vacuum pump (purification chamber); and
- Elution of nucleic acids with elution buffer (purification chamber and TC);
- Mixing of the purified nucleic acid (eluate) with lyophilized "Master Mix" reagents ● (Dry chemistry container (DCC) and TC);
- Sequential transfer of defined aliquots of mixed eluate/Master Mix from the ● Transfer Chamber to each of eight Reaction Chambers containing the specified, airdried primers and probes;
- Within each Reaction Chamber, real-time, multiplex PCR ("rtPCR") testing is ● performed. Increase in fluorescence (indicative of detection of each target analyte) is detected directly within each Reaction Chamber; and
- The detected signal per fluorescent marker per Reaction Chamber is then used by the system software to generate the assay result.
The provided document is a 510(k) Summary for the QIAGEN GmbH QIAstat-Dx Meningitis/Encephalitis (ME) Panel. Here's a breakdown of the acceptance criteria and study information:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state formal acceptance criteria (i.e., predefined thresholds for sensitivity and specificity). However, it reports sensitivity (Positive Percent Agreement - PPA) and specificity (Negative Percent Agreement - NPA) values from its clinical performance study. The reported performance is implicitly the "met acceptance criteria" as the device received 510(k) clearance.
Here's a summary of the clinical performance for each pathogen from the prospective clinical study (Table 16), which represents the primary evidence for diagnostic performance:
| Pathogen | Sample Category | PPA (TP/TP+FN) (%) | 95% CI (PPA) | NPA (TN/TN+FP) (%) | 95% CI (NPA) |
|---|---|---|---|---|---|
| Escherichia coli K1 | Overall | 50.0 (2/4) | 15.0-85.0 | 100.0 (1520/1520) | 99.7-100.0 |
| Haemophilus influenzae | Overall | 80.0 (4/5) | 37.6-96.4 | 99.8 (1516/1519) | 99.4-99.9 |
| Listeria monocytogenes | Overall | 80.0 (4/5) | 37.6-96.4 | 100.0 (1519/1519) | 99.7-100.0 |
| Neisseria meningitidis (encapsulated) | Overall | 100.0 (1/1) | 20.7-100.0 | 99.9 (1522/1523) | 99.6-100.0 |
| Streptococcus agalactiae | Overall | 100.0 (3/3) | 43.9-100.0 | 100.0 (1521/1521) | 99.7-100.0 |
| Streptococcus pneumoniae | Overall | 100.0 (8/8) | 67.6-100.0 | 99.6 (1360/1365) | 99.1-99.8 |
| Streptococcus pyogenes | Overall | N/A (0/0) | N/A | 100.0 (1291/1291) | 99.7-100.0 |
| Enterovirus (EV) | Overall | 91.7 (22/24) | 74.2-97.7 | 99.9 (1499/1500) | 99.6-100.0 |
| Cryptococcus gattii / Cryptococcus neoformans | Overall | 57.1 (4/7) | 25.0-84.2 | 99.9 (1515/1517) | 99.5-100.0 |
Additionally, for contaminants that were confirmed by culture (fungal and bacterial), in table 19 and 20:
| Pathogen | Sample Category | Sensitivity (compared to culture) (%) | 95% CI (Sensitivity) | Specificity (compared to culture) (%) | 95% CI (Specificity) |
|---|---|---|---|---|---|
| Bacteria | |||||
| Escherichia coli Kl | Archived | 100.0 (1/1) | 20.7-100.0 | 90.9 (10/11) | 62.3-98.4 |
| Prospective Fresh | 50.0 (1/2) | 9.5-90.5 | 100.0 (760/760) | 99.5-100.0 | |
| Haemophilus influenzae | Archived | 100.0 (1/1) | 20.7-100.0 | 90.9 (10/11) | 62.3-98.4 |
| Prospective Frozen | 100.0 (3/3) | 43.9-100.0 | 99.7 (339/340) | 98.4-99.9 | |
| Listeria monocytogenes | Prospective Fresh | 100.0 (1/1) | 20.7-100.0 | 100.0 (761/761) | 99.5-100.0 |
| Prospective Frozen | 66.7 (2/3) | 20.8-93.9 | 100.0 (340/340) | 98.9-100.0 | |
| Neisseria meningitidis (encapsulated) | Archived | 100.0 (2/2) | 34.2-100.0 | 90.0 (9/10) | 59.6-98.2 |
| Streptococcus agalactiae | Prospective Fresh | 100.0 (1/1) | 20.7-100.0 | 99.9 (760/761) | 99.3-99.9 |
| Prospective Frozen | 100.0 (1/1) | 20.7-100.0 | 100.0 (342/342) | 98.9-100.0 | |
| Streptococcus pneumoniae | Prospective Frozen | 100.0 (3/3) | 43.9-100.0 | 99.7 (339/340) | 98.4-99.9 |
| Fungi / Yeast | |||||
| Cryptococcus gattii / Cryptococcus neoformans | Archived | 100.0 (2/2) | 34.2-100.0 | 100.0 (1/1) | 20.7-100.0 |
| Prospective Fresh | 100.0 (1/1) | 20.7-100.0 | 98.5 (129/131) | 94.6-99.6 |
2. Sample Sizes Used for the Test Set and Data Provenance
- Test Set (Clinical Performance Study):
- Prospective Specimens: 1524 evaluable specimens.
- 552 (36.2%) were frozen before testing.
- 972 (63.8%) were tested fresh.
- Archived Specimens: 41 evaluable archived specimens (from an initial 195 collected).
- Contrived Specimens: Not specified as a "test set" in the context of clinical performance, but used to supplement for rare analytes.
- Ranges from 79 to 96 samples per pathogen, tested at 2xLoD and 5xLoD (e.g., Cryptococcus neoformans/gattii had 79 samples). These were likely individual spiked samples.
- Prospective Specimens: 1524 evaluable specimens.
- Data Provenance:
- Country of Origin: 13 geographically diverse clinical sites across 4 countries (10 U.S. sites and 3 European sites).
- Retrospective/Prospective: The study included both prospective (March 2022 to March 2023) and retrospective (archived) specimens.
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 of "experts" used to establish ground truth or their specific qualifications (e.g., radiologist with X years of experience).
Instead, the ground truth for the clinical performance study was established using:
- An FDA-cleared molecular comparator method.
- Two validated end point PCRs followed by bidirectional sequencing (BDS) for Streptococcus pneumoniae and Streptococcus pyogenes.
- Standard of Care (SoC) testing, which varied across sites and included bacterial culture, Laboratory Developed PCR tests (LDT), FDA-cleared molecular methods, and Cryptococcus antigen screen and culture.
- Discrepancy investigations were conducted for discordant results, implying a review process, but details on who performed this review are not given.
4. Adjudication Method for the Test Set
The document mentions that discrepancies between the QIAstat-Dx ME Panel and the comparator methods were investigated. This implies an adjudication process was in place to determine the true positive/negative status for discordant results. However, the specific method (e.g., 2+1, 3+1, none) is not explicitly described. The footnotes in Table 16 (Clinical Performance) provide details on how some discordant cases were resolved (e.g., "no organisms were detected with resolution method PCR/BDS," "negative result was confirmed positive with SoC culture and LDT result was positive").
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study comparing human readers with and without AI assistance was not done. This device is an in vitro diagnostic (IVD) test for nucleic acid detection, not an imaging AI device that assists human readers.
6. Standalone (i.e., algorithm only without human-in-the-loop performance) Study
Yes, a standalone performance study was done. The entire clinical performance study (Prospective, Archived, and Contrived Specimens Testing) evaluates the performance of the QIAstat-Dx ME Panel (the algorithm/device) directly against comparator methods (other molecular tests, culture, PCR/BDS), without a human-in-the-loop component. The device generates results automatically, and its accuracy is assessed based on these outputs.
7. Type of Ground Truth Used
The ground truth for the clinical performance studies was established using a combination of:
- FDA-cleared molecular comparator method.
- Validated end point PCRs followed by bidirectional sequencing (BDS).
- Standard of Care (SoC) culture (for bacterial and fungal analytes).
- Laboratory-Developed PCR tests (LDT).
- Discrepancy investigations where discordant results were resolved using additional testing.
For the contrived specimens, the ground truth was known by design, as the samples were intentionally spiked with quantified strains.
8. Sample Size for the Training Set
The document does not provide details about a specific "training set" sample size for the QIAstat-Dx ME Panel. As an IVD based on real-time PCR, its "training" is typically in the form of analytical validation and optimization during its development, rather than machine learning model training with a distinct training dataset. The studies described are primarily for clinical performance validation, demonstrating the device's accuracy in a real-world setting.
9. How the Ground Truth for the Training Set Was Established
Since a dedicated "training set" for a machine learning model is not described, the concept of establishing ground truth for it is not applicable here in the conventional sense of AI/ML. The analytical validation studies (Limit of Detection, Analytical Reactivity/Inclusivity, Analytical Specificity/Exclusivity, etc.) involved known concentrations and strains of pathogens (e.g., ATCC strains, commercial stocks) in artificial or negative clinical CSF. The "ground truth" for these analytical studies was based on the known composition and concentration of these prepared samples.
§ 866.3970 Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.
(a)
Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.
(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.
(10) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.