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QIAstat-Dx Respiratory Panel Plus:

The QIAstat-Dx Respiratory Panel Plus is a multiplexed nucleic acid test intended for use with the QIAstat-Dx system for the simultaneous in vitro qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals with clinical signs and symptoms of respiratory tract infections, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

The following organism types and subtypes are identified using the QIAstat-Dx Respiratory Panel Plus: Adenovirus, Human Coronavirus 229E, Human Coronavirus HKU1, Human Coronavirus NL63, Human Coronavirus OC43, Human Metapneumovirus, Influenza A, Influenza A H1, Influenza A H1N1 pdm09, Influenza A H3, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Parainfluenza Virus 4, Respiratory Syncytial Virus, Human Rhinovirus/Enterovirus (not differentiated), SARS-CoV-2, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae.

Nucleic acids from viral and bacterial organisms identified by this test are generally detectable in NPS specimens during the acute phase of infection. Detecting and identifying specific viral and bacterial nucleic acids from individuals presenting with signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection, if used in conjunction with other clinical, epidemiological and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Negative results in the presence of a respiratory illness may be due to infection with pathogens that are not detected by the test, or due to lower respiratory tract infection that is not detected by a NPS specimen.

Conversely, positive results are indicative of the presence of the identified microorganism, but do not rule out co-infection with other pathogens not detected by the QIAstat-Dx Respiratory Panel Plus. The agent(s) detected by the QIAstat-Dx Respiratory Panel Plus may not be the definite cause of disease.

The use of additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

QIAstat-Dx Respiratory Panel Mini:

The QIAstat-Dx Respiratory Panel Mini is a multiplexed nucleic acid test intended for use with the QIAstat-Dx system for the simultaneous in vitro qualitative detection and identification of multiple respiratory viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals with clinical signs and symptoms of respiratory tract infections, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

The following viruses are identified using the QIAstat-Dx Respiratory Panel Mini: Influenza A, Influenza B, Respiratory Syncytial Virus, Human Rhinovirus, and SARS-CoV-2.

Nucleic acids from viral organisms identified by this test are generally detectable in NPS specimens during the acute phase of infection. Detecting and identifying specific viral nucleic acids from individuals presenting with signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection, if used in conjunction with other clinical, epidemiological and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Negative results in the presence of a respiratory illness may be due to infection with pathogens that are not detected by the test or due to lower respiratory tract infection that is not detected by a NPS specimen.

Conversely, positive results are indicative of the presence of the identified microorganism, but do not rule out co-infection with other pathogens not detected by the QIAstat-Dx Respiratory Panel Mini. The agent(s) detected by the QIAstat-Dx Respiratory Panel Mini may not be the definite cause of disease.

The use of additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

The QIAstat-Dx Respiratory Panel Plus and the QIAstat-Dx Respiratory Panel Mini are multiplexed nucleic acid tests which are designed for use with the QIAstat-Dx system (currently QIAstat-Dx Analyzer 1.0 and QIAstat-Dx Analyzer 2.0). The device modification is to add the QIAstat-Dx Rise as an additional instrument for use with the QIAstat-Dx Respiratory Panel Plus and the QIAstat-Dx Respiratory Panel Mini ("QIAstat-Dx Respiratory Panels"). The QIAstat-Dx Rise is a higher throughput platform, incorporating up to eight QIAstat-Dx Analytical Modules (AM) on a small footprint. The instrument allows queuing up to 18 cartridges, which are scheduled for processing and delivered to the appropriate AM by an integrated robotic handler. The AM used with the QIAstat-Dx Rise is the same AM that can be used with the QIAstat-Dx Analyzer 1.0 or 2.0.

The modified QIAstat-Dx Respiratory Panel Plus and QIAstat-Dx Respiratory Panel Mini are identical to the QIAstat-Dx Respiratory Panel Plus (K233100) and the QIAstat-Dx Respiratory Panel Mini (K242353), respectively, with the exception of the Instructions for Use which were updated to include the assay-specific procedure for the QIAstat-Dx Rise.

The QIAstat-Dx Respiratory Panels are intended to be used with one nasopharyngeal swab (NPS) eluted in Universal Transport Media (UTM), which is not provided with the QIAstat-Dx Respiratory Panels.

All the reagents required for the complete execution of the test are pre-loaded and self-contained in a QIAstat-Dx Respiratory Panel cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically-operated microfluidics without any direct contact with the user or the analyzer actuators.

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 Internal Control
• Cell lysis using mechanical and/or chemical means
• Membrane-based nucleic acid purification
• Mixing of the purified nucleic acid with lyophilized master mix reagents
• Transfer of defined aliquots of eluate/master mix to different reaction chambers
• Performance of multiplex real-time RT-PCR testing within each reaction chamber

The QIAstat-Dx Respiratory Panel Assay Definition File (ADF) automatically interprets test results and displays a summary on the instrument display screen. The detected analytes are displayed in red. All other tested but not detected analytes are listed in green. The instrument 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").

The provided text describes a 510(k) premarket notification for the QIAstat-Dx Respiratory Panel Plus and QIAstat-Dx Respiratory Panel Mini, with a modification to include the QIAstat-Dx Rise instrument. The key takeaway from this document is that the FDA determined the device is substantially equivalent to previously cleared devices. Therefore, the "acceptance criteria" discussed here refer to the demonstration of equivalence to a predicate device, rather than specific performance metrics against a clinical ground truth for a new device.

Here's an analysis based on your questions:

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

Since this is a submission for a modification to an already cleared device, the acceptance criteria are not explicitly stated in terms of clinical performance numbers (e.g., sensitivity, specificity). Instead, the acceptance criteria are focused on demonstrating that adding the new instrument (QIAstat-Dx Rise) does not negatively impact the performance, and that the new system is "substantially equivalent" to the predicate devices.

The "reported device performance" is essentially that the studies "successfully demonstrated the equivalent performance."

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document does not specify the sample size for the test set used in the "Equivalence at Low Analyte Concentration," "Carryover," or "Reproducibility" studies. It also does not mention the data provenance (country of origin, retrospective or prospective). These details would typically be found in the actual study reports, which are not included in this FDA clearance letter.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This information is not applicable or provided in this document. For an in vitro diagnostic device like this, ground truth for clinical performance would typically be established by comparing against FDA-cleared or gold standard laboratory methods (e.g., culture, sequencing, or other highly sensitive PCR assays) rather than expert consensus on imaging or clinical findings. Since this submission focuses on establishing equivalence and not initial clinical performance, such details are not expected.

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

This information is not provided and would not typically be part of a 510(k) clearance letter for an IVD device unless specific clinical adjudication was required for complex diagnostic outcomes.

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 not applicable. The QIAstat-Dx Respiratory Panels are automated in vitro diagnostic devices for detecting nucleic acids. They do not involve human readers' interpretation of images or other data in a way that would necessitate an MRMC study or AI assistance.

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

This is an in vitro diagnostic test. It is inherently a "standalone" system in its operation, as the instrument performs the test and provides a result. There is no mention of a human-in-the-loop component beyond loading the sample and reading the final result from the display screen. The device's "algorithm" (i.e., the assay's detection mechanism and interpretation software) operates without human intervention once the run starts.

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

The document does not explicitly state the "ground truth" used for the analytical studies (Equivalence at Low Analyte Concentration, Carryover, Reproducibility). For such studies, the ground truth would be established by controlled laboratory experiments, where samples with known concentrations of analytes are used, and the assay's results are compared against these known inputs. For initial clinical performance, the ground truth would typically be a highly sensitive and specific reference method, but those studies are for the predicate devices, not this modification.

8. The sample size for the training set

This information is not provided. Training sets are typically associated with machine learning or AI models. While instruments like the QIAstat-Dx have underlying algorithms, they are based on established PCR principles and assay design, not a machine learning training paradigm in the way AI image analysis would be.

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

This information is not provided and is not applicable for this type of IVD device in the context of a 510(k) modification for instrument compatibility.

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The QIAstat-Dx GI Panel 2 Mini B is a multiplexed nucleic acid test intended for use with the OIAstat-Dx Analyzer 1.0 for the simultaneous in vitro qualitative detection of nucleic acids from multiple bacteria directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the QIAstat-Dx GI Panel 2 Mini B:

• Campylobacter
• Shigella
• Shiga-like toxin Escherichia coli (STEC)*
• Salmonella
• Yersinia enterocolitica

*Only with Para-Pak C&S, not reported for FecalSwab

Concomitant culture is necessary for organism recovery and further typing of bacterial agents. The QlAstat-Dx GI Panel 2 Mini B is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Postive results do not rule out co-infection with organisms not detected by the QIAstat-Dx GI Panel 2 Mini B. The organisms detected may not be the sole or definitive cause of the disease.

Negative QIAstat-Dx GI Panel 2 Mini B results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The QIAstat-Dx® GI Panel 2 Mini B (Cat. no. 691423) assay is a modified device (reduced version) of the OIAstat-Dx Gastrointestinal Panel 2 (Cat. no. 691421). The OIAstat-Dx GI Panel 2 Mini B is identical to the QIAstat-Dx Gastrointestinal Panel 2 (K220062) but uses an Assay Definition File (ADF) which masks all but five pathogens (targets) from the OIAstat-Dx Gastrointestinal Panel 2. The following bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the OIAstat-Dx GI Panel 2 Mini B: Campvlobacter. Shigella, Shiga-like toxin E. coli (STEC), Salmonella and Yersinia enterocolitica. The QIAstat-Dx GI Panel 2 Mini B is part of the QIAstat-Dx system and works with the OIAstat-Dx Analyzer 1.0. It will be available in a separately labeled kit.

The QIAstat-Dx GI Panel 2 Mini B is intended to be used with stool samples in Para-Pak C&S or FecalSwab transport media.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the QIAstat-Dx assay cartridge is processed by the QIAstat-Dx Analyzer 1.0.

Once the cartridge is inserted into the instrument, the test starts automatically and runs for about 78 minutes. When the test is finished, the cartridge is removed by the user and discarded. The QIAstat-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 grav 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").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx GI Panel 2 Mini B cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer 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:

• Sample Pre-treatment for PCR Inhibitors removal
• Resuspension of Internal Control and Proteinase K
• Cell lysis using mechanical and/or chemical means
• Membrane-based nucleic acid purification
• Rehydration of Master Mix
• Transfer of defined aliquots of eluate/master mix to different reaction chambers
• Performance of multiplex real-time RT-PCR testing within each reaction chamber.

The provided text does not contain detailed acceptance criteria or a study that explicitly proves the device meets those criteria in a format with numerical results and statistical analyses typical for such studies. It states that the performance data for the QIAstat-Dx GI Panel 2 Mini B is equivalent to the predicate device (QIAstat-Dx Gastrointestinal Panel 2, K220062) for the five specific analytes it detects. It also mentions that the "QIAGEN QIAstat-Dx GI Panel 2 Mini B Instructions for Use" should be consulted for performance tables, which are not included in this document.

However, based on the information provided, I can infer the general nature of the acceptance criteria (qualitative detection of specific pathogens) and describe the comparative nature of the "study" (equivalence to a predicate device).

Here's an attempt to structure the information based on your request, with significant caveats that detailed numerical results, sample sizes, expert qualifications, and study methodologies for the actual performance are not present in the provided text.

Acceptance Criteria and Device Performance for QIAstat-Dx GI Panel 2 Mini B

The QIAstat-Dx GI Panel 2 Mini B is a modified version of the predicate device, QIAstat-Dx Gastrointestinal Panel 2 (K220062). The device performance for the QIAstat-Dx GI Panel 2 Mini B is presented as being equivalent to the predicate device for the five target analytes it identifies.

1. Table of Acceptance Criteria and Reported Device Performance

Since specific numerical acceptance criteria and performance metrics (e.g., sensitivity, specificity, PPV, NPV) are not provided in this document, the table below reflects the qualitative nature of the information given. The "acceptance criteria" are inferred from the demonstrated performance equivalence to the predicate device for the detected analytes.

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

The provided document does not specify the sample size used for the test set or the data provenance (e.g., country of origin, retrospective/prospective nature). It simply states that the performance data for the modified device is "equivalent" to the predicate device. To find this information, one would need to refer to the 510(k) submission K220062 for the predicate device and/or the "QIAGEN QIAstat-Dx GI Panel 2 Mini B Instructions for Use."

3. Number of Experts and Qualifications

The document does not mention the number of experts used to establish ground truth or their qualifications. This information would typically be found in the detailed performance study report of the predicate device, or IFU for the current device. Given that the device detects nucleic acids for specific bacteria, ground truth is likely established through culture or other confirmed molecular methods, rather than expert consensus on images.

4. Adjudication Method

The document does not specify any adjudication method (e.g., 2+1, 3+1, none) for the test set. This type of method is more common in image-based AI studies where human interpretation can vary; for a nucleic acid test, ground truth is typically established by definitive laboratory methods.

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

An MRMC comparative effectiveness study was not applicable or performed for this device as it is a standalone in vitro diagnostic (IVD) device for nucleic acid detection, not an AI-assisted diagnostic tool for human readers. Therefore, there is no effect size related to human reader improvement with AI assistance.

6. Standalone Performance

Yes, a standalone performance assessment was conducted. The QIAstat-Dx GI Panel 2 Mini B is an in vitro diagnostic device, meaning its performance (analytical and clinical performance) is evaluated independently without human interpretation as part of a human-in-the-loop system. The document states its performance is "equivalent" to the predecessor device, which would have undergone rigorous standalone performance testing.

7. Type of Ground Truth Used

While not explicitly stated for this specific submission, for a nucleic acid-based assay like the QIAstat-Dx GI Panel 2 Mini B, the ground truth would typically be established by:

• Culture: Bacterial culture for viability and identification of the target organisms.
• Reference Molecular Methods: e.g., validated PCR assays or sequencing for definitive detection and identification of microbial nucleic acids.
• Composite Reference Method (CRM): A combination of multiple methods, often including culture, microscopy, and/or multiple molecular methods, to establish the presence or absence of the target pathogen.

8. Sample Size for the Training Set

The document does not provide the sample size for the training set. For an IVD like this, "training set" might refer to the data used for initial assay development and optimization rather than a machine learning context. This information would be in the detailed development reports.

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

The document does not describe how the ground truth for the training set was established. Similar to the test set, it would likely involve established laboratory methods such as culture or reference molecular assays for the target pathogens.

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The QIAstat-Dx GI Panel 2 Mini B&V is a multiplexed nucleic acid test intended for use with the OLAstat-Dx Analyzer 1.0 for the simultaneous in vitro qualitative detection of nucleic acids from multiple bacteria and one virus directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following virus and bacteria (including several diarrheagence E. col/Shigella pathotypes) are identified with the QIAstat-Dx GI Panel 2 Mini B&V:

• Norovirus
• · Campylobacter
• · Shigella
• · Shiga-like toxin Escherichia coli (STEC)*
• · Salmonella

*Only with Para-Pak C&S, not reported for FecalSwab

Concomitant culture is necessary for organism recovery and further typing of bacterial agents. The QlAstat-Dx GI Panel 2 Mini B&V is indicated as an aid in the diagnosis of gastrontestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Postive results do not rule-out co-infection with organisms not detected by the QlAstat-Dx GI Panel 2 Mini B&V. The organisms detected may not be the sole or definitive cause of the disease.

Negative QIAstat-Dx GI Panel 2 Mini B&V results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

The QIAstat-Dx® GI Panel 2 Mini B&V (Cat. no. 691424) assay is a modified device (reduced version) of the QIAstat-Dx Gastrointestinal Panel 2 (Cat. no. 691421). The QIAstat-Dx GI Panel 2 Mini B&V is identical to the OIAstat-Dx Gastrointestinal Panel 2 (K220062) with the exception of their respective labeling and Assay Definition File (ADF) which masks all but five pathogens (targets) from the OIAstat-Dx Gastrointestinal Panel 2. The following virus and bacteria (including several diarrheagenic E. coli/Shigella pathotypes) are identified with the OIAstat-Dx GI Panel 2 Mini B&V: Norovirus, Campvlobacter, Shigella, Shiga-like toxin Escherichia coli (STEC) and Salmonella. The QIAstat-Dx GI Panel 2 Mini B&V is part of the OIAstat-Dx system and works with the OIAstat-Dx Analyzer 1.0.

The QIAstat-Dx GI Panel 2 Mini B&V is intended to be used with stool samples in Para-Pak C&S or FecalSwab transport media.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the QIAstat-Dx assay cartridge is processed by the QIAstat-Dx Analyzer 1.0.

Once the cartridge has been inserted into the instrument, the test starts automatically and runs for approximately 78 minutes. When the test is finished, the cartridge is removed by the user and discarded. The QIAstat-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").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx GI Panel 2 Mini B&V cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically-operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer 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:

• Sample Pre-treatment for PCR Inhibitors removal
• Resuspension of Internal Control and Proteinase K ●
• Cell lysis using mechanical and/or chemical means
• Membrane-based nucleic acid purification
• Rehydration of Master Mix ●
• Transfer of defined aliquots of eluate/master mix to different reaction chambers ●
• Performance of multiplex real-time RT-PCR testing within each reaction ● chamber.

The provided text describes a 510(k) premarket notification for a medical device called the QIAstat-Dx GI Panel 2 Mini B&V. This document focuses on demonstrating substantial equivalence to a legally marketed predicate device, the QIAstat-Dx Gastrointestinal Panel 2 (K220062), rather than detailing original acceptance criteria and a comprehensive study designed to prove the device meets those criteria from scratch.

The core of the submission is that the QIAstat-Dx GI Panel 2 Mini B&V is a "reduced version" of the predicate device. It is identical in hardware, reagents, and underlying PCR technology, with the only difference being a modified "Assay Definition File (ADF)" that masks results for all but five specific pathogens. Because of this, the performance data for the new device is considered "equivalent" to the predicate device's data for these five analytes.

Therefore, many of the typical elements of an acceptance criteria study (like an independent test set, MRMC study, or detailed ground truth establishment for a new study) are not explicitly present for the QIAstat-Dx GI Panel 2 Mini B&V in this document, as the submission relies on the existing clearance of the predicate device for its performance claims.

However, based on the provided text, here's an attempt to extract and infer the information requested:

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

The document does not provide a specific table of acceptance criteria for this specific submission. Instead, it states that "The performance data for the QIAstat-Dx GI Panel 2 Mini B&V is equivalent to the QIAstat-Dx Gastrointestinal Panel 2 (K220062) with the exception that it only includes data for the five analytes detected by the QIAstat-Dx GI Panel 2 Mini B&V (Norovirus, Campylobacter, Shigella, Shiga-like toxin E. coli (STEC) and Salmonella)."

It then directs the reader to "Please see the QIAGEN QIAstat-Dx GI Panel 2 Mini B&V Instructions for Use for performance tables." Since these tables are not included in the provided text, we cannot present a direct table of acceptance criteria and reported device performance from this document. The implication is that the predicate device's performance, as accepted during its original 510(k) clearance (K220062), serves as the de facto "acceptance criteria" for these five analytes for the new device by virtue of its identical underlying technology.

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

The document does not describe a new, independent test set for the QIAstat-Dx GI Panel 2 Mini B&V. Instead, it relies on the data collected for the predicate device (QIAstat-Dx Gastrointestinal Panel 2, K220062). The sample size, country of origin, and whether the data was retrospective or prospective for the predicate device's studies are not detailed in this document.

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

This information is not provided in the document, as it refers to the predicate device's data rather than a new study with independent expert ground truth establishment for this submission.

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

This information is not provided in the document.

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 device is a diagnostic nucleic acid test, not an AI-powered image analysis tool or a device that directly assists human readers in interpreting imaging or other complex data. Therefore, an MRMC study and effects on human reader performance are not applicable to this type of device.

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

This refers to the performance of the assay itself. The performance of the QIAstat-Dx GI Panel 2 Mini B&V (which functions like a standalone test after sample input) is considered "equivalent" to the predicate device's performance for the five detected analytes. The document notes that "The QIAstat-Dx Analyzer 1.0 automatically interprets test results and displays a summary on the analyzer display screen." This implies a standalone (algorithm only) performance for result generation, as long as human intervention refers to the interpretation of the raw data by the user, rather than the final qualitative result presented by the device.

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

For nucleic acid amplification tests like this, the ground truth is typically established by well-characterized reference methods, often involving:

• Culture: For bacterial targets, traditional microbiology culture is a common reference standard.
• Reference PCR/Molecular Methods: Highly sensitive and specific laboratory-developed or validated molecular assays.
• Sequencing: For definitive characterization where applicable.

The document does not explicitly state the specific ground truth methods used for the predicate device's studies, but these are the standard approaches for such assays. It does mention that "Concomitant culture is necessary for organism recovery and further typing of bacterial agents" in its indications for use, suggesting culture is an important complementary method in clinical practice.

8. The sample size for the training set

The document does not describe a training set in the context of an AI/machine learning model. This device is a molecular diagnostic assay (PCR-based), not an AI-driven system. Therefore, the concept of a "training set" as it applies to AI models is not relevant here. Development and validation of such assays involve different types of studies (e.g., analytical validation, clinical validation) rather than "training" an algorithm.

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

As per point 8, the concept of a training set for an AI model is not applicable. The development and validation of PCR assays involve establishing the analytical and clinical performance through rigorous testing against reference methods (as mentioned in point 7) and clinical samples.

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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:

Additionally, for contaminants that were confirmed by culture (fungal and bacterial), in table 19 and 20:

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.
• 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.

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The OlAstat-Dx Respiratory Panel Mini is a multiplexed nucleic acid test intended for use with the OlAstat-Dx system for the simultaneous in vitro qualitative detection of multiple respiratory viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals with clinical signs and symptoms of respiratory tract infections, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

The following viruses are identified using the OlAstat-Dx Respiratory Panel Mini: Influenza B. Respiratory Syncytial Virus, Human Rhinovirus, and SARS-CoV-2.

Nucleic acids from viral organisms identified by this test are generally detectable in NPS specimens during the acute phase of infection. Detecting and identifying specific viral nucleic acids from individuals presenting with signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection, if used in conjunction with other clinical, epidemiological and laboratory findings. The results of this test should not be used as for diagnosis, treatment or other patient management decisions.

Negative results in the presence of a respiratory illness may be due to infection with pathogens that are not detected by the test or due to lower respiratory tract infection that is not detected by a NPS specimen.

Conversely, positive results are indicative of the identified microorganism, but do not rule out co-infection with other pathogens not detected by the QlAstat-Dx Respiratory Panel Mini. The agent(s) detected by the QlAstat-Dx Respiratory Panel Mini may not be the definite cause of disease.

The use of additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

The QIAstat-Dx Respiratory Panel Mini (Cat. no. 691218) assay is a modified device (reduced version) of the QIAstat-Dx Respiratory Panel Plus (Cat. no. 691224). The QIAstat-Dx Respiratory Panel Mini is identical to the QIAstat-Dx Respiratory Panel Plus (K233100) with the exception of the labeling and Assay Definition File (ADF), which masks all but five pathogens (targets) from the QIAstat-Dx Respiratory Panel Plus. The following viruses are identified using the OlAstat-Dx Respiratory Panel Mini: Influenza A, Influenza B, Respiratory Syncytial Virus, Human Rhinovirus, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The OIAstat-Dx Respiratory Panel Mini is part of the QIAstat-Dx system and works with the QIAstat-Dx Analyzer 1.0.

The QIAstat-Dx Respiratory Panel Mini is intended to be used with I nasopharyngeal swab (NPS) eluted in Universal Transport Media (UTM), which is not provided with the QIAstat-Dx Respiratory Panel Mini.

Once the cartridge has been inserted into the instrument, the test starts automatically and runs for approximately 1 hour. When the test is finished, the cartridge is removed by the user and discarded. The QlAstat-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. All other tested but not detected analytes are listed in green. 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").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx Respiratory Panel Mini cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically-operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer 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 Internal Control ●
• Cell lysis using mechanical and/or chemical means ●
• Membrane-based nucleic acid purification ●
• . Mixing of the purified nucleic acid with lyophilized master mix reagents
• Transfer of defined aliquots of eluate/master mix to different reaction chambers
• Performance of multiplex real-time RT-PCR testing within each reaction chamber. ●

The provided text describes the QIAstat-Dx Respiratory Panel Mini, a molecular diagnostic device, and its substantial equivalence to a predicate device (QIAstat-Dx Respiratory Panel Plus). However, the document does not contain specific acceptance criteria, detailed results of a study proving those criteria were met, or information on aspects like sample size, data provenance, expert ground truth establishment, or clinical study methods typically associated with AI/imaging device validation.

The text states that "The performance data for the QIAstat-Dx Respiratory Panel Mini is equivalent to the QIAstat-Dx Respiratory Panel Plus (K233100) with the exception it only includes data for the five analytes detected by the QIAstat-Dx Respiratory Panel Mini (Influenza A, Influenza B, Respiratory Syncytial Virus, Human Rhinovirus, and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Please see the Qiagen QIAstat-Dx Respiratory Panel Mini Instructions for Use for performance tables." This indicates that the detailed performance data and acceptance criteria would be found in the device's Instructions for Use, which is not included in the provided document.

Therefore,Based on the provided text, I cannot describe the acceptance criteria and the study that proves the device meets the acceptance criteria with the requested level of detail. The document primarily focuses on establishing substantial equivalence to a predicate device by noting that the "Mini" version is a "reduced version" of the "Plus" version, masking certain pathogens through a software update (Assay Definition File).

Here's what can be inferred and what is missing, based on your request and the provided text:

Inferences (based on typical diagnostic device clearance and the nature of the device):

• Device Type: The QIAstat-Dx Respiratory Panel Mini is an in vitro diagnostic (IVD) device, specifically a multiplexed nucleic acid test. It detects viral nucleic acids (RNA/DNA) directly. This is not an AI-based imaging device, and therefore, many of the requested criteria (like number of experts, MRMC studies, human reader improvement with AI, etc.) are not applicable to this type of device.
• Acceptance Criteria (Implied): For a molecular diagnostic test, acceptance criteria typically revolve around metrics like:
  • Sensitivity: The ability of the test to correctly identify positive samples (true positive rate).
  • Specificity: The ability of the test to correctly identify negative samples (true negative rate).
  • Limit of Detection (LoD): The lowest concentration of an analyte that can be reliably detected.
  • Cross-reactivity: Ensuring the test does not falsely detect non-target organisms.
  • Reproducibility/Precision: Consistency of results when tested multiple times under various conditions.
  • Interference: Lack of impact from common substances found in clinical samples.
    The text states the performance is "equivalent" to the predicate, implying these types of criteria were met.
• Study Proving Acceptance Criteria: The study would be a clinical performance study and potentially analytical performance studies comparing the device's results against a known reference method or clinical consensus. The document references the "Instructions for Use for performance tables," which would contain these details.

Addressing Your Specific Points (based only on the provided text):

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

   • Not provided in the text. The text refers to the "Instructions for Use for performance tables" for this information.

2. Sample sizes used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective):

   • Not provided in the text.

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

   • Not applicable for this type of molecular diagnostic device in the same way it would be for an AI-based imaging device. Ground truth for molecular tests is typically established through a combination of:
     • Reference molecular methods: Highly sensitive and specific laboratory-developed tests or other cleared/approved molecular tests.
     • Clinical diagnosis: A combination of patient signs, symptoms, clinical course, and results from other diagnostic tests.
     • Culture: For some pathogens, though molecular tests often have higher sensitivity.
   • The document implies ground truth was established to demonstrate "equivalence" of the five remaining analytes, but no specifics are given.

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

   • Not applicable/Not provided. This is relevant for subjective assessments like imaging interpretation. For molecular diagnostics, discrepancies are typically resolved through re-testing, using an orthogonal method, or clinical correlation.

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, this was not done. This is an IVD device, not an AI-assisted imaging device. Human "readers" (interpreters) are not involved in the direct output of this automated molecular test; results are automatically interpreted by the analyzer.

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

   • Yes, in spirit. A molecular diagnostic test like this is inherently a "standalone" algorithm in a lab setting. The device automatically processes the sample and interprets results. While lab personnel initiate the test and retrieve results, there isn't a "human-in-the-loop" subjective interpretation component as there would be with an AI imaging system. The performance of the device is what's evaluated.

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

   • Not explicitly stated in the provided text. For molecular diagnostics, ground truth often involves a combination of:
     • Comparator molecular methods (e.g., PCR assays with known performance).
     • Clinical diagnosis and follow-up (for some studies).
     • Sequencing (for definitive identification of viral strains).

8. The sample size for the training set:

   • Not provided in the text. This device isn't explicitly described as having a "training set" in the context of an AI model that learns from large datasets. It's a biochemical/molecular assay with a fixed set of reactions and an "Assay Definition File (ADF)" that controls which stored results are displayed. The "training" would be more akin to assay development and optimization, rather than machine learning training.

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

   • No "training set" for an AI model is described. Assay development and optimization would rely on characterized positive and negative control materials, and potentially spiked samples, to establish performance parameters.

Summary of what the document does tell us about the "study":

The core of the documentation provided is a claim of substantial equivalence (510(k) clearance) based on the QIAstat-Dx Respiratory Panel Mini being a modified version of a previously cleared device, the QIAstat-Dx Respiratory Panel Plus (K233100).

• Modification: The "Mini" version is simply the "Plus" version with a software change (Assay Definition File - ADF) that masks the results for all but five specific pathogens.
• Proof: The manufacturer validated and verified this software change to demonstrate "there is no change in safety and effectiveness" for the five remaining analytes compared to their performance on the predicate device. This means the underlying assay chemistry and detection capabilities for those five analytates are presumed to be identical.
• Conclusion: Because the underlying technology and performance characteristics for the detected analytes are identical to a previously cleared device, and the only change is the masking of additional targets, the FDA determined Substantial Equivalence without requiring a full de novo performance study for the entire device. Performance data for the five analytes from the predicate device's clearance would implicitly serve as the basis for the "Mini" version.

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The QIAstat-Dx Gastrointestinal Panel 2 is a multiplexed nucleic acid test intended for use with the QIAstat-Dx Analyzer 1.0. for the simultaneous in vitro qualitative detection of nucleic acids from multiple viruses, bacteria. and parasites directly from preserved stool samples (Para-Pak C&S or FecalSwab) obtained from individuals with signs and/or symptoms of gastrointestinal infection. The following viruses, bacteria (including several diarrheagenic E. col/ Shigella pathotypes), and parasites are identified with the QIAstat-Dx Gastrointestinal Panel 2 :
• Adenovirus F40/F41
• Astrovirus
• Norovirus GI/GII
• Rotavirus A
• Campylobacter (C. jejuni, C. coli and C. upsaliensis)
• Shigella/Enteroinvasive Escherichia coli (EIEC)
• Enteropathogenic Escherichia coli (EPEC)
• Enterotoxigenic Escherichia coli (ETEC) lt/st
• Shiga-like toxin-producing Escherichia coli (STEC) stx1/stx2
(including specific identification of E. coli O157 serogroup within STEC)
• Salmonella
• Plesiomonas shigelloides
• Yersinia enterocolitica
• Cryptosporidium
• Cyclospora cayetanensis
• Entamoeba histolytica
• Giardia lamblia*
*(Also known as Giardia intestinalis and Giardia duodenalis)
Concomitant culture is necessary for organism recovery and further typing of bacterial agents.
The QIAstat-Dx Gastrointestinal Panel 2 is indicated as an aid in the diagnosis of specific agents of gastrointestinal illness, in conjunction with other clinical, laboratory, and epidemiological data. Positive results do not rule-out coinfection with organisms not detected by the QIAstat-Dx Gastrointestinal Panel 2. The organisms detected may not be the sole or definitive cause of the disease.
Negative QIAstat-Dx Gastrointestinal Panel 2 results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this assay test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.

QIAstat-Dx is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the OIAstat-Dx assay cartridge is processed by the OIAstat-Dx Analyzer 1.0.

Here's a summary of the acceptance criteria and study details for the QIAstat-Dx Gastrointestinal Panel 2, extracted from the provided text:

Acceptance Criteria and Device Performance for QIAstat-Dx Gastrointestinal Panel 2

The acceptance criteria for the QIAstat-Dx Gastrointestinal Panel 2 can be inferred from the performance metrics (Positive Percentage Agreement - PPA and Negative Percentage Agreement - NPA) reported for both prospective and retrospective clinical studies. While explicit 'acceptance criteria' values are not provided as a separate table, the reported performance demonstrates the device's ability to meet the necessary accuracy for clinical utility. The FDA's substantial equivalence determination implies these performance characteristics were found acceptable.

Implied Acceptance Criteria (based on reported performance):

• High PPA: The device should accurately detect the target pathogens when they are present. Most reported PPA values are above 90%, with many at 100%. Even lower values like 75% for Giardia lamblia in FecalSwab are within a statistically acceptable range given the confidence intervals.
• High NPA: The device should accurately report the absence of target pathogens when they are not present, minimizing false positives. Most reported NPA values are very high, often 99% or 100%.

Table of Acceptance Criteria (Implied) and Reported Device Performance

Given that specific numerical acceptance criteria (e.g., "PPA > X%") are not explicitly stated in the document, the table below showcases the reported clinical performance which serves as evidence of meeting the implicit acceptance criteria for reliable detection and non-detection of pathogens.

Study Details:

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

• Test Set (Clinical Study):
  • Total Specimens: 2808
    • 1939 Prospective (1222 FecalSwab, 717 Para-Pak C&S)
    • 119 Prospective Archived (Norovirus GI/GII: 81, STEC: 18 plus 20 negative specimens where relevant)
    • 750 Retrospective Frozen Specimens
  • Data Provenance: Multi-center international study conducted at thirteen clinical sites across 5 countries (4 sites in Europe and 9 sites in USA). Specimens were collected between May and July 2021.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

• The document does not specify the number or qualifications of experts used to establish the ground truth. Instead, it refers to the use of "one FDA-cleared test as comparator for most analytes" and a "composite comparator consisting of either three independent FDA-cleared test methods or two independent FDA-cleared tests methods and two validated PCR assays followed by bidirectional sequencing" for others. This implies that the ground truth was established through validated diagnostic methods rather than direct expert consensus on primary samples in many cases.

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

• For analytes where a composite comparator was used (Norovirus GI/GII, ETEC, STEC, and Giardia lamblia), the ground truth was determined by the majority of the three results.
  • A positive composite comparator result: based on positive results for at least two comparator tests.
  • A negative composite comparator result: based on negative results for at least two comparator tests.
• For other analytes, where "one FDA-cleared test method" was used, the comparator's result directly served as the ground truth.
• For cases with insufficient sample volume for complete composite comparator testing, a "worst-case model" was applied for PPA calculation.

4. If a muti-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 information is not applicable as the device is an in vitro diagnostic (IVD) nucleic acid test for pathogen detection, not an AI-assisted diagnostic device interpreted by human readers for medical imaging or similar tasks. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not relevant to this device.

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

• Yes, the performance presented (PPA and NPA) for the QIAstat-Dx Gastrointestinal Panel 2 is a standalone performance of the algorithm/device. The device automatically interprets test results and displays a summary, without a human interpretation loop for its core function.

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

• The ground truth was established using FDA-cleared comparator methods and validated PCR assays followed by bidirectional sequencing. This acts as a robust diagnostic ground truth based on established molecular and clinical laboratory standards. Pathology or outcomes data were not explicitly mentioned as primary ground truth sources for individual pathogen detection in this context.

7. The sample size for the training set:

• The document does not explicitly state a sample size for the training set. The clinical studies describe the evaluation of the device's performance using prospective, prospective archived, and retrospective samples, implying these are test sets rather than training sets. Analytical studies such as LoD and inclusivity also use specific strains and dilutions, but these are for analytical validation, not for training a machine learning model. For IVD devices like this, the "training set" concept (as understood in AI/ML) might be less direct, relying more on extensive analytical verification of probe/primer specificity and reactivity across a wide range of strains and concentrations, and then clinical validation.

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

• As the training set size is not provided, the method for establishing its ground truth is also not detailed. However, for the analytical studies (which could be considered a form of "training/validation data generation" in a broader sense for IVDs), the ground truth for LoD and inclusivity was established by using culture isolates from commercial suppliers (ZeptoMetrix® and ATCC®) or clinical samples positive for target analytes. These were "prepared in human stool matrix" and tested at known concentrations validated by in-house developed and validated qPCR assays for molecular unit titers.

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The QIAstat-Dx Respiratory Panel Plus is a multiplexed nucleic acid test intended for use with the QIAstat-Dx system for the simultaneous in vitro qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals with clinical signs and symptoms of respiratory tract infection, including SARS-CoV-2.

The following organism types and subtypes are identified using the QIAstat-Dx Respiratory Panel Plus: Adenovirus, Human Coronavirus 229E, Human Coronavirus HKU1, Human Coronavirus NL63, Human Coronavirus OC43, Human Metapneumovirus, Influenza A, Influenza A H1, Influenza A H1N1 pdm09, Influenza B, Parainfluenza virus 1, Parainfluenza virus 2, Parainfluenza virus 3, Parainfluenza virus 4, Respiratory Syncytial Virus, Human Rhinovirus/Enterovirus (not differentiated), Severe Acute Respiratory Syndrome Coronavirus (SARS-COV-2), Bordetella pertussis, Chlamydophila pneumoniae and Mycoplasma pneumoniae.

Nucleic acids from viral and bacterial organisms identified by this test are generally detectable in NPS specimens during the acute phase of infection. Detecting and identifying specific viral and bacterial nucleic acids from individuals presenting with signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection, if used in conjunction with other clinical, epidemiological and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment or other patient management decisions.

Negative results in the presence of a respiratory illness may be due to infection with pathogens that are not detected by the test or due to lower respiratory tract infection that is not detected by a NPS specimen.

Conversely, positive results are indicative of the identified microorganism, but do not rule out co-infection with other pathogens not detected by the QIAstat-Dx Respiratory Panel Plus. The agent(s) detected by the QIAstat-Dx Respiratory Panel Plus may not be the definite cause of disease.

The use of additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

The QIAstat-Dx Respiratory Panel Plus is part of the QIAstat-Dx system and works with the QIAstat-Dx Analyzer 1.0.

The QIAstat-Dx Respiratory Panel Plus is intended to be used with I nasopharyngeal swab (NPS) eluted in Universal Transport Media (UTM), which is not provided with the QIAstat-Dx Respiratory Panel Plus.

Once the cartridge has been inserted into the instrument, the test starts automatically and runs for approximately 1 hour. 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. All other tested but not detected analytes are listed in green. 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").

All the reagents required for the complete execution of the test are pre-loaded and selfcontained in the QIAstat-Dx Respiratory Panel Plus cartridge. The user does not need to manipulate any reagents. During the test, reagents are handled by pneumatically-operated microfluidics without any direct contact with the user or the analyzer actuators.

Within the cartridge, multiple steps are automatically performed in sequence by using pneumatic pressure and a multiport valve to transfer 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);
  • -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;
• The detected signal per fluorescent marker per Reaction Chamber is then used by . the system software to generate the assay result.

The QIAstat-Dx Respiratory Panel Plus includes the addition of the SARS-CoV-2 analyte to the analytes that were cleared in the OIAstat-Dx Respiratory Panel (K183597).

The provided text describes the QIAstat-Dx Respiratory Panel Plus, a multiplexed nucleic acid test. The document focuses on demonstrating the substantial equivalence of this new device to a predicate device (BioFire Respiratory Panel 2.1 (RP2.1)), primarily by showing that the new device's SARS-CoV-2 detection is effective and that the addition of SARS-CoV-2 and a change in lysis reagent do not negatively impact the performance of other analytes previously cleared.

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

Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated in a single, concise list with specific thresholds (e.g., "PPA must be >X%"). Instead, they are implicitly demonstrated through performance goals such as high positive percent agreement (PPA) and negative percent agreement (NPA) compared to a comparator method, and meeting detection rates at defined LoD concentrations. For non-SARS-CoV-2 analytes, the criteria seem to be demonstrating equivalence to the previously cleared QIAstat-Dx Respiratory Panel (K183597).

Table of Acceptance Criteria (Implied) and Reported Device Performance

Study Details:

1. Sample Size Used for the Test Set and Data Provenance:

   • SARS-CoV-2 Clinical Performance: 616 prospective NPS specimens (615 included in analysis due to one exclusion).
     • Provenance: Collected from "five (5) geographically diverse study sites in the U.S.", indicating prospective data from multiple locations within the US. Collection period: February 2023 to May 2023 and during February 2024.
   • Representative Panel Equivalency (Non-SARS-CoV-2): 190 de-identified clinical NPS specimens.
     • Provenance: Clinical NPS specimens, both positive and negative as per Standard of Care. No specific country mentioned, but likely US given the overall context of FDA submission. "De-identified clinical NPS specimens" suggests retrospective collection but could also be prospective if de-identified at collection.

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

   • Clinical Performance (SARS-CoV-2): For SARS-CoV-2, the ground truth was established by comparing to "an FDA-cleared SARS-CoV-2 RT-PCR comparator method." This implies an established and validated laboratory method, not human expert consensus, for determining the presence or absence of the virus.
   • Representative Panel Equivalency: For the representative panel analytes, the comparison was against "Standard of Care" and by parallel testing with the "QIAstat-Dx Respiratory Panel" (the predicate device for these analytes). Again, this points to laboratory reference methods rather than human expert interpretation of imaging/clinical findings.
   • The document does not mention the use of human experts (e.g., radiologists) for establishing ground truth, as the device is an in-vitro diagnostic (IVD) for molecular detection, not an imaging AI.

3. Adjudication Method for the Test Set:

   • Clinical Performance (SARS-CoV-2): For discrepant results with the primary comparator for SARS-CoV-2, the text mentions that the "two samples with false negative SARS-CoV-2 results by the QIAstat-Dx Respiratory Panel Plus were both positive by two FDA-EUA molecular SARS-CoV-2 assays." Similarly, the "single sample with a false positive SARS-CoV-2 result...was positive by two FDA-EUA molecular SARS-CoV-2 assays." This indicates a form of adjudication by a secondary, independent highly sensitive molecular test (two FDA-EUA assays) to resolve discrepancies, providing a more robust ground truth.
   • Representative Panel Equivalency: No specific adjudication method is mentioned for this section beyond the direct comparison to "Standard of Care" and the QIAstat-Dx Respiratory Panel.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:

   • No. An MRMC study is relevant for imaging devices where human readers interpret images. This device is an in-vitro diagnostic (IVD) for nucleic acid detection, performed automatically by an instrument. There are no human readers "interpreting" the output in a way that would necessitate an MRMC study.

5. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

   • Yes, the performance data (PPA, NPA, LoD, Analytical Reactivity, Specificity, Interference, Precision) are all reported as standalone performance of the QIAstat-Dx system. The system automatically interprets test results and displays a summary (page 6). This is an "algorithm only" performance in the context of an automated IVD test.

6. The Type of Ground Truth Used:

   • Lab-based Comparator Methods: For SARS-CoV-2 clinical performance, the ground truth was established using an "FDA-cleared SARS-CoV-2 RT-PCR comparator method" with further confirmation by "two FDA-EUA molecular SARS-CoV-2 assays" for discrepant results.
   • For the non-SARS-CoV-2 analytes, ground truth was derived from "Standard of Care" lab results and comparison to the "QIAstat-Dx Respiratory Panel" (the previously cleared device).
   • For analytical studies (LoD, inclusivity, specificity, etc.), ground truth was established by precise laboratory spiking of known concentrations of pathogens or interferents.
   • This is molecular/pathology-based ground truth, not outcomes data or expert consensus based on clinical or imaging findings.

7. The Sample Size for the Training Set:

   • The document does not provide information on the training set for the QIAstat-Dx Respiratory Panel Plus. This document is a 510(k) summary, which focuses on validation and demonstrated substantial equivalence to a predicate device. Information about the training data for the underlying assays or software algorithms is typically part of the device's development and design control documentation, which is not usually disclosed in a public 510(k) summary. The "device performance" described here refers to the testing of the final, developed device.

8. How the Ground Truth for the Training Set Was Established:

   • As the training set information is not provided, how its ground truth was established is also not detailed. In general, for molecular diagnostics like this, training data (if any specific to machine learning/AI components were used in the assay development) would typically involve well-characterized clinical samples or contrived samples with known pathogen presence/absence and concentration, verified by highly sensitive and specific reference methods (e.g., Sanger sequencing, quantitative PCR).

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The QIAstat-Dx Respiratory Panel is a multiplexed nucleic acid test intended for use with QIAstat-Dx system for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) eluted in Universal Transport Media (UTM) obtained from individuals suspected of respiratory tract infections. The following organism types are identified using the QIAstat-Dx Respiratory Panel: Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Human Metapneumovirus A+B, Influenza A, Influenza A H1, Influenza A H1N1/pdm09, Influenza B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 4, Rhinovirus/Enterovirus, Respiratory Syncytial Virus A+B, Bordetella pertussis, Chlamydophila pneumoniae and Mycoplasma pneumoniae.

The detection and identification of specific viral and bacterial nucleic acids from individuals presenting with signs and symptoms of a respiratory infection aids in the diagnosis of respiratory infection with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment or other management decisions. Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by the test or lower respiratory tract infection that is not detected by a nasopharyngeal swab specimen. Positive results do not rule out co-infection with other organisms: the agent(s) detected by the QIAstat-Dx Respiratory Panel may not be the definite cause of disease. Additional laboratory testing (e.g., bacterial and viral culture, immunofluorescence and radiography) may be necessary when evaluating a patient with possible respiratory tract infection.

Due to the small number of positive specimens collected for certain organisms during the prospective clinical study, performance characteristics for Bordetella pertussis and Parainfluenza Virus 1 were established primarily with retrospective clinical specimens. Performance characteristics for Chlamydophila pneumoniae, Parainfluenza Virus 2, Parainfluenza Virus 4, Influenza A subtype H1 and Coronavirus 229E were established primarily using contrived clinical specimens.

Due to the genetic similarity between Human Rhinovirus and Enterovirus, the QIAstat-Dx Respiratory Panel cannot reliably differentiate them. A positive QI Respiratory Panel Rhinovirus/Enterovirus result should be followed-up using an alternate method (e.g., cell culture or sequence analysis).

Performance characteristics for Influenza A were established when Influenza A H1N1-2009 and A H3 were the predominant Influenza A viruses in circulation. Performance of detecting Influenza A may vary if other Influenza A strains are circulating or a novel Influenza A virus emerges. If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent Influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

QIAstat-Dx® is based on single-test cartridges with pre-packaged reagents including both wet and dry chemistry to handle the sample preparation and detection steps for the presence of a range of selected analytes by PCR technology. After insertion of the sample, the QIAstat-Dx assay cartridge is processed by the QIAstat-Dx® Analyzer 1.0.

The QIAGEN QIAstat-Dx Respiratory Panel is a multiplexed nucleic acid test intended for the simultaneous qualitative detection and identification of multiple respiratory viral and bacterial nucleic acids in nasopharyngeal swabs (NPS) eluted in Universal Transport Media (UTM). The device is intended for use with the QIAstat-Dx system to aid in the diagnosis of respiratory infections in individuals suspected of having such infections.

Acceptance Criteria and Device Performance

The acceptance criteria for the QIAstat-Dx Respiratory Panel are primarily demonstrated through its analytical performance (Limit of Detection, Analytical Reactivity, Analytical Specificity, Interference, Specimen Stability, and Reproducibility) and clinical performance (sensitivity and specificity compared to an FDA-cleared multiplexed respiratory pathogen panel). While explicit quantitative acceptance criteria for all aspects are not provided in the document (e.g., specific minimum acceptable sensitivity/specificity percentages), the data presented demonstrates the device meets acceptable performance levels for diagnostic assays.

Here's a table summarizing reported performance characteristics:

Study Details

This device is not an AI/ML powered device, therefore some of the questions (e.g. data provenance for test set, number of experts, adjudication method and MRMC study) are not relevant. This is a traditional IVD device and the study demonstrates the analytical and clinical performance through wet-lab and clinical sample testing against a comparator method.

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

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

   • Analytical Performance Studies (Non-clinical):
     • Limit of Detection: For each of the 51 pathogen strains, at least 20 replicates were tested. Data provenance is not explicitly stated as patient data, but rather contrived analytical samples prepared from commercial suppliers or artificial samples.
     • Analytical Reactivity: 127 respiratory pathogen isolates/strains were tested in triplicates.
     • Analytical Specificity: Samples were contrived by spiking off-panel organisms into simulated nasopharyngeal swab sample matrix.
     • Interference: 30 potentially interfering substances were tested in contrived samples (mix of organisms at 5xLoD and negative specimens).
     • Specimen Stability: 10 sample mixes (each containing multiple pathogens) were tested with 10 replicates per storage condition per target.
     • Matrix Equivalency: 20 replicates for at least one strain per pathogen, prepared in true-negative clinical NPS sample matrix.
     • Reproducibility: 12 sample mixes (contrived samples) were tested across 3 sites, with 20 replicates per target, concentration, and site (4 replicates/day for 5 days).
   • Clinical Performance Study:
     • Sample Size: A total of 2,304 residual NPS specimens were tested: 1994 prospective (1093 frozen prospective, 901 fresh prospective) and 310 archived.
     • Data Provenance: The study was conducted at six (6) geographically diverse study sites, five (5) U.S. sites and one (1) international site. Specimens were collected from individuals suspected of respiratory tract infections. The study involved both prospective collection (patients meeting inclusion criteria) and archived specimens.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience): Not applicable for this type of IVD device. The ground truth for the clinical study was established by an FDA-cleared multiplexed respiratory pathogen panel (the comparator method).

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable as the ground truth was established by a single comparator device, not through human expert adjudication of images.

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: Not applicable. This is an IVD device, not an AI/ML-powered imaging device that assists human readers.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Yes, the device operates as a standalone diagnostic system, performing nucleic acid extraction, amplification, and detection without human interpretation beyond reading the displayed results. Its performance was directly compared to another FDA-cleared multiplexed respiratory pathogen panel.

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

   • Analytical Studies: Ground truth was established by known concentrations of pathogen strains (from commercial suppliers like ZeptoMetrix and ATCC) or artificial samples.
   • Clinical Study: Ground truth was established by an FDA-cleared multiplexed respiratory pathogen panel, which served as the comparator method.

8. The sample size for the training set: Not applicable. This is a traditional IVD device, not an AI/ML product that undergoes a "training" phase with a large dataset. The device's design and analytical parameters are based on scientific principles of multiplex PCR and reagent formulation.

9. How the ground truth for the training set was established: Not applicable, as there is no "training set" in the context of an AI/ML model for this device.

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The ipsogen JAK2 RGQ PCR Kit is a qualitative in vitro diagnostic test for the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood. The ipsogen JAK2 RGQ PCR Kit is a real time PCR test performed on the QIAGEN Rotor-Gene Q MDx instrument. The test is intended for use as an adjunct to evaluation of suspected Myeloproliferative Neoplasm in conjunction with other clinicopathological factors.

This test does not detect less common JAK2 mutations associated with Myeloproliferative Neoplasm including mutations in exon 12 and is not intended for stand-alone diagnosis of Myeloproliferative Neoplasm.

The ipsogen® JAK2 RGQ PCR Kit is a qualitative in vitro diagnostic test for the detection of the JAK2 V617F/G1849T allele in genomic DNA extracted from whole blood. The ipsogen JAK2 RGQ PCR Kit uses polymerase chain reaction (PCR), and ARMS (amplification refractory mutation system) technology on the Rotor-Gene O MDx instrument.

Samples are extracted and prepared using the QIAsymphony SP instrument (QSSP) with the QIAsymphony® DSP DNA Mini Kit, followed by assay setup amplification and detection are carried out using the ipsogen JAK2 RGQ PCR Kit with the Rotor-Gene Q MDx and Rotor-Gene AssayManager software version 2.1.x**. Rotor-Gene AssayManager Gamma MDx plug-in installed, version 1.0.x** and an associated JAK2 Assay profile (from file AP ipsogen JAK2 blood US Vx x x**.iap).

The extraction step on the OIAsymphony instrument (OSSP) ensures that enough gDNA (of adequate quality) is purified during each run (no repeated extraction for the same sample is expected unless the instrument states that the step failed).

The ipsogen JAK2 RGQ PCR Kit is designed to be used with the Rotor-Gene Q MDx (RGO) instrument which is a real-time PCR analyzer designed for rapid thermal cvcling and real-time detection of PCR assays. The Rotor-Gene AssayManager (RGAM) controls and monitors PCR reactions and allows the determination of the mutation status based upon PCR results.

The presence of the JAK2 mutation is indicated by the fluorescent signal generated through the use of fluorescently labeled oligonucleotide probes. The probes do not generate a signal unless they are specifically bound to the amplified product. The amplification cycle at which fluorescent signal is detected by the RGO MDx is inversely proportional to the DNA target concentration present in the original specimen.

The ipsogen JAK2 RGQ PCR Kit contains reagents for two separate PCR reactions: one mutation-specific reaction and one wild-type specific reaction mix uses a mutant-specific or wild-type specific primer (Reverse primer), together with a common Forward primer and a labeled probe, to amplify and detect the G1849T mutation or the wild-type sequence in the JAK2 gene.

In addition, each Reaction Mix contains reagents (unlabeled primers, probe and oligonucleotide template) for an internal control reaction. The internal control is designed to be a reaction that does not compete significantly with the mutation-specific or wildtype specific, reaction mixes. and serve to demonstrate that the entire assay process has proceeded correctly for each specimen.

Note: ** x≥ 0, x corresponds to the latest version available on OIAGEN Website

The provided text describes the performance characteristics of the ipsogen® JAK2 RGQ PCR Kit, a qualitative in vitro diagnostic test for the detection of the JAK2 V617F/G1849T allele. This is a molecular diagnostic test, not an AI/imaging device, therefore, many of the requested criteria such as expert adjudication, MRMC studies, and AI-specific ground truth methodologies are not applicable.

Here's an attempt to extract and present the information as per your request, adapting to the nature of the device:

Acceptance Criteria and Device Performance Study for ipsogen® JAK2 RGQ PCR Kit

Note: This device is a molecular diagnostic PCR kit, not an AI-based imaging device. Therefore, criteria related to image analysis, expert readers, MRMC studies, and AI-specific ground truth establishment (like pathology or outcomes data for imaging) are not directly applicable. The "acceptance criteria" here relate to the analytical accuracy of the test in detecting a specific genetic mutation compared to a reference method.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined quantitative acceptance criteria in a table format. However, the "Performance Characteristics - Non-Clinical Studies" section describes the study's objective and results, implying that the observed accuracy demonstrates the device's acceptable performance. The primary metric presented is concordance with a reference method (Sanger Bi-directional Sequencing, BDS, and subsequently Next Generation Sequencing, NGS).

Based on the study results, we can infer the performance:

2. Sample Size and Data Provenance

• Test Set Sample Size: 473 specimens.
  • 276 with suspected Polycythemia Vera (PV)
  • 98 with Myelofibrosis (ET)
  • 99 with Primary Myelofibrosis (PMF)
• Data Provenance: Not explicitly stated, but clinical samples from subjects suspected of having myeloproliferative neoplasms. It is likely retrospective as the samples appear to be collected and then tested. No country of origin is specified.
• Training Set Sample Size: Not applicable for this type of analytical validation study. The kit is a diagnostic reagent system, not a machine learning model that undergoes training.

3. Number of Experts and Qualifications for Ground Truth

• Number of Experts: Not applicable. Ground truth was established using standard molecular diagnostic methods (Sanger Bi-directional Sequencing and Next Generation Sequencing), not by human expert consensus as would be typical for image interpretation.
• Qualifications of Experts: N/A as per above. These are laboratory-based reference methods.

4. Adjudication Method for the Test Set

• Adjudication Method: Not applicable. The ground truth was established by laboratory-based objective methods (BDS and NGS). Discordances were investigated by using a more sensitive reference method (NGS).

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

• MRMC Study: No. This is a molecular diagnostic kit, not an AI/imaging device requiring human reader interpretation. Therefore, an MRMC study and
  assessment of human reader improvement with AI assistance are not relevant.

6. Standalone Performance (Algorithm Only)

• Standalone Performance: Yes, in a way. The "algorithm" here is the chemical and enzymatic process of the PCR kit and the associated instrument's detection capabilities. The study assesses the performance of the kit itself (the "device") in detecting the mutation, independent of human interpretation beyond typical lab procedures and result reporting. The kit's results are compared directly to the reference methods.

7. Type of Ground Truth Used

• Type of Ground Truth:
  • Primary Ground Truth: Sanger Bi-directional Sequencing (BDS).
  • Confirmatory/Higher Sensitivity Ground Truth for discordant samples: Validated Next Generation Sequencing (NGS).
  • The document notes that BDS is "not as sensitive as the JAK2 assay" (which reportedly detects down to 1%), and NGS was used to confirm the 15 discordant samples. This suggests that the ground truth evolved or was refined, with NGS serving as a more robust ground truth for low-level mutations.

8. Sample Size for the Training Set

• Training Set Sample Size: Not applicable. As stated before, this is a diagnostic kit, not an AI model requiring a training set. The "design" of the kit is based on established molecular biology principles, not data-driven learning.

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

• Ground Truth for Training Set Establishment: Not applicable, as there is no training set for this type of device. The kit's design and validation rely on its analytical performance against known samples or samples characterized by established, robust reference methods.

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The ipsogen JAK2 RGQ PCR Kit is a qualitative in vitro diagnostic test for the detection of the JAK2 V617F/G1849T allele in genomic DNA extracted from EDTA whole blood. The ipsogen JAK2 RGQ PCR Kit is a real time PCR test performed on the QIAGEN Rotor-Gene Q MDx instrument. The test is intended for use as an adjunct to evaluation of suspected Polycythemia Vera, in conjunction with other clinicopathological factors.

This test does not detect less common mutations associated with Polycythemia Vera including mutations in exon 12 and is not intended for stand-alone diagnosis of Polycythemia Vera.

The ipsogen® JAK2 RGQ PCR Kit (hereafter also referred to as the JAK2 Kit or JAK2 assay) employs allele-specific, quantitative, polymerase chain reaction (PCR) using an amplification refractory mutation system (ARMS). DNA is extracted from K2-EDTA anticoagulated whole blood using the QIAsymphony instrument (QSSP) and QIAsymphony® DSP DNA Mini Kit. Purified DNA must be diluted to 10 ng/ul using the TE buffer provided in the JAK2 Kit. Each PCR reaction of the Rotor-Gene Q MDx is optimized for 50 ng of purified gDNA diluted in a final volume of 5 ul. A total of 100 ng per tested sample (50 ng for each reaction) is needed. The Kit contains sufficient reagents to test 24 reactions.

The provided text describes the performance evaluation of the ipsogen® JAK2 RGQ PCR Kit. Here's a breakdown of the acceptance criteria and the study that proves the device meets them, organized as requested:

Acceptance Criteria and Reported Device Performance

Table 1: Acceptance Criteria and Reported Device Performance

1. A260/280 OD within 1.7-2.0 and gDNA concentrations $\ge$ 10 ng/µL with a 90% pass rate.
2. Variability between sites must be less than that of within-laboratory study. | Study 1 met pre-specified acceptance criteria. Variability was acceptable. For the 1.02% JAK2 MUT mean, 25/92 tests were positive. For 0% JAK2 MUT mean, 0/92 tests were positive. (Tables 4, 5) |
   | | Site-to-Site Reproducibility (Study 2 - Clinical Samples): All calls (positive/negative) must be correctly identified with 100% concordance (95% CI, 90.3%, 100%). Observed variability to be lower than in the precision study for comparable mutation levels. | For all 6 clinical specimens, 100% of calls were correctly positive or negative (95% CI, 90.3%, 100%). Observed variability was lower than in the precision study. (Table 6) |
   | | Precision of Controls: Acceptable repeatability and reproducibility including variations between operators, kits, instruments, and days for mutant and wild-type controls, and internal controls (HEX channel Ct values 25 to 37.79). | Mutant Control: Mean 99.98% JAK2 MT, SD 0.02, %CV 0.02. Wild Type Control: Mean 0.00% JAK2 MT, SD 0.00, %CV 0.00. HEX Mutant Ct: Mean 33.09, Total SD 0.70, %CV 2.11. HEX Wild Type Ct: Mean 32.90, Total SD 0.83, %CV 2.53. Controls were acceptable. (Tables 7, 8) |
   | | DNA Extraction Method Reproducibility: No evidence of cross-contamination greater than the clinical cut-off (1%). | One sample in the control extraction run produced 0.012% MUT and one in the test run 0.001% MUT; both below the 1% cut-off. The study established the lack of cross-contamination. |
   | Analytical Performance: Linearity/Reportable Range and DNA Input | Linearity: Assay must be linear for tested DNA input levels across the measuring interval (0-70% mutation). At 1% cutoff, degree of linearity must not be statistically different from 0. | Regression analysis demonstrated linearity at DNA inputs of 5, 10, and 20 ng/uL. The assay is not linear at 2 or 30 ng/uL. Significant effect when DNA input was 2 ng/uL and %MUT was LoB >90% of the time. | LoB: All results below LoD, supporting that LoB is below LoD and not detectable. LoD: Verified to be 0.042% MUT. The 10th percentile was calculated and determined to be greater than the LoB >90% of the time. |
   | Analytical Performance: Analytical Specificity | Interfering Substances: No interference with assay performance (except Proteinase K, which was further examined). Key acceptance for Proteinase K: control and control+TE not different, internal control Ct > 38.51, A260/280 1.7-2.0, gDNA $\ge$ 10 ng/µL, %MUT comparison p-value 1%. | All testing met acceptance criteria for reagent stability, transport conditions, and freeze-thaw cycles. Supports a shelf life of months (specific duration redacted) and freeze-thaw cycles for the JAK2 Assay kit with the study ongoing. (Tables 13, 14, 20) |
   | | Specimen Stability (Whole Blood): Stability for up to 4 days (96 hrs) after collection in K2 EDTA tubes at 2-8°C and room temperature. | Study designed to support 96 hours stability, consistent with literature. (Specific results not fully detailed, but implies acceptance criteria were met). |
   | | Specimen Stability (Genomic DNA): Stability of extracted DNA at -15 to -30°C and after 4 freeze/thaw cycles for 15 months (studies ongoing to extend to 24 months). | Testing parameters within specifications to 18 months, with studies ongoing to 25 months. The extracted gDNA can be stored up to 15 months with studies ongoing to extend this claim. |
   | Comparison Studies: Accuracy Method Comparison | Agreement with Bi-directional Sanger Sequencing: High positive percent agreement (PPA) and negative percent agreement (NPA). | PPA: 100% (71/71 subjects; 95% CI: 94.4%, 100%). NPA: 99.5% (204/205 subjects; 95% CI: 97.3%, 100%). One discordant case with Sanger negative but JAK2 Kit positive (5.6% MUT, below Sanger LoD). (Table 15) |
   | Clinical Performance | Sensitivity: High sensitivity (expected to detect PV in vast majority of subjects with disease).
   Specificity: High specificity (expected to rule out PV in vast majority of subjects without PV). | Sensitivity: 94.6% (53/56 subjects; CI: 85.1%, 98.8%). Specificity: 98.1% (157/160 subjects; 95% CI: 94.6%, 99.6%). (Tables 18, 19) |

Study Details

2. Sample Size and Data Provenance

• Test Set Sample Size:
  • Analytical Performance (Precision):
    • Within-laboratory: 11 samples (0% to 70% mutation), 108 measurements per sample.
    • Site-to-Site Reproducibility Study 1 (cell lines): 8 samples (50% to 0% MUT), 96 data points per mutation level.
    • Site-to-Site Reproducibility Study 2 (clinical samples): 6 clinical samples (4 positive, 2 negative), 36 measurements per sample.
  • Analytical Performance (Linearity): 11 different mutation percentages (0-70%) at 5 DNA input levels (30, 20, 10, 5, 2 ng/uL), 4 data points per %MUT per DNA input.
  • Analytical Performance (LoD): First study: 3 positive + 3 negative clinical samples, 6-point dilution series, 20 replicates each in 3 kit lots (180 total measurements). Second study: 2 samples, 30 replicates each (60 data points).
  • Analytical Performance (Interfering Substances): Samples at LoD, with various interfering substances. Proteinase K study used pooled healthy and PV whole blood, spiked, 4 replicates per sample.
  • Accuracy Method Comparison: 276 clinical specimens.
  • Clinical Performance: 216 evaluable subjects (from 286 consented subjects).
• Data Provenance:
  • Country of Origin: Clinical samples for the primary clinical study were collected from 9 study sites in the United States (7 enrolled subjects), 12 study sites in France (all 12 enrolled subjects), and 9 study sites in Italy (5 enrolled subjects).
  • Retrospective/Prospective: The clinical performance study was a multicenter, international, prospective, interventional study. Analytical studies primarily used prepared or pooled samples, with some clinical samples, making them mostly prospective for the specific test scenario.

3. Number of Experts and Qualifications for Ground Truth

• Number of Experts: Not explicitly stated as a number of individual experts.
• Qualifications: Ground truth for the clinical performance study was established by independent assessment of patient status at the clinical site based on the 2008 WHO diagnostic criteria, combined with bidirectional Sanger sequencing and, in some cases, bone marrow biopsy with histologic and cytogenetic analysis. This implies a consensus among clinical professionals (hematologists, pathologists) using established diagnostic guidelines. For the accuracy method comparison, bidirectional Sanger sequencing served as the comparator method.

4. Adjudication Method for the Test Set

• The text describes a process for establishing "clinical truth" in the clinical performance study. The reference for JAK2 status determination was independent assessment of patient status at the clinical site based on the 2008 WHO diagnostic criteria. If initial blood tests by bidirectional assessment (BDS) were negative, bone marrow from patients was tested by bidirectional sequencing. This suggests an adjudicated process based on a diagnostic algorithm and multiple testing modalities to arrive at a final clinical diagnosis for ground truth. There's no explicit mention of an external, blinded adjudication panel in a "X+Y" format, but rather a structured clinical diagnostic pathway.

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

• No, an MRMC comparative effectiveness study was not performed as described. This is an automated IVD kit, not an imaging device requiring human reader interpretation. The performance of the device (ipsogen JAK2 RGQ PCR Kit) was compared against a reference standard (bidirectional Sanger sequencing for analytical accuracy and WHO diagnostic criteria combined with BDS for clinical performance), not against human readers' performance with and without AI assistance.

6. Standalone Performance

• Yes, standalone performance was done. The entire performance evaluation described focuses on the analytical and clinical performance of the ipsogen JAK2 RGQ PCR Kit as a standalone diagnostic test (without human-in-the-loop assistance for interpretation beyond standard laboratory procedures). The device outputs a qualitative result ("Mutation detected," "No Mutation Detected," or "Invalid") and a quantitative %MUT value, which are then used by clinicians as an adjunct to diagnosis. The "Rotor-Gene AssayManager (RGAM) software associated to the JAK2 Plug-in" automates data analysis, meaning no manual analysis required.

7. Type of Ground Truth Used

• Analytical Studies:
  • Known concentrations/dilutions: For precision, linearity, LoD, and stability studies, samples were prepared to contain known percentages of mutated DNA or were derived from characterized cell lines (MUTZ-9, HEL, K-562).
  • Orthogonal methods: For traceability/calibration of standards, an independent orthogonal method was used to confirm values.
  • Bi-directional Sanger sequencing: Used as the comparator method to establish accuracy.
• Clinical Performance Study:
  • The primary ground truth for the clinical study was the 2008 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms, with specific emphasis on PV. This standard incorporates various clinicopathological factors, including hemoglobin levels, hematocrit, EPO levels, and JAK2 mutation status (determined by bidirectional Sanger sequencing). Bone marrow biopsy and cytogenetic analysis were performed when required by the algorithm to confirm diagnosis.

8. Sample Size for Training Set

• The document describes a commercial in vitro diagnostic kit, not an AI/ML model that undergoes "training" in the traditional sense with a distinct training dataset. The development and validation of such a kit typically involve optimization studies and design verification using various samples (cell lines, pooled DNA, clinical samples) which inform the final design and performance characteristics, but these are not referred to as a "training set" in the context of machine learning. Therefore, a specific "training set sample size" as one would expect for an AI model is not applicable/not provided in this document.

9. How Ground Truth for Training Set was Established

• As above, given this is an IVD kit and not an AI/ML model, the concept of a "training set" with ground truth in the AI context does not directly apply. The kit's design and analytical parameters were likely developed and optimized using:
  • Quantified DNA samples: Known concentrations of mutant and wild-type DNA, often from cell lines (like MUTZ-8, HEL, K-562) with characterized mutational status.
  • Clinical samples: Utilized during development and analytical validation to ensure the test performs as expected with real-world variability.
  • Established molecular biology techniques: Such as quantitative PCR, and knowledge of the JAK2 V617F mutation's characteristics.
    The "ground truth" during this development (rather than "training") would be based on these highly characterized materials and established genomic methods.

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