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The MALDI Biotyper CA System is a mass spectrometer system using matrix-assisted laser desorption/ionization - time of flight (MALDI-TOF) for the identification and differentiation of microorganisms cultured from human specimens.

The MALDI Biotyper CA System is a qualitative in vitro diagnostic device indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and fungal infections.

The MBT-CA System consists of the Microflex LT/SH mass spectrometer, reference library, kit reagents (US IVD HCCA, US IVD Bacterial Test Standard), US IVD 48 Spot Target or MBT Biotarget 96 US IVD plate, and software. The MALDI Biotyper CA System with closed safety covers is a Class 1 Laser product. With the safety cover opened it becomes a Class 4 Laser product.

The MALDI Biotyper CA System reference library was established by analyzing the type strain from each claimed species combined with 4 to ~30 additional strains from the same species provided by clinical laboratories or commercial strain collections. Currently a total of 3029 strains (covering 334 species / groups with 294 bacteria plus 40 yeasts) are contained in the clinically validated MBT-CA library.

Implementation methodology, construction parameters and quality assurance protocols use a standard operating protocol for generation of reference entries and all testing parameters are the same.

MBT-CA microorganism identification is based on isolate MALDI spectra using Bruker reference libraries with a 1:1 comparison of unknown MALDI spectra against each single entry of a given reference library. During a single identification event, an unknown MALDI spectra is compared against each single reference entry producing individual log(score) results. This number of log(scores) is sorted based on their value and the highest one is used to generate the final result. The addition of new reference entries does not influence the already included entries. If no reference entries are removed within a library update the log(score) calculation remains unchanged for the same MALDI spectra.

MALDI Biotyper CA System client software displays a user-interface which guides the user through the MALDI Biotyper CA System workflow. The MALDI Biotyper CA System client also interfaces to the flexControl software for automated acquisition of mass spectra on the microflex LT/SH instrument.

The MALDI Biotyper CA System server communicates with the MALDI Biotyper CA System client and the MBT-DB server. It performs preprocessing on acquired spectra, and matches peak lists against the Main Spectrum (reference pattern, (MSP)) for matching and calculates the score value (log (score)).

The MBT-DB server stores all information for the MALDI Biotyper CA System. The MBT-DB maintains spectra data (creation information and mass/intensity lists), project data (results of defined and executed runs), method data (parameter lists for spectra preprocessing and identification), user management data, reference patterns and other peak lists plus additional maintenance data.

GTPS firmware communicates with the flexControl PC software, controls and monitors the vacuum, moves the sample carrier and performs the docking of the target plate, controls and monitors high voltages in the ion source, generates trigger signals, and monitors instrument status.

The flexControl acquisition software communicates with the MALDI Biotyper CA System client, loads automatic run jobs, communicates with the GTPS firmware, communicates with the laser in the microflex LT/SH instrument, sets the acquisition parameters in the digitizer and reads the acquired data from the digitizer, performs automated data acquisition, evaluates acquired spectra, adjusts the laser power during automatic data acquisition, performs a re-calibration of the time-of-flight to mass transformation, stored acquired spectra on disk and performs source cleaning. The flexControl software does not display a user interface.

The optional Honeywell (Hyperion 1300g) Barcode Reader USB cable is connected to the MALDI Biotyper CA System computer. The barcode reader scans the unique ten-digit target ID which appears in the Target ID box on the target plate. After the target ID has been entered, the a new Run page opens and the ten-digit target ID appears as the Plate ID and is appended to the Run name. Sample identifications are entered into the computer corresponding to the target plate position for that run.

Here's a breakdown of the acceptance criteria and study information for the MALDI Biotyper CA System, extracted from the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document describes performance for the addition of Candida auris to the existing MBT-CA reference library, rather than a full de novo clearance study of the entire device. Therefore, the "acceptance criteria" here refer to the performance required for the inclusion of this new organism into the established system.

Additionally, for analytical specificity (cross-identification studies):

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

• For C. auris performance evaluation:

  • Number of C. auris isolates: 28 isolates for performance evaluation, 22 of which were used for generating the truth tables (excluding 6 strains used for reference entries).
  • Total C. auris spectra: 22 strains * 3 sample preparations (DT, eDT, Ext) * 8 spots = 528 spectra for truth table counting. (The document states 888 spectra for identification across (37 strains * 3 sample preparations * 8 spots), where 37 strains includes 28 C. auris and 9 related yeasts).
  • Data Provenance: CDC & FDA Antibiotic Resistance Isolate Bank (USA), isolates from (b) (4) (Europe/US likely), and field strains (unspecified location).

• For Analytical Specificity (wet testing of claimed organisms):

  • Sample Size: 10 "cleared species" (e.g., E. coli, K. pneumoniae, S. aureus, C. albicans, C. glabrata).
  • Total Spectra: 10 species * 3 sample prep techniques * 3 replicates * 2 instruments = 360 spectra/log(scores).
  • Data Provenance: Not explicitly stated but inferred to be well-characterized strains from resource centers (e.g., ATCC).

• For Analytical Specificity (wet testing of RUO organisms):

  • Sample Size: 9 RUO species.
  • Total Spectra: Not explicitly stated (marked as (0) pectra / log(scores) which could be a typo or redaction for a large number). Each species tested with 3 replicates, 3 sample prep techniques, on 2 instruments.
  • Data Provenance: Not explicitly stated but inferred to be well-characterized strains from resource centers.

• For Analytical Specificity (in silico evaluation):

  • Sample Size: 6822 log(scores) from a subset of stored spectra for previously claimed organisms.
  • Data Provenance: Not explicitly stated but refers to historical data from previous studies (K130831, K142677, K163536).

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

The document does not explicitly state the number of experts or their qualifications for establishing the ground truth for the Candida auris test set. However, it indicates that the ITS sequence was determined for the 6 strains used for the new reference library entries, and implies that the remaining C. auris isolates were well-characterized from reputable sources (CDC & FDA, other resource centers). The "Reference Algorithm" is used as the comparative method for C. auris performance. Given this is a microbiology identification device, ground truth is typically established by established phenotypic, genotypic (e.g., DNA sequencing), or biochemical methods, often confirmed by expert microbiologists.

4. Adjudication Method for the Test Set

The document does not describe an explicit adjudication method (like 2+1 or 3+1) involving multiple human readers for setting the ground truth for the test set. Instead, it relies on:

• Established sources for isolates (CDC & FDA Antibiotic Resistance Isolate Bank, other resource centers).
• ITS sequence determination for reference strains.
• "Reference Algorithm" as the gold standard for comparison (likely a combination of genotypic and phenotypic characterization).

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study is described in this document. The device is for automated microorganism identification, so human reader improvement with AI assistance is not directly applicable in the same way it would be for image interpretation tasks. The comparison is between the device's automated identification and a reference method.

6. Standalone Performance Study (Algorithm Only)

Yes, a standalone performance study was done. The entire evaluation focuses on the performance of the MALDI Biotyper CA System (algorithm plus instrument) in identifying microorganisms without human-in-the-loop during the identification process itself. Users "aid in the diagnosis" using the output, but the identification is automated. The log(score) output directly reflects the algorithm's confidence in its standalone identification.

7. Type of Ground Truth Used

The ground truth used for the Candida auris evaluation was based on:

• Genetic Sequencing: ITS sequence determination for the 6 C. auris strains used for reference library generation.
• Established Reference Materials: Isolates obtained from reputable sources like the CDC & FDA Antibiotic Resistance Isolate Bank, which are generally well-characterized by various methods (genotypic and phenotypic). The document refers to it as the "Reference Algorithm" in performance tables.

For the analytical specificity studies, "well-characterized set of cleared species" and "well-characterized set of RUO species" from resource centers implies established identification through various, often molecular, methods.

8. Sample Size for the Training Set

The document describes the content of the reference library (which serves as the training/reference data for the algorithm), but does not specifically refer to it as a "training set" in the context of machine learning model development. Instead, it's a reference database.

• Total Reference Entries (database): 3029 strains covering 334 species/groups (294 bacteria + 40 yeasts).
• C. auris specific reference entries: 6 strains.
• How reference entries are built: Each entry is based on analyzing the type strain from each claimed species combined with 4 to ~30 additional strains from the same species.

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

The ground truth for the reference library (training set) entries was established by:

• Analyzing type strains: For each claimed species.
• Analyzing additional strains: 4 to ~30 additional strains per species from clinical laboratories or commercial strain collections.
• Standard Operating Protocol: Implementation methodology, construction parameters, and quality assurance protocols use a standard operating protocol for the generation of reference entries.
• DNA Sequencing: For the newly added C. auris strains, ITS sequencing was performed for all 6 strains used for the new reference library entries. It's also mentioned as a requirement for "all type strains and at least 20% of the non-type strains of a species detected by the device" to be characterized by DNA sequence analysis (as part of special controls for this device type). This implies that a significant portion of the existing library entries also have DNA sequencing as part of their ground truth establishment.

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The Bruker Daltonics, Inc. MALDI Biotyper CA System is a mass spectrometer system using matrix-assisted laser desorption/ionization – time-of-flight (MALDI-TOF) for the identification of microorganisms cultured from human specimens.

The MALDI Biotyper CA System is a qualitative in vitro diagnostic device indicated for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of bacterial and yeast infections.

The Bruker Daltonics, Inc. MALDI Biotyper CA System is a mass spectrometer system using matrix-assisted laser desorption/ionization – time-of-flight (MALDI-TOF) for the identification of microorganisms cultured from human specimens. The system measures the time (in the nanosecond range) between pulsed acceleration and the corresponding detector signal, the speed is converted into an exact molecular mass. The mass-to-charge ratio of an ion is proportional to the square of its drift time. Highly abundant microbial proteins (mainly ribosomal proteins) result in a mass spectrum with characteristic mass and intensity distribution. It is specific for many bacteria and is interpreted as a molecular fingerprint to identify the test organism.

Here's an analysis of the provided text to extract the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a formal table format with numerical targets. However, based on the performance data presented, the implicit acceptance criteria for identification confidence (log(score) ≥ 2.00) are assessed. The reported performance for "Overall Isolate Performance" (Table 6) shows the aggregate performance across all claims.

2. Sample Sizes and Data Provenance

• Test Set Sample Size: 4,395 fresh and stored organisms, generating 4,399 data points for the method comparison study (which serves as the primary test set for demonstrating performance against a reference). This also includes 3,802 replicate testing results reported separately.
• Data Provenance: The method comparison study was performed at six (6) US clinical test sites and an in-house laboratory. The organisms included both fresh and stored organisms. The document indicates that due to the rarity of some organisms, replicates were tested by multiple sites.

3. Number of Experts and Qualifications for Ground Truth of Test Set

The document does not explicitly state the number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience") for establishing the ground truth of the test set organisms. However, it indicates:

• "The interim reference laboratory stored all organisms included in the study and sent all organisms to the sequencing reference laboratory for sequencing and protein sequencing when requested."
• This implies that a reference laboratory, likely staffed by expert microbiologists and molecular biologists, was responsible for confirming the identity of the organisms used as ground truth, primarily through sequencing and protein sequencing.

4. Adjudication Method for the Test Set

The document does not mention a specific adjudication method like "2+1" or "3+1" for discrepancies in the test set. The ground truth was established by a "sequencing reference laboratory for sequencing and protein sequencing." This suggests that the final identification was based on these molecular methods, rather than an expert consensus process between multiple readers.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an automated mass spectrometry system for identifying microorganisms. The evaluation focuses on the device's ability to identify organisms compared to a reference method (sequencing/protein sequencing), not on how it assists human readers or improves their performance.

6. Standalone (Algorithm Only) Performance

Yes, a standalone performance study was done. The entire Method Comparison section (pages 20-25) describes the performance of the MALDI Biotyper CA System (the algorithm/device) in identifying microorganisms without human intervention in the identification process other than following the described workflow. The log(score) system is an output of the algorithm.

7. Type of Ground Truth Used

The primary type of ground truth used for the test set was molecular sequencing (sequencing and protein sequencing), which is considered a highly accurate and definitive method for microorganism identification. This was handled by a "sequencing reference laboratory."

8. Sample Size for the Training Set

The document does not explicitly state the sample size for the training set. It refers to a "reference spectra library (database)" against which the test organism's spectrum is compared. This library is implicitly the training data, but its specific size or composition is not detailed in terms of number of unique isolates or spectra.

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

The document states: "Calculates matches by comparing a new spectrum against each single reference entry of a reference database." It also mentions "MALDI Biotyper for Clinical Applications (MBT-CA)" as the database. While it doesn't describe the exact process for establishing ground truth for each entry within that database, it's generally understood that such reference libraries are built using highly characterized strains whose identities have been confirmed through gold-standard methods (e.g., 16S rRNA gene sequencing, whole-genome sequencing, or polyphasic taxonomy). The context implies that the internal reference library's entries serve as the established ground truth for comparison.

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