(227 days)
The Accelerate PhenoTest BC kit is a multiplexed in vitro diagnostic test utilizing both qualitative nucleic acid fluorescence in situ hybridization (FISH) identification and quantitative, antimicrobial susceptibility testing (AST) methods and is intended for use with the Accelerate Pheno system. The Accelerate PhenoTest BC kit is capable of simultaneous detection and identification of multiple microbial targets followed by susceptibility testing of the appropriate detected bacterial organisms. The Accelerate PhenoTest BC kit is performed directly on blood culture samples identified as positive by a continuous monitoring blood culture system. Results are intended to be interpreted in conjunction with Gram stain results.
The Accelerate PhenoTest BC kit identifies the following Gram-positive and Gram-negative bacteria and yeasts utilizing FISH probes targeting organism-specific ribosomal RNA sequences: Staphylococcus aureus, Staphylococcus lugdunensis, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (i.e., Streptococcus mitis, Streptococcus oralis, Streptococcus gallolyticus, Streptococcus agalactiae, Streptococcus pneumoniae, not differentiated), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated), Serratia marcescens, Candida albicans and Candida glabrata.
The Accelerate PhenoTest BC kit tests the following antimicrobial agents with the specific target organisms identified below:
Amikacin: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ampicillin: Enterococcus faecalis and Enterococcus faecium
Ampicillin/Sulbactam: Escherichia coli, Klebsiella spp. (i.e., Klebsiella pneumoniae, . Klebsiella oxytoca, not differentiated), and Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated)
Aztreonam: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated). Proteus spp. (i.e., Proteus mirabilis. Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftazidime: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftaroline : Staphylococcus aureus .
Cefepime: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ceftriaxone: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Ciprofloxacin: Pseudomonas aeruginosa, Klebsiella spp. (i.ess, Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Daptomycin: Staphylococcus aureus, Coagulase-negative Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis and Enterococcus faecium
Erythromycin: Staphylococcus aureus
Ertapenem: Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Gentamicin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Linezolid: Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium .
Meropenem: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis. Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii. Citrobacter koseri, not differentiated) and Serratia marcescens
Piperacillin/Tazobactam: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Tobramycin: Pseudomonas aeruginosa, Klebsiella spp. (i.e., Klebsiella pneumoniae, Klebsiella ● oxytoca, not differentiated), Escherichia coli, Enterobacter spp. (i.e., Enterobacter cloacae, Enterobacter aerogenes, not differentiated), Proteus spp. (i.e., Proteus mirabilis, Proteus vulgaris, not differentiated), Citrobacter spp. (i.e., Citrobacter freundii, Citrobacter koseri, not differentiated) and Serratia marcescens
Vancomycin: Staphylococcus aureus, Staphylococcus lugdunensis, Coagulase-negative . Staphylococcus species (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus lugdunensis, Staphylococcus warneri, not differentiated), Enterococcus faecalis and Enterococcus faecium
The following resistance phenotypes are reported based on qualitative tests: Methicillin-resistance (S. aureus S. lugdunensis, coagulase negative staphylococci) and macrolide-lincosamide-streptogramin B resistance (MLSb) (S. lugdunensis and coagulase negative staphylococci).
The Accelerate PhenoTest BC kit is indicated as an aid in the diagnosis of bacteremia and fungemia. It is also indicated for susceptibility testing of specific pathogenic bacteria as identified above commonly associated with or causing bacteremia. Results are intended to be used in conjunction with other clinical and laboratory findings.
Standard laboratory protocols for processing positive blood cultures should be followed to ensure availability of isolates for supplemental testing as needed. Additionally, subculture of positive blood culture is necessary for the identification and susceptibility testing of: organisms not identified by the Accelerate PhenoTest BC kit, organisms present in polymicrobial samples, organisms for which species identification is critical for patient care (e.g., speciation of Streptococcus spp.), samples for which an "indeterminate" result for any probe was obtained, for testing antimicrobial agents not included on the Accelerate panel and for epidemiologic testing.
The Accelerate Pheno system is comprised of the Accelerate Pheno instrument, software, host computer, analysis computer, and the Accelerate PhenoTest BC kit. The Accelerate PhenoTest BC Kit contains a sample vial, a 48-channel disposable test cassette and a reagent cartridge needed to test samples from a blood culture bottle that has been flagged as positive by a continuous monitoring blood culture system. All identification (ID) and antimicrobial susceptibility testing (AST) is performed in individual flowcells of the test cassette. The reagent cartridge contains gel electrofiltration (GEF) stations, fluorescence in situ hybridization (FISH) probes, antibiotics, and reagents for automated sample preparation, identification of bacterial and fungal target organisms (Table 1), and antimicrobial susceptibility testing and phenotypic resistance detection testing for bacterial target organisms (Tables 2 and 3). The user loads an aliquot of the positive blood culture into the sample vial, places the test cassette, reagent cartridge and sample vial into an Accelerate Pheno System module, and then presses the module button to close the module door and start the run. The remainder of the operations are automated as described below.
Automated Sample Preparation
Automated sample preparation is performed using gel electro-filtration (GEF) which is based on gel electrophoresis principles. The sample is automatically transferred to a gel containing pores smaller than bacterial or yeast cells. Application of an electric field causes lysed blood cells and/or other sample debris to pass into the gel while bacterial/yeast cells remain inside the gel well. The electric field is briefly reversed to dislodge bacterial/yeast cells from the gel wall prior to removal.
Cell Capture
Following sample preparation, recovered cells are automatically pipetted into multiple flowcell channels of the test cassette. Conductive layers of transparent indium tin oxide (ITO) coat the top and bottom inner surfaces of each flowcell channel and act as electrodes. An additional cationic poly-Llysine layer on the bottom of each flowcell acts as a capture surface. When a voltage is applied, the negatively-charged bacterial/yeast cells migrate to the positively-charged capture surface where they are captured prior to imaging.
Fluorescence in situ Hybridization (FISH) for Identification
Cocktails of ATTO-532 (green) fluorescently-labeled DNA probes bind to the ribosomal RNA of target organisms following permeabilization. Each cocktail also includes ATTO-647 (red) labeled universal bacterial probe that binds to the ribosomal RNA of all clinically relevant bacterial ID channels) or universal eukaryotic probe that binds to the ribosomal RNA of all clinically relevant yeast (yeast ID channels). The system images each flowcell using an epifluorescence microscope with camera at 532 nm, 647 nm and in dark-field. To exclude debris, only dark-field objects that are colocalized with universal probe signal are included in analysis. Colocalization of target probe signal and universal probe signal identifies a target organism.
The software also quantitates the total number of organisms present in a sample using a nucleic acid stain in a separate control flowcell. Comparing the relative numbers of each target organism to the number of objects lit up by the universal probes and universal nucleic acid stain allows for non-target organism and polymicrobial sample detection. FISH ID results are reported approximately 90 minutes after loading the sample, and the ID result determines the selection of appropriate antibiotics for subsequent antimicrobial susceptibility testing.
Morphokinetic Cellular Analysis (MCA) for Antimicrobial Susceptibility Testing (AST)
Sample remaining after the identification assay is initiated is combined with growth media and organisms contained in the sample undergo a pre-growth step during the FISH ID assay to normalize growth rates prior to AST. Following automated sample preparation and cell capture, growth media containing single concentrations of each test antibiotic are added to separate flowcell channels; antibiotics are selected based on the identification provided by the FISH identification (Tables 2 and 3). The bacteria in each flowcell are imaged every 10 minutes for up to 4.5 hours, creating a timelapse record of bacterial growth from individual progenitor cells into clones of daughter cells.
During this period. several microscopic features are measured through morphokinetic cellular analysis, such as cell morphology and the light intensity of a growing clone over time, and used for analysis. The precise quantitative measurement of individual clone growth rate over time is an indicator of antimicrobial efficacy. Onboard software algorithms derive minimum inhibitory concentration (MIC) values from the measured features, and apply appropriate expert rules for proper interpretation and reporting of categorical interpretations - S, I or R (susceptible, intermediate, or resistant) for MIC determinations and positive or negative for phenotypic resistance markers. AST results are reported in approximately 5 hours after ID results. The reportable ranges for each antimicrobial and phenotypic resistance markers are listed in Tables 4 and 5.
The provided text describes the evaluation of the Accelerate PhenoTest BC Kit. Here's a breakdown of the acceptance criteria and study details:
1. Table of Acceptance Criteria & Reported Device Performance:
The document outlines performance metrics that serve as acceptance criteria for different aspects of the device.
| Performance Metric Category | Specific Metric (Acceptance Criteria Mentioned or Implied) | Reported Device Performance (as stated in the text) |
|---|---|---|
| Identification (ID) Assay | Reproducibility (>95% for most probes) | 11 of 12 probe targets showed reproducibility > 95%. The Enterobacter probe (ENT) initially showed 87.5% but improved to 93.2% after a post-study imaging processing change and re-evaluation. |
| Growth & Detection (ID Consistency over time) | Correct identifications obtained for all samples at both t=0 and t=8 hours post-positivity, validating the sponsor's claim for testing within 8 hours. | |
| Analytical Inclusivity (Detection & Identification) | All isolates included in the Inclusivity Study (Tables 15-17) were detected and correctly identified by the PhenoTest BC Kit. | |
| Analytical Specificity (Exclusivity - Non-Cross Reactive) | Organisms in Tables 18 and 19 (non-cross-reacting, some with indeterminate results) were tested. In silico analysis also predicted some cross-reactivity (Table 20). | |
| Limit of Detection (LoD) (Reliable detection >95%) | In most cases, the LoD is at or below the concentration of organisms present when blood cultures are determined to be positive. Average LoD: Gram-negative (4 x 10^8 CFU/mL), Gram-positive (5 x 10^8 CFU/mL), Candida sp. (2 x 10^6 CFU/mL). S. agalactiae LoD was not established. (Tables 21-23). | |
| Interference Studies (ID) | 99.5% agreement with expected results; all samples returned an ID result with endogenous substances and heparin. | |
| Blood Bottle Type (ID) (>95% detected & correctly identified) | For 12 of 13 bottle types, the ID assay provided acceptable results (>95% of organisms detected and correctly identified). One bottle type (BACTEC PLUS Anaerobic F) detected and identified 94.3% of aerobic isolates. | |
| Polymicrobial LoD (ID) | Acceptable detection and identification of all isolates in various concentrations, except S. aureus (with C. albicans at high concentration) was not detected. | |
| Biological Interference (ID) | 15 of 17 polymicrobial combinations resulted in 100% detection of all organisms. S. aureus and K. pneumoniae (with C. albicans at high concentration) were not detected. | |
| Clinical Sensitivity/PPA (ID) | Gram-Positive: CNS (95.3%), EFS (97.0%), EFM (98.0%), SAU (97.9%), SLU (97.5%), STR (97.2%). Gram-Negative: ABA (98.6%), CIT (96.8%), ENT (97.3%), ECO (97.3%), KLE (96.1%), PRO (97.7%), PAE (100%), SMA (100%). Candida spp.: CAL (100%), CGL (100%). (Tables 27-29) | |
| Clinical Specificity/NPA (ID) | Gram-Positive: CNS (98.2%), EFS (99.9%), EFM (99.1%), SAU (98.5%), SLU (99.9%), STR (97.6%). Gram-Negative: ABA (99.7%), CIT (99.3%), ENT (99.5%), ECO (99.7%), KLE (99.6%), PRO (99.6%), PAE (99.4%), SMA (99.9%). Candida spp.: CAL (99.6%), CGL (98.4%). (Tables 27-29) | |
| Antimicrobial Susceptibility Testing (AST) Assay | Reproducibility (>95% acceptable, some exceptions) | 17 of 18 antimicrobials and resistance phenotypes had best case reproducibility > 95%. Erythromycin had best and worst case reproducibility of 93.6%, which was considered acceptable. (Table 7). |
| Growth & Detection (AST Consistency and Agreement) | For parameter 1 (consistency of MIC values): 421/429 (98%) repeatability of all MIC values. For parameter 2 (EA and CA vs reference): All antimicrobials showed EA and CA ≥ 89.9% except for some specific antimicrobial/organism combinations with lower performance, addressed by limitations. (Table 14). | |
| Interference Studies (AST) | Endogenous substances/organism/antimicrobial combinations demonstrated >89.9% EA for 98% (352/360) and >89.9% CA for 94% (340/360) of combinations. | |
| Blood Bottle Type (AST) | All bottle types provided acceptable EA and CA values for most organisms. MLSb detection had insufficient data for some bottle types, leading to specific limitations. | |
| Biological Interference (AST) | AST testing of two organisms was not supported; only one organism in a polymicrobic sample will be tested. | |
| Clinical Essential Agreement (EA) | Ampicillin (100.0%), Ceftaroline (93.3%), Daptomycin-Staphylococcus (99.1%), Daptomycin-Enterococcus (95.5%), Erythromycin (98.2%), Linezolid-S. aureus (99.5%), Linezolid-Enterococcus (96.4%), Vancomycin-S. aureus (98.0%), Vancomycin-others (96.4%), Amikacin (94.2%), Ampicillin/Sulbactam (91.0%), Aztreonam (96.6%), Cefepime-Enterobacteriaceae (97.7%), Cefepime-P. aeruginosa (88.1%), Ceftazidime-Enterobacteriaceae (86.2%), Ceftazidime-P. aeruginosa (86.8%), Ceftriaxone (89.8%), Ciprofloxacin (96.7%), Ertapenem (98.9%), Gentamicin (99.2%), Meropenem-Enterobacteriaceae (97.0%), Meropenem-P. aeruginosa (88.2%), Piperacillin/Tazobactam (92.1%), Tobramycin (96.4%). (Tables 32-33) | |
| Clinical Categorical Agreement (CA) | Ampicillin (99.6%), Ceftaroline (99.7%), Daptomycin-Staphylococcus (99.7%), Daptomycin-Enterococcus (99.1%), Erythromycin (96.7%), Linezolid-S. aureus (100.0%), Linezolid-Enterococcus (98.2%), Vancomycin-S. aureus (99.0%), Vancomycin-others (96.4%), Amikacin (94.0%), Ampicillin/Sulbactam (84.2%), Aztreonam (97.7%), Cefepime-Enterobacteriaceae (96.8%), Cefepime-P. aeruginosa (92.9%), Ceftazidime-Enterobacteriaceae (93.9%), Ceftazidime-P. aeruginosa (88.7%), Ceftriaxone (96.6%), Ciprofloxacin (98.2%), Ertapenem (98.6%), Gentamicin (98.4%), Meropenem-Enterobacteriaceae (98.1%), Meropenem-P. aeruginosa (90.2%), Piperacillin/Tazobactam (92.1%), Tobramycin (96.1%). (Tables 32-33) | |
| Clinical Phenotypic Resistance (CA) | Cefoxitin (98.2%), MLSb (98.2%). (Table 34) |
2. Sample Size Used for the Test Set and the Data Provenance:
-
Clinical Study Test Set:
- Total 1850 positive blood culture samples were evaluated for clinical performance.
- Provenance:
- 793 fresh samples (aliquots of left-over positive blood cultures from patients suspected of bacteremia or fungemia). These were prospectively collected in the U.S.
- 65 fresh seeded samples (blood cultures seeded with human blood and previously characterized fresh clinical isolates isolated within seven days of seeding). These were prospectively collected in the U.S.
- 477 samples seeded with challenge isolates (obtained from culture collections).
- 515 samples seeded with stock isolates (obtained from clinical specimens at the clinical sites and stored for longer than seven days).
- Study conducted at 13 geographically distinct U.S. sites.
-
Analytical Studies (various test sets):
- Reproducibility: At least 90 data points per probe target for ID, ~10 organisms with on-scale MICs for AST (total 1644 tests).
- Growth & Detection: 21 on-panel organisms and 1 off-panel organism tested in triplicate (total 175 tests).
- Inclusivity & Exclusivity: Three strains of each on-panel target species for inclusivity (total 253 tests for ID section). Individual representative strains for exclusivity (total 318 tests for ID section).
- LoD: Varied by organism, usually >20 replicates per strain (e.g., 22/22, 21/22 etc. reported). Total 849 tests for monomicrobial LoD. Total 182 for polymicrobial LoD.
- Interference: Varied by organism/substance (total 526 tests).
- Blood Bottle Type: Minimum of 10 replicates per sample/bottle type (total 1419 tests overall for this study).
- Polymicrobial LoD: 13 pairs of different microbial species, tested in duplicate (total 182 tests).
- Biological Interference: 17 combinations tested (total 49 tests).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts:
The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.
- For AST, the ground truth was established by CLSI broth microdilution reference method. The isolates were tested in triplicate by this method, with the mode MIC value serving as the reference.
- For ID, the ground truth was VITEK2 (bioMérieux). For isolates where VITEK2 yielded an invalid result, 16S rRNA gene sequencing was used as the reference identification.
- For phenotypic resistance markers (cefoxitin and MLSb), the ground truth was disk diffusion performed singly, with triplicate testing and modal category if the initial test failed or was near the breakpoint.
The implication is that these reference methods themselves represent an "expert consensus" or established standard, rather than a panel of human experts explicitly reviewing each case's ground truth.
4. Adjudication Method for the Test Set:
The document does not describe an explicit adjudication method (e.g., 2+1, 3+1) for discrepant results between the device and the reference methods. The reference methods (CLSI broth microdilution, VITEK2, 16S rRNA gene sequencing, and disk diffusion) are considered the definitive ground truth.
For AST, if no mode value could be determined or if a QC failure occurred for the reference method, an additional three replicates were tested to determine the mode MIC. This implies a process to ensure a robust reference result, but not an independent adjudication by experts comparing device output to reference.
5. If a Multi Reader Multi Case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was NOT done. This device is an automated, in vitro diagnostic test for microbial identification and antimicrobial susceptibility, not an AI-assisted diagnostic imaging tool that would typically involve human readers. Its performance is compared directly to established laboratory reference methods.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
Yes, the primary clinical and analytical performance studies were effectively standalone (algorithm only) performance studies. The Accelerate PhenoTest BC Kit is described as a "fully-integrated and fully automated system" that uses "onboard software algorithms" to derive results. The performance metrics (accuracy, sensitivity, specificity, EA, CA) are calculated by comparing the device's automated results to established reference methods, without human interpretation of the device's raw data directly influencing the reported output. The system is designed to provide final identification and AST results automatically.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The ground truth for the studies was based on:
- Reference Laboratory Methods:
- Identification (ID): Primarily VITEK2 (bioMérieux). For invalid VITEK2 results, 16S rRNA gene sequencing was used.
- Antimicrobial Susceptibility Testing (AST): CLSI broth microdilution reference method.
- Phenotypic Resistance: Disk diffusion.
- Known Characteristics of Seeded Isolates: For a significant portion of the test set (fresh seeded, challenge, and stock isolates), the identity and susceptibility profiles were "previously characterized" or "known characteristics" of the spiked organisms. This implies a highly controlled and validated ground truth for these samples.
This is a form of reference standard ground truth, using established, highly accurate laboratory methods as the benchmark rather than direct patient outcomes or a panel of human experts interpreting raw data.
8. The sample size for the training set:
The document does not explicitly state the sample size for the training set. The evaluation focuses on the performance of the developed device using a test set against reference methods. It describes "onboard software algorithms" but doesn't detail their development or the data used for internal training/validation.
9. How the ground truth for the training set was established:
Since the training set size is not provided, the method for establishing its ground truth is also not detailed. However, given the nature of the device and the performance studies, it is highly probable that any data used for training/algorithm development would have had its ground truth established through similar rigorous microbiological reference methods (e.g., CLSI, sequencing, culture).
§ 866.1650 A cellular analysis system for multiplexed antimicrobial susceptibility testing.
(a)
Identification. A cellular analysis system for multiplexed antimicrobial susceptibility testing is a multiplex qualitative and/or quantitative in vitro diagnostic device intended for the identification and determination of the antimicrobial susceptibility results of organisms detected in samples from patients with suspected microbial infections. This device is intended to aid in the determination of antimicrobial susceptibility or resistance when used in conjunction with other laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) Detailed device description documentation, including the device components, ancillary reagents required but not provided, a detailed explanation of the methodology, including primer/probe sequence, design, rationale for sequence selection, and details of the antimicrobial agents, as applicable.
(ii) Detailed documentation from the following analytical and clinical performance studies: limit of detection, inclusivity, precision, reproducibility, interference, cross-reactivity, carryover, and cross-contamination, quality control and additional studies, as applicable to specimen type and assay intended use.
(iii) Detailed documentation from an appropriate clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) Limitations and protocols regarding the need for correlation of results by standard laboratory procedures, as applicable.
(ii) A detailed explanation of the interpretation of results and acceptance criteria.
(iii) A detailed explanation of the principles of operation and procedures for assay performance and troubleshooting.