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The ALPHA Histoplasma Antigen EIA is an immunoenzymatic sandwich microplate assay for the detection of Histoplasma antigens in urine samples. The ALPHA Histoplasma Antigen EIA is a test which, when used in conjunction with other diagnostic procedures such as microbiological culture, histological examination of biopsy samples and radiographic evidence, can be used as an aid in the diagnosis of histoplasmosis.

The ALPHA Histoplasma Antigen EIA is an immunoenzymatic sandwich microplate assay which detects Histoplasma antigens in urine. Rabbit anti-Histoplasma IgG antibodies bound to microwell plates are used as capture antibodies and biotinylated rabbit anti-Histoplasma IgG antibodies are used as detect antibodies. The positive control is made of buffer spiked with Histoplasma capsulatum antigens and the negative control is buffer only. Standards are made of Histoplasma capsulatum antigens from culture filtrate. The kit contains the 100 Standard, 30 Standard, and 2 Standard that are used to generate a sigmoid calibration curve using a four-parameter fit of the blanked absorbance values versus the assigned EIA Values. R-squared values must be greater than or equal to 0.990. Urine samples are run untreated and undiluted. The samples are added to the microwells coated with the capture antibody and incubated. If the patient specimen contains Histoplasma antigens that are recognized by the capture antibody, those antigens will become bound to the microwell. The wells are washed to remove unbound patient material and biotinylated detection antibody is added to the wells. If Histoplasma antigens are bound to the microwell by the capture antibody, then the detect antibody will also become bound to the microwell. The wells are then washed to remove any unbound detect antibody. For detection, biotin-streptavidin chemistry reagents including 3,3′,5′,5′ tetramethybenzadine (TMB) and stop solution are used. Streptavidin conjugated to horseradish peroxidase (HRP) is added to the microwells. In the presence of the biotinylated detect antibody, streptavidin-HRP will become bound to the plate. The plate is then washed to remove any unbound streptavidin-HRP, and TMB substrate solution is added to the microwells. A blue color develops in the presence of the HRP enzyme. The reaction is stopped by the addition of a stop solution. The optical density (absorbance) is determined with a microplate reader at 450nm or 450nm or 450nm alone. EIA Units for specimens are calculated using a four-parameter curve-fit generated with the 4 standards supplied in the kit.

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

ALPHA Histoplasma Antigen EIA Performance Study Analysis

The ALPHA Histoplasma Antigen EIA is an immunoenzymatic sandwich microplate assay designed for the detection of Histoplasma antigens in urine samples, serving as an aid in the diagnosis of histoplasmosis when combined with other diagnostic procedures.

1. Acceptance Criteria and Reported Device Performance

The direct acceptance criteria for this device are not explicitly stated in a consolidated manner as pass/fail thresholds in the provided document. However, the studies conducted demonstrate acceptable performance characteristics. Based on the "Comparison to Culture/Histopathology" section, two key performance metrics were evaluated: Sensitivity and Specificity.

Note: The document implies "acceptable" performance for these metrics rather than specifying strict numerical thresholds for acceptance prior to the study.

2. Sample Size and Data Provenance

• Test Set Sample Size: A total of 278 urine specimens were used for the clinical performance evaluation (comparison to culture/histopathology).
• Data Provenance: The document does not explicitly state the country of origin for the clinical samples. It does mention that "urine specimens containing various substances were obtained from a national reference laboratory" for analytical interference studies, suggesting some US-based data. However, for the main clinical performance, the geographic origin is not specified. The data is retrospective, as specimens were "culture- or histopathology-confirmed" prior to testing with the device.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number of experts used to establish the ground truth or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, the ground truth was established by "culture- or histopathology-confirmed" results. This implies that the diagnoses were made by medical professionals, likely pathologists and/or microbiologists, following standard diagnostic procedures.

4. Adjudication Method for the Test Set

The document does not describe a specific adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of the clinical test set. The ground truth was based on "culture- or histopathology-confirmed" results, which are considered definitive diagnostic methods. This suggests that individual confirmation by these methods was sufficient, and a separate adjudications process was not deemed necessary for the diagnostic truth.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. The study evaluates the performance of the device against established diagnostic methods (culture/histopathology) and against another, non-FDA-cleared Histoplasma antigen EIA, but it does not assess human reader improvement with or without AI assistance.

6. Standalone Performance Study

Yes, a standalone performance study was done. The "Comparison to Culture/Histopathology" section directly assesses the algorithm's (device's) ability to detect Histoplasma antigens in urine samples against established clinical diagnostic methods, without human interpretation as part of the primary outcome.

7. Type of Ground Truth Used

The type of ground truth used was expert consensus, pathology, and microbiological culture results. Specifically, the clinical performance was evaluated against "culture- or histopathology-confirmed urine specimens."

8. Sample Size for the Training Set

The document does not provide information regarding the sample size used for the training set. This is a 510(k) submission, typically focusing on validation rather than development details.

9. How Ground Truth for the Training Set Was Established

The document does not provide information on how the ground truth for any potential training set was established. Given this is a 510(k) for an immunoassay, the device itself is a diagnostic test, and the development process likely involved internal validation and optimization, but specific training set details are not included in this regulatory summary.

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