(447 days)
The Wiener Laboratory enzyme-linked Immunosorbent assay (ELISA) recombinante V. 3.0 test system is a manual and automated instrument assay for the qualitative detection of total antibodies (IgG and IgM) to Trypanosoma cruzi in human serum and plasma (EDTA, heparin, or Citrate) using recombinant antigens of T. cruzi. Reactive results are presumptive evidence of present or past infection with Trypanosoma cruzi.
In this qualitative technique for the detection of antibodies anti-T. Cruzi, the sample is diluted in the wells in which recombinant antigens starting from specific proteins from the epimastigote and trypomastigote stages of the T. cruzi corresponding to highly conserved zones are immobilized. These antigens are proteins with aminoacid sequences repeated in tandem. SAPA (shed acute phase antigen) antigens detect antibodies in 93% of the patients' sera during the acute phase of the infection. It comes from the trypomastigote-bloodstream form of the parasite; #1, #2 and #30 antigens detect antibodies in chronic patients; #13 and #36 specially detect antibodies in sera both from acute and chronic patients.
If the sample contains Chagas' antibodies, they bind to the antigens bound to the support. The unbound antigens and antibodies are removed by washing, after which anti-human immunoglobulin antibodies conjugated to peroxidase are added. If a reaction was produced in the first step of the process, the conjugate is bound. After a new washing step and the addition of a chromogenic substrate and stopping reagent, specimens containing antibodies to T. cruzi produce a color reaction which can be read with a standard ELISA plate reader.
Here's an analysis of the provided text to extract information about acceptance criteria and the study that proves the device meets them:
Device Name: Chagatest ELISA recombinante v.3.0 (also referred to as Wiener lab Chagatest ELISA rec. v.3.0)
Intended Use: Qualitative detection of antibodies to Trypanosoma cruzi (causative agent of Chagas' disease) in human serum and plasma. Useful in establishing prior exposure to T. cruzi and as an aid in diagnosis.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in a dedicated section. However, it presents "Performance Characteristics" including "Relative Sensitivity," "Relative Specificity," and "Relative Agreement," with specified confidence intervals. It also highlights an overall relative sensitivity of 97.9% and relative specificity of 97.8% (after resolution of discordant samples) or 97.9% and 97.8% (before resolution of discordant samples) from a combined analysis of multiple sites.
Given the context of a 510(k) summary seeking substantial equivalence, implicit acceptance criteria would likely involve demonstrating high relative sensitivity and specificity that are comparable to or better than predicate devices and meet general diagnostic accuracy expectations for such assays. While not explicitly stated as "acceptance criteria," the reported performance values are what would be used by the FDA to determine substantial equivalence.
| Performance Metric | Reported Device Performance (after resolution unless specified) |
|---|---|
| Relative Sensitivity | 97.9% (95% CI: 95.6 - 99.1%) |
| Relative Specificity | 97.8% (95% CI: 97.0 - 98.5%) |
| Relative Agreement | 97.9% (95% CI: 97.1 - 98.5%) |
| Intra-assay Precision (%CV) - Manual | 4.8% to 19.7% |
| Intra-assay Precision (%CV) - Automated | 7.7% to 14.0% |
| Inter-assay Precision (%CV) - Manual | 7.4% to 26.4% |
| Inter-assay Precision (%CV) - Automated | 15.7% to 29.2% |
2. Sample Sizes Used for the Test Set and Data Provenance
The test set consisted of multiple studies performed at different sites. The total sample size and data provenance are:
| Study/Site | Sample Size | Data Provenance |
|---|---|---|
| 1.1 Comparison with MERIDIAN (U.S. low-risk) | 500 | U.S. (Iowa), low-risk individuals (retrospective, assumed) |
| 1.2 Comparison with MERIDIAN (Mexican Blood Bank) | 83 | Mexican Blood Bank (Guadalajara and Iowa) (retrospective, assumed) |
| 1.3 Comparison with ABBOTT (Argentina) | 790 | Argentina (Rosario, SF) (retrospective, assumed) |
| 1.4 Comparison with ABBOTT (Argentina) | 286 | Argentina (Buenos Aires, Hospital de Clínicas) (retrospective, assumed) |
| 1.5 Comparison with ABBOTT and MERIDIAN | 90 | Unspecified; panel of sera (retrospective, assumed) |
| 2.1 Specificity (U.S. low-risk) | 500 | U.S. (Iowa Hospitals, Iowa City, USA) (retrospective, assumed) |
| 2.2 Sensitivity (Endemic Area, Argentina) | 118 | Argentina (Centro de Enfermedades y Patología Regional, Santiago del Estero), selected reactive specimens (retrospective, assumed) |
| 2.3 Sensitivity (Chile) | 51 | Chile (Instituto de Ciencias Biomedical, Facultad de Medicina, Universidad de Chile, Santiago de Chile) (retrospective, assumed) |
| 2.4 ISP Evaluation (Chile) | 150 | Chile (ISP, Santiago de Chile) (retrospective, assumed) |
| 2.5 High Prevalence (Salta, Argentina) | 58 | Argentina (San Carlos, Provincial de Salta), blood bank specimens (retrospective, assumed) |
| 2.5 High Prevalence (Salta, Argentina) - IHA | 52 | Argentina (Salta), IHA-reactive specimens (retrospective, assumed) |
| 2.6 Specificity (Buenos Aires, Argentina) | 286 | Argentina (Hospital de Clínicas, Buenos Aires) (retrospective, assumed) |
| 2.7 Blood Donors (Sao Paulo, Brazil) | 1236 | Brazil (Hemocentro de Sao Paulo, Sao Paulo), blood donors (retrospective, assumed) |
| 2.7 Blood Donors (Sao Paulo, Brazil) - Panels | 300 | Brazil (Sao Paulo), selected reactive/non-reactive panels (retrospective, assumed) |
| 2.8 Sensitivity Panel (Sao Paulo, Brazil) | 188 | Brazil (Centro de Imunologia e Imunogenetica, Sao Paulo), sensitivity panel (retrospective, assumed) |
| 2.9 Blood Donors (Sao Paulo, Brazil) | 400 | Brazil (Centro de Imunologia e Imunogenetica, Sao Paulo), blood donors (retrospective, assumed) |
| 2.10 Study (Rio de Janeiro, Brazil) | 914 | Brazil (Fundação Oswaldo Cruz, Rio de Janeiro), reactive and non-reactive specimens (retrospective, assumed) |
| 2.11 Xenodiagnosed Positive | 70 | Unspecified, xenodiagnosed positive specimens (retrospective, assumed) |
| 5. Patient Populations (Salta, Argentina) | 52 | Argentina (Salta), IHA-reactive specimens (retrospective, assumed) |
| 5. Patient Populations (Santiago del Estero, Argentina) | 118 | Argentina (Santiago del Estero), IHA/IFA/ELISA-reactive specimens (retrospective, assumed) |
| 5. Patient Populations (Xenodiagnosed) | 70 | Unspecified, xenodiagnosed positive individuals (retrospective, assumed) |
| 5. Pregnant Women (Santiago del Estero, Argentina) | 368 | Argentina (Santiago del Estero), pregnant women (retrospective, assumed) |
Total combined sample size for comparative effectiveness/performance studies appears to be over 5000 specimens across various studies. All data appears to be retrospective based on the nature of the studies (testing existing specimens, panels, or comparing against established methods). The countries of origin include Argentina, Mexico, Chile, and Brazil, with some studies also including low-risk individuals from the U.S.
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 or specific qualifications of individual experts. However, it describes that ground truth was established using:
- Comparison methods: Predicate devices (MERIDIAN Premier™ Chagas' IgG ELISA, ABBOTT Chagas Antibody EIA) were used as primary comparators.
- Confirmatory/Reference tests: Radio Immuno Precipitation Assay (RIPA), Indirect Hemagglutination Assay (IHA), Immunofluorescence Assay (IFA), and xenodiagnosis were used as reference methods, particularly for resolving discordant results or establishing the status of selected panels.
- Clinical context: Specimens were often from "patients with confirmed Chagas' disease by xenodiagnosis, IHA and IFA," "blood donors," or "patients from an endemic area."
- The reference tests (IHA, IFA, RIPA, xenodiagnosis) are typically performed and interpreted by experienced laboratory personnel or medical professionals.
4. Adjudication Method for the Test Set
Adjudication methods are described for discordant results:
- Discordant results between the Wiener lab ELISA and predicate devices were often adjudicated using reference methods like RIPA, IHA, and/or IFA.
- For example: "Out of 5 specimens with discordant results, all 5 were reactive by Wiener lab ELISA and a RIPA, but non-reactive by Meridian." (Section 1.2)
- "Of the 12 specimens with discordant results... 6 specimens were reactive by Wiener lab Chagatest ELISA rec.v.3.0 and non-reactive by Abbott Chagas Antibody EIA. Out of those 6 specimens, 3 were reactive by IFA." (Section 1.3)
- "7 specimens were reactive by Wiener lab ELISA, reactive by IHA / IFA / RIPA and/or Meridian ELISA and non-reactive by Abbott ELISA." (Section 1.5a)
The specific process for how these reference results were used to adjudicate a final ground truth (e.g., majority vote, hierarchy of tests) is not explicitly detailed but implied that the consensus or superior reference test determined the final status.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not explicitly described. This is an in vitro diagnostic device for laboratory use, and its performance is typically assessed by comparing its numerical output (e.g., signal/cut-off ratio) to a threshold and then to gold standard/reference methods, rather than human readers interpreting images or data for diagnosis. The studies focused on comparing the device's diagnostic accuracy (sensitivity, specificity, agreement) to other assays and established reference methods.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, the studies reported are standalone performance evaluations of the Wiener lab Chagatest ELISA recombinante v.3.0. The "algorithm" here refers to the ELISA assay itself, which generates quantitative results (absorbance, s/c ratio) that are then interpreted against a predefined cutoff. The performance metrics (relative sensitivity, specificity, agreement) measure the device's accuracy in identifying positive or negative samples independently, without direct human intervention in the interpretation of each test result beyond comparing it to the cutoff. The studies compare the device's output to other test systems.
7. The Type of Ground Truth Used
The ground truth for the test sets was established using a combination of:
- Expert Consensus/Reference Methods: Primarily through established serological tests like Indirect Hemagglutination Assay (IHA), Immunofluorescence Assay (IFA), Radio Immuno Precipitation Assay (RIPA), and in some cases, previous ELISA results from other reference systems.
- Pathology/Outcomes Data (Indirectly): Xenodiagnosis, a biological method for detecting T. cruzi infection, was used for some "confirmed Chagas' disease" cases (e.g., Section 2.3, 2.11, 5). This can be considered a strong indicator of true infection.
- Clinical context: Patients from endemic areas and those with confirmed Chagas' disease were used to ensure the presence of antibodies, while low-risk individuals were used for specificity studies.
Therefore, the ground truth is a composite ground truth, derived from multiple established diagnostic methods and clinical confirmation strategies.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" or "validation set" in the context of machine learning model development. This is an ELISA kit, which is a biochemical assay, not a machine learning algorithm that requires a training phase. The "studies" described are performance evaluations against established predicate devices and reference methods using various clinical samples. The "training" data for such a kit would implicitly be the data used during its development and optimization, which is not detailed here. The studies provided demonstrate the device's performance on various patient populations, which serves as a clinical validation.
9. How the Ground Truth for the Training Set Was Established
As noted above, this is an ELISA assay, not a machine learning model, so the concept of a "training set" ground truth in the AI context does not directly apply. The establishment of ground truth for the samples used in the performance evaluations (analogous to a test set in ML) is described in point 7 (composite ground truth from various reference methods and clinical confirmation).
§ 866.3870
Trypanosoma spp. serological reagents.(a)
Identification. Trypanosoma spp. serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies toTrypanosoma spp. in serum. The identification aids in the diagnosis of trypanosomiasis, a disease caused by parasitic protozoans belonging to the genusTrypanosoma. Trypanosomiasis in adults is a chronic disease characterized by fever, chills, headache, and vomiting. Central nervous system involvement produces typical sleeping sickness syndrome: physical exhaustion, inability to eat, tissue wasting, and eventual death. Chagas disease, an acute form of trypanosomiasis in children, most seriously affects the central nervous system and heart muscle.(b)
Classification. Class I (general controls).