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The Factor VIII Antibody Screen is a qualitative solid phase enzyme linked immunosorbent assay (ELISA) designed to detect IgG antibodies reactive with recombinant human factor VIII (FVII) in human serum and plasma.

The Factor VIII Antibody Screen is designed as a solid phase enzyme-linked immunosorbent assay (ELISA) with a colorimetric endpoint. This product is intended to be used as an in vitro diagnostic kit by hemostasis and other laboratories to screen patient samples for the presence of IgG antibodies reactive with human Factor VIII.

The Factor VIII Antibody Screen is an Enzyme Linked Immunosorbent Assay with a colorimetric endpoint. The Factor VIII Antibody Screen is designed to detect IgG antibodies reactive with recombinant human Factor VIII in human serum and plasma. The Factor VIII Antibody Screen kit contains all of the reagents necessary to perform the assay.

The Factor VIII Antibody Screen solid phase ELISA microwells provide immobilized recombinant human FVIII as target molecules for the detection of anti-Factor VIII IgG antibodies.

Diluted patient serum or plasma is added to microwells coated with recombinant FVIII molecules allowing antibody, if present, to bind. Unbound material is then washed away. An alkaline phosphatase labeled anti-human immunoglobulin reagent (Anti-IgG) is added to the wells and incubated. The unbound Anti-IgG is washed away and the substrate PNPP (p-nitrophenyl phosphate) is added. After a 30 minute incubation period, the reaction is stopped by a sodium hydroxide solution. The optical density of the color that develops is measured in a spectrophotometer at 405 nm with no reference filter.

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 define a list of "acceptance criteria" with specific thresholds in a standardized table format. Instead, it discusses the performance against a predicate device and a "gold standard" (Bethesda assay), and establishes internal precision and reproducibility standards. Based on the "Conclusions" sections of the performance studies, here's a reconstructed table:

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

• Accuracy Study (Method Comparison):
  • Sample Size: "more than 200 samples"
  • Data Provenance: Combined internal study at GTI and an external study at the Special Coagulation Lab, Mayo Clinic, Rochester, MN, USA.
  • Sample Types: Serum, serum converted from plasma (3.2% or 3.8% sodium citrate), and plasma collected in ACD, from hemophiliac donors (with and without FVIII antibodies).
• Precision Study:
  • Sample Size: 8 samples
  • Data Provenance: Not explicitly stated, likely internal.
• Sample Type Qualification Study:
  • Sample Size:
    • 59 normal healthy, non-hemophiliacs (for serum vs. 3.2% sodium citrate plasma comparison).
    • 14 healthy, non-hemophilia donors (for serum vs. 3.2% sodium citrate vs. ACD plasma comparison).
    • Spiked samples: "12 plasma and serum pairs" and "24 plasma pairs" (for antibody positive plasma spiked into different matrices).
  • Data Provenance: Normal plasma samples were purchased as whole blood or collected from GTI employees. Antibody-positive samples were, by inference, either existing positive samples or spiked for the experiment.
• Interfering Substances Study:
  • Sample Size: 3 samples (1 negative, 1 with medium reactivity, 1 with high reactivity)
  • Data Provenance: Internal study at GTI.
• Lot-to-Lot Reproducibility Study:
  • Sample Size: 12 samples (7 known negative, 5 known positive)
  • Data Provenance: Not explicitly stated, likely internal.
• Shelf-life Study:
  • Sample Size:
    • Accelerated microwell stability: "no time points constituted a failed assay" (implies multiple tests).
    • Real-time kit stability: 3 kit lots tested with "known negative sample" and "known positive samples" (number of samples not specified, but at least two: one negative, one positive).
  • Data Provenance: Internal testing at GTI.

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

The document does not specify the number of experts or their qualifications for establishing ground truth.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method for the test set. Ground truth was established by comparison to existing assays (Factor VIII Inhibitor Assay and Bethesda assay).

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

No multi-reader multi-case (MRMC) comparative effectiveness study was mentioned. The device is an in vitro diagnostic (IVD) ELISA test, not an imaging or interpretation device that would typically involve human readers.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the studies described are for the standalone performance of the Factor VIII Antibody Screen kit as an in vitro diagnostic device. There is no human-in-the-loop component mentioned for the interpretation of the optical density (OD) values, which are converted to positive/negative based on a predefined cutoff relative to a kit control.

7. Type of Ground Truth Used

• Comparator Assays:
  • For Accuracy studies: The primary ground truth was established by comparison to the GTI Factor VIII Inhibitor Assay (predicate device) and the Bethesda assay. The Bethesda assay is explicitly stated as the "gold standard for detection and quantitation of inhibitory antibodies to Factor VIII."
  • For the method comparison, samples were categorized as "hemophiliac donors without Factor VIII antibodies (negative Bethesda titers or a negative Bethesda Screen)" and "hemophiliac donors with Factor VIII antibodies (positive Bethesda titers)."
• Internal Standards:
  • For Precision, Sample Type Qualification, Interfering Substances, and Lot-to-Lot Reproducibility studies, ground truth relied on "known negative samples" and "known positive samples" or spiked samples, implying prior characterization or experimental manipulation.
  • The kit control itself is based on a "diluted serum known to contain antibodies to Factor VII."

8. Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of an algorithm or machine learning model. However, the Factor VIII Antibody Screen Assay Cutoff study involved determining the appropriate value for the kit control. This process can be seen as analogous to establishing a threshold or "training" the cutoff for optimal discrimination.

• Cutoff Determination Study (analogous to training set):
  • Sample Size: 78 different serum samples from normal, healthy, non-hemophilic donors and 3 known positive samples with low reactivity.

9. How Ground Truth for the Training Set Was Established

For the Cutoff Determination Study:

• Normal Samples: "normal, healthy, non-hemophiliacs." The average OD value for these 78 normal samples was calculated.
• Positive Samples: "3 known positive samples with low reactivity."
• Method: A target cutoff value for the kit control was chosen to be three times (3x) the average OD value of the normal samples. A specific dilution of a FVIII antibody positive serum was then selected to match this target OD, with the additional constraint that the 3 known positive samples with low reactivity must be positive and >98% of the normal samples must be negative. This iterative process established the "ground truth" for setting the kit's operational cutoff.

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PF4 IgG™ is a qualitative solid phase enzyme linked immunosorbent assay (ELISA) designed to detect antibodies reactive with Platelet Factor 4 (PF4) when it is complexed to polyanionic compounds such as polyvinyl sulfonate (PVS). These antibodies are found in some patients undergoing heparin therapy.

PF4 IgG™ is designed as a solid phase enzyme-linked immunosorbent assay (ELISA). This product is intended to be used as an in vitro diagnostic kit by hematology, coagulation, or other pathology laboratories to assist in screening patient samples for the presence of heparin-associated antibodies commonly found in patients with heparin-induced thrombocytopenia or thrombosis.

PF4 IgG™ is a qualitative screening assay for the detection of heparin associated IgG antibodies in human serum. The presence of heparin associated antibodies are commonly found in patients with Heparin Induced Thrombocytopenia (HIT).

The PF4 IgGTM assay is an Enzyme Linked Immunosorbent Assay (ELISA). The PF4 IgG™ ELISA is intended to detect IgG antibodies in human serum that react with Platelet Factor 4 (PF4) when it is complexed to heparin or other polyanionic compounds. The PF4 IgG™ kit contains all of the reagents necessary to perform the assay.

In the PF4 IgG™ assay, a complex of PF4/PVS, which has been immobilized in the microwells serve as a target for the binding of antibodies associated with Type II HIT.

In the PF4 IgG™ assay, patient serum is first diluted (1:4), with the specimen diluent provided in the kit. The diluted sample is then added to microwells to which Platet Factor 4 (PF4) complexed to polyvinyl sulfonate (PVS) has been immobilized. The sample is then incubated for 30 minutes at 37°C. If an antibody which recognizes a site on PF4/PVS complex is present in the patient sample, binding will occur. Following this incubation, a wash step then removes any unbound antibodies. A goat anti-human IgG - alkaline phosphatase conjugate is then added to the wells. The conjugate is incubated for 30 minutes at 37°C. Following this incubation, a wash step then removes any unbound conjugate. The alkaline phosphate substrate, p-nitrophenyl phosphate (pNPP) is then added to the microwells. After a 30 minute incubation at room temperature (22 -- 25°C), the reaction is stopped by addition of the stopping solution (3 M sodium hydroxide). The optical density of the color that develops is measured in a spectrophotometer at 405 or 410 nm using a reference wavelength of 490 nm.

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document does not explicitly state pre-defined acceptance criteria values for sensitivity, specificity, and agreement. Instead, it presents the results of the comparison studies and concludes that the device "performs comparable to the predicate device." The conclusion for assay imprecision and reportable results states that the assay "showed acceptable assay imprecision" and "100% agreement."

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

• Test Set Sample Size: 229 serum samples.
• Data Provenance: The samples were obtained from the BloodCenter of Wisconsin (BCW) and were from patients receiving heparin treatment. The data is retrospective as the samples had been previously tested by BCW for PF4/heparin antibodies using the SRA. The country of origin is the USA.

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

The document does not specify the number of experts or their qualifications for establishing the ground truth using the Serotonin Release Assay (SRA). It refers to the SRA as an "in house assay" at BCW.

4. Adjudication method for the test set

The document does not describe an adjudication method for conflicting results. The SRA results from BCW were used as the primary comparator (gold standard). For the PF4 IgG™ and PF4 ENHANCED® assays, samples were tested in duplicate, and the mean of the O.D. values was obtained. Results were considered positive if the mean O.D. value was ≥0.400.

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

A Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study describes an in vitro diagnostic (IVD) ELISA test, not an AI-assisted diagnostic tool that would involve human readers for interpretation of results.

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

This study describes a standalone assay's performance, which is an analogous concept to an algorithm-only performance for an IVD test. The PF4 IgG™ assay itself is the "algorithm only" in this context, providing a quantitative optical density value that is then interpreted as positive or negative based on a cutoff. No human-in-the-loop performance data is provided beyond implicitly trained lab technicians performing the assay.

7. The type of ground truth used

The primary ground truth for the comparison of methods study was the Serotonin Release Assay (SRA). The document states that the SRA is "considered to be the gold standard for testing for antibodies that can cause HIT."

8. The sample size for the training set

The document does not explicitly describe a "training set" in the context of machine learning or algorithm development. However, for determining the normal range and assay cutoff, 120 serum samples from normal healthy individuals were used. This set of samples was used to statistically establish the assay's cutoff, which plays a role similar to calibrating or "training" a threshold.

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

For the "training set" (120 normal healthy individuals used for normal range and cutoff determination):

• The ground truth was established by defining these individuals as "normal healthy" and their serum samples were tested with the PF4 IgG™ and PF4 ENHANCED® assays.
• The normal range was determined non-parametrically using these samples, and the cutoff for the assays (≥0.400) was set based on the upper end of these calculated normal ranges.
• Calculations for the normal range were performed by GTI's Manager of Clinical and Scientific Affairs (Melissa Pressman, Ph.D.), using the Med Calc software program. This implies statistical analysis of the optical density values from these known normal samples.

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GTI PF4 ENHANCED® is designed as a solid phase enzyme-linked immunosorbent assay (ELISA). The product is intended to be used as an in vitro diagnostics kit by hematology, (ELIG/Y). The produce is the pathology laboratories to assist in screening patient samples for the presence of heparin-associated antibodies commonly found in patients with heparin induced thrombocytopenia or thrombosis.

PF4 ENHANCED® Solid Phase ELISA microwells provide immobilized PF4:PVS complexes as a target for the detection of antibodies associated with Type II HIT which are found in some patients undergoing heparin therapy. The presence of these antibodies has been shown to be associated with heparin induced thrombocytopenia Type II (Type II HIT).

Patient serum is added to microwells coated with platelet factor 4 (PF4) complexed to polyvinyl sulfonate (PVS). If an antibody recognizing a site on PF4:PVS is present, binding will occur. Unbound antibodies are then washed away. An alkaline phosphatase labeled anti-human globulin reagent (Anti-IgG/A/M) is added to the wells and incubated. The unbound Anti-IgG/A/M is washed away and the substrate PNPP (p-nitrophenyl phosphate) is added. After a 30-minute incubation period, the reaction is stopped by addition of a sodium hydroxide solution. The optical density of the color that develops is measured in a spectrophotometer.

The document describes a 510(k) premarket notification for a device called "PF4 ENHANCED® Solid Phase ELISA" and its substantial equivalence to a predicate device, the "GTI-PF4 ELISA". The focus of the provided text is on demonstrating that the new device performs as well as the predicate device, especially considering changes to certain materials.

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

1. Table of Acceptance Criteria and the Reported Device Performance

The document does not explicitly state numerical "acceptance criteria" in a typical table format with specific thresholds (e.g., sensitivity > 90%). Instead, the acceptance criteria are implicitly defined by the goal of demonstrating substantial equivalence to the predicate device, the GTI-PF4 ELISA. The performance data was used to show that the PF4 ENHANCED® device performs "as well as" the predicate.

The reported device performance is a qualitative statement of equivalence rather than specific quantitative metrics against pre-defined thresholds.

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

The document explicitly states that the studies used "known patient samples." However, it does not provide the specific sample size for the test set or the data provenance (e.g., country of origin, retrospective or prospective nature of the samples). The summary refers to "Section 8: Performance Data Section" for details, which is not included in the provided text.

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

The document does not provide information on the number of experts used or their qualifications to establish ground truth for the test set. Given that it's an ELISA for detecting antibodies, the "ground truth" would likely be derived from a combination of clinical diagnosis of Type II HIT and potentially other laboratory tests, rather than expert interpretation of an image or signal that requires adjudication. The document states "known patient samples," implying the status of these samples (e.g., positive or negative for the target antibodies/HIT) was already established.

4. Adjudication method for the test set

The document does not specify an adjudication method. This type of assay (ELISA) typically produces quantitative results (Optical Density) that are then interpreted against cut-offs to yield a qualitative (Positive/Negative) result. Adjudication by multiple readers is less common for such objective assays unless there are borderline results or discrepancies in initial interpretations, which isn't mentioned here.

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 in-vitro diagnostic (IVD) ELISA kit, which is a laboratory assay. It does not involve human readers interpreting images or data directly to make a diagnosis in a way that would be "assisted by AI." Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable to this device.

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

The device itself is a "standalone" assay in the sense that it produces an objective result (Optical Density) which leads to a qualitative determination (Positive/Negative). It is an "algorithm only" in the context of the assay's biochemical steps and optical density measurement leading to a result. However, this is not an "AI algorithm" in the common sense of the term. The performance data described are for the assay itself.

7. The type of ground truth used

The ground truth for the "known patient samples" would be based on clinical diagnosis of Type II HIT and potentially confirmatory laboratory tests, which establish whether the patient samples are truly positive or negative for the antibodies associated with Type II HIT. The document refers to "known patient samples," implying this established truth. It's not pathology (as in tissue biopsy) or purely outcomes data from a large cohort, but rather a pre-established clinical and laboratory status.

8. The sample size for the training set

The document does not mention a training set in the context of machine learning or AI. This is an ELISA kit validation, not an AI model development. The "known patient samples" mentioned would be considered the test set for validating the new device against the predicate.

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

As there is no mention of a training set in the context of AI, there's no information on how its ground truth was established. The "known patient samples" for the performance studies would have their ground truth established as described in point 7.

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GTI-FVIII Inhibitor Assay is designed as a solid phase Enzyme-Linked Immunosorbent Assay (ELISA). The product is intended to be used as an in vitro diagnostic kit by hemostasis and other laboratories providing factor VIII inhibitor assay to assist in screening samples for the presence of alloantibodies to epitopes on FVIII molecule.

FVIII Inhibitor Assay is an ELISA platform which is designed to detect IgG antibodies to human recombinant FVIII in human plasma samples. Recombinant human FVIII molecules are passively immobilized in microtiter wells. Patient plasma is tested against wells containing immobilized recombinant FVIII and compared to the reaction obtained from the negative control sera included in the kit. The results are obtained in optical density (OD) values. The patient samples having OD values greater than the cutoff value are regarded as being positive.

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

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

The sample size for the test set is not explicitly stated in the provided text.
The data provenance is retrospective, comparing the GTI-FVIII Inhibitor Assay to the Bethesda assay in previously collected samples. The country of origin is not specified, but the study was conducted in "two independent clinical laboratories."

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. The Bethesda assay is used as the reference standard (ground truth), but the number and qualifications of experts involved in performing or interpreting the Bethesda assay results are not detailed.

4. Adjudication method for the test set

Not explicitly stated. Given that the comparison is against the Bethesda assay, it's implied that the Bethesda assay results served as the reference without a separate adjudication process for the test set itself beyond what is inherent in the Bethesda assay's methodology.

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, an MRMC comparative effectiveness study was not done. The study compares the performance of a device (ELISA kit) to a predicate assay, not the performance of human readers with or without AI assistance.

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

Yes, a standalone study was done. The reported performance (concordance, sensitivity, negative predictive value) is for the GTI-FVIII Inhibitor Assay device itself, without human interpretation as part of the primary outcome measure. The device provides "optical density (OD) values" which are then compared to a cutoff value to determine positive or negative results. While human technical staff operate the ELISA, the interpretation of the results as positive or negative is algorithm-driven based on the OD values.

7. The type of ground truth used

The type of ground truth used is a reference assay/methodology, specifically the Bethesda assay.

8. The sample size for the training set

The text does not mention a separate training set. The study describes the comparison of the GTI-FVIII Inhibitor Assay to the Bethesda assay, implying a validation or test set, but no distinct training set for developing the device is detailed in this summary.

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

Not applicable, as a separate training set and its ground truth establishment are not discussed in the provided summary. The device's underlying principles (ELISA platform detecting IgG antibodies to FVIII) suggest it was developed based on established immunological assays, but the specifics of its internal development and training (if any, in a machine learning sense) are not provided.

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INDICATIONS FOR USE OF GTI-PF4 ELISA FOR THE DETECTION OF ANTIBODIES DIRECTED AGAINST PLATELET FACTOR 4 (PF4):POLYVINYL SULFONATE (PVS) COMPLEX
GTI-PF4 ELISA is designed as a solid phase enzyme-linked immunosorbent assay (ELISA). The product is intended to be used as an in vitro diagnostic kit by hematology, coagulation or other pathology laboratories to assist in screening patient samples for the presence of heparin-associated antibodies commonly found in patients with heparin-induced thrombocytopenia or thrombosis.

GTI-PF4 ELISA is designed as a solid phase enzyme-linked immunosorbent assay (ELISA).

This is an FDA 510(k) clearance letter and an Indications for Use statement, not a scientific study report. Therefore, it does not contain the detailed information needed to describe acceptance criteria and a study proving a device meets those criteria in the format requested.

The document states:

• Device Name: GTI-PF4 ELISA
• Intended Use: "as an in vitro diagnostic kit by hematology, coagulation or other pathology laboratories to assist in screening patient samples for the presence of heparin-associated antibodies commonly found in patients with heparin-induced thrombocytopenia or thrombosis."
• Regulatory Class: II

To answer your request, a comprehensive study report or a 510(k) summary would be required. The provided text only informs that the device has received 510(k) clearance based on substantial equivalence to a predicate device, but it does not detail the specific performance studies, acceptance criteria, or ground truth methodologies used by the manufacturer to demonstrate that equivalence.

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