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

PF4 IgG assay is an enzyme linked immunosorbent assay (ELISA). The PF4 IgG ELISA is intended to detect IgG antibodies in human serum or plasma 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.

The Immucor GTI Diagnostics, Inc. PF4 IgG assay is a qualitative screening assay for the detection of heparin-associated IgG antibodies in human serum or plasma, commonly found in patients with Heparin Induced Thrombocytopenia (HIT). The device is a Class II medical device, product code LCO.

This 510(k) submission is for modifications to a previously cleared device (K071781) and includes: a change in the Positive Serum Control raw material, the addition of plasma as a sample type, and a change in the Stopping Solution.

1. Table of acceptance criteria and reported device performance:

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

• Positive Serum Control Raw Material Change (Precision Study):
  • No specific "test set" sample size for patient samples is provided. The study focused on the performance of the new positive serum control material within the assay.
  • The study used a single lot of the PF4 IgG kit and three validation lots of the Positive Serum Control.
  • Data provenance is internal, generated as part of process validation.
• Addition of Plasma as a Sample Type:
  • Test set size: 174 frozen serum and plasma samples.
  • Data provenance: Samples obtained from Florida Hospital for an internal study. Retrospective, as samples were frozen.
  • Sub-study for ACD/Sodium Citrate vs. Serum: Blood collected from 24 individuals. Origin not specified beyond "internal study." Retrospective.
• Stopping Solution Change:
  • Test set size: No patient samples explicitly mentioned in the summary for the Stopping Solution evaluation itself. The testing involved comparing the performance of the new Stopping Solution with the predicate using various assay components and a QC panel.
  • QC Panel: 21 positive samples and 24 negative samples.
  • Data provenance: Internal, generated as part of lot-to-lot comparison and process validation.

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 or qualifications of experts used to establish ground truth for the test sets. For the plasma sample type study, it states 174 frozen serum and plasma samples were used, and for the ACD/Sodium Citrate comparison, blood was collected from 24 individuals "known to be PF4: heparin antibody negative." How this "known" status was established (e.g., by experts, by a predicate device, by clinical diagnosis) is not detailed. The ground truth for the QC panel used in the stopping solution study is based on "expected qualitative result," implying pre-characterized samples, not expert consensus at the time of the study.

4. Adjudication method for the test set:

The document does not describe any adjudication method for establishing ground truth for the test sets. The studies appear to rely on the inherent reactivity of the samples (e.g., "known to be PF4: heparin antibody negative," "high level reacting anti:PF4 heparin antibody sample," "expected qualitative result" for QC panels).

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:

This device is an in vitro diagnostic (IVD) assay, specifically an ELISA. It is not an AI-assisted diagnostic tool that involves human readers interpreting images or data. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed.

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

The device is an IVD assay, not an algorithm. Its performance is evaluated biochemically based on optical density measurements, which are then interpreted qualitatively (positive/negative) according to the assay's cut-offs. The studies described are standalone performance evaluations of the modified assay components and sample compatibility.

7. The type of ground truth used:

• For the plasma sample type comparison, the ground truth appears to be based on the qualitative results obtained from the serum sample, as the goal was to demonstrate equivalence between serum and plasma samples. For the sub-study on ACD/Sodium Citrate, it refers to individuals "known to be PF4: heparin antibody negative" and "high level reacting anti:PF4 heparin antibody sample," indicating pre-characterized samples.
• For the stopping solution change, the ground truth for the QC panel was based on "expected qualitative result," implying pre-defined and characterized positive and negative samples.
• The primary ground truth for the assay itself (predicate and candidate) would typically be established against either clinical diagnosis of HIT (outcome data) or a well-established reference method, but this is not explicitly detailed for these specific modification studies. The studies focus on demonstrating that the modifications do not adversely affect the device's performance compared to its previous state.

8. The sample size for the training set:

The document does not describe a training set as this is not an algorithm requiring machine learning. The studies are performance and validation studies for changes to an IVD assay.

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

Not applicable, as there is no training set for this type of device.

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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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