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The IOS™ Serum Pregnancy Test Cartridge is to be used for the qualitative determination of human chorionic gonadotropin (hCG) in serum for the early detection of pregnancy. It is intended to be used with the IOS™ instrument in clinical laboratories, physicians' office laboratories, and other alternate sites of use close to the point of patient care.

The IOS™ Immunoassay Controls Kit is to be used to assist in monitoring accuracy and precision in the IOSTM immunoassay test cartridges.

Serum Pregnancy Test Cartridges: Human chorionic gonadotropin is a glycoprotein that is synthesized by the placenta during pregnancy. hCG appears in both serum and urine relatively soon after implantation of the developing embryo. The presence of hCG, and its rapid rise following conception, is thus the basis of pregnancy testing. hCG testing can aid in the determination of ectopic pregnancy and spontaneous abortion. hCG is also secreted by a wide variety of tumors: gestational trophoblastic tumors, testicular and prostatic tumors, and some breast cancers.

hCG is composed of two noncovalently linked polypeptides: the alpha and beta subunits. The individual subunits lack biological activity, but become active when linked to form the intact hormone. The alpha subunit of hCG is structurally similar to the alpha subunits of LH (luteinizing hormone), FSH (follicle stimulating hormone), and TSH (thyroid stimulating hormone). The beta subunits of each of the hormones are structurally unique and confer the biologic and immunologic specificity to each hormone. The beta subunit of hCG contains a unique chain of 30 carboxy-terminal amino acids that confers its specificity (1). Monoclonal antibodies directed against this portion of the beta subunit permit differentiation between hCG and the other pituitary glycoprotein hormones.

The IOS™ Serum Pregnancy test is a two-site simultaneous sandwich immunoassay which utilizes two antibodies directed against intact hCG: a polyclonal antibody immobilized on the plastic cartridge surface (capture antibody) and a monoclonal antibody labeled with alkaline phosphatase (detection antibody, 'conjugate'). hCG in the patient sample binds to conjugate in the test cartridge, and this hCG-conjugate complex then binds to the immobilized capture antibody. After a short incubation period, excess hCG-conjugate complex is washed away. Substrate is added, which reacts with the alkaline phosphatase conjugate-hCG-capture antibody 'sandwich' and produces a fluorescent signal. The level of fluorescence is directly proportional to the amount of bound hCG-conjugate, which is directly proportional to the amount of hCG present in the patient sample. All reagents necessary to perform the test are dried in the IOSTM cartridge, and are rehydrated by the addition of patient sample by the operator, or by the addition of buffer by the instrument.

To perform a test, the operator inserts an IOS™ Serum Pregnancy Test Cartridge in the IOS™ instrument. When prompted, the operator adds sample well. Each cartidge can test two different patient samples, with one patient sample added to the left well and the second to the right well. The operator starts the test sequence when sample addition is complete. Patient sample rehydrates conjugate dried in the sample well; the conjugate binds to hCG present in the patient serum sample. This hCG-conjugate complex then flows into the incubation/reaction chamber where it binds to the immobilized capture antibody. At the end of the incubation time, excess sample-conjugate is washed away by buffer. Buffer is used to rehydrate the dried substrate necessary for signal generation and quantitation of hCC, in a second reaction chamber. Substrate flows into the incubation/reaction chamber where signal is produced as a result of substrate reacting with conjugate bound to captured patient hCG (the 'sandwich'). The fluorescent signal is read as a rate by front-surface fluorometry, compared to the rate for the cut-off value stored in the barcode on the test cartridge, and determined to be higher or lower than the cut-off value.

Immunoassay Controls: The use of materials derived from human blood to monitor quality control of clinical chemistry testing in the clinical laboratory has been widely established over the past several years. The Biocircuits IOS™ Immunoassay Controls are two levels of bloodbased material for use with Biocircuits IOS™ Test Cartridges.

To run a control, the operator inserts the Control Cartridge (packaged with the controls) into the IOS™ instrument. The instrument reads the lot number and ranges of acceptable values for the control solutions from the Control Cartridge barcode, and then ejects the Control Cartridge. The operator then inserts a test cartridge and follows the instrument prompts to identify the control level, apply control solutions, and begin the test sequence. The IOS™ instrument performs the required buffer additions to rehydrate assay reagents and perform wash steps as necessary, reads the fluorescence signal generated, and calculates and prints the control result just as it would if the cartridge were used to test a patient sample.

Here's a breakdown of the acceptance criteria and the study details for the Biocircuits IOS™ Serum Pregnancy Test Cartridges, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Sizes and Data Provenance

• Test Set (Non-Clinical - Accuracy):
  • Positive samples: n = 142
  • Negative samples: n = 149
  • Data Provenance: Retrospective. Samples were tested in the manufacturer's laboratories.
• Test Set (Clinical - Accuracy):
  • Total patient samples: n = 172
  • Positive samples: n = 82
  • Negative samples: n = 90
  • Data Provenance: Prospective, clinical. Samples were tested by users in three different physicians' office laboratories (OB/GYN, Internal Medicine, Reproductive Endocrinology/Fertility practices) in typical clinical settings. The reference method (ICON II) was performed in the manufacturer's lab.
• Test Set (Analytical Sensitivity - Detection Limit):
  • Zero calibrator replicates: n = 60
  • Spiked serum samples: n.a. (specific number of samples at each hCG level not stated, but covered 0, 15, 20, 25, 30, 35, 40, and 100 mIU/mL hCG)
  • Data Provenance: Retrospective, internal laboratory testing.
• Test Set (Cross-Reactivity and Interfering Substances):
  • Samples tested: Not explicitly stated, but involved serum samples with 0 and 100 mIU/mL hCG spiked with each potential substance.
  • Data Provenance: Retrospective, internal laboratory testing.
• Immunoassay Controls (Range Establishment):
  • Cartridges per level: at least 40 cartridges each
  • Days: over at least 10 days
  • Instruments: several IOS™ instruments
  • Data Provenance: Retrospective, internal manufacturer's laboratories.

3. Number of Experts and Qualifications for Ground Truth

• Non-Clinical and Clinical Accuracy: The ground truth was established by comparison to the Hybritech ICON II hCG ImmunoConcentration Assay. The document doesn't explicitly state the number or qualifications of "experts" involved in interpreting the ICON II results, as it was treated as the reference method. For the clinical study, the samples tested using the IOS device in the physician's offices were then sent to the manufacturer's laboratory for testing with the ICON II, implying that the manufacturer's lab personnel performed these reference tests.
• There's no mention of external experts or panels used to establish ground truth.

4. Adjudication Method for the Test Set

• No explicit adjudication method is described. The comparison is made directly against the results of the predicate device (Hybritech ICON II Assay). For discrepancies, the document only states the agreement rates but does not detail a process for resolving discordant results between the IOS and the ICON II.

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

• No, an MRMC comparative effectiveness study was not done in the sense of comparing human readers with AI assistance vs. without AI assistance.
• The clinical study did involve multiple types of human users (medical technologists, medical assistants, and front-office personnel) across three different physician's office laboratories, representing a multi-reader, multi-site evaluation of the new device itself. However, it was not designed to measure the effect size of AI assistance on human readers as this is an automated device performing the test, not an AI assisting human interpretation of an image or data.

6. Standalone (Algorithm Only) Performance

• Yes, the primary study described is a standalone performance study. The Biocircuits IOS™ Serum Pregnancy Test Cartridge used with the IOS™ instrument is an automated system where the instrument reads the fluorescent signal, compares it to a cut-off value, and determines the result (positive/negative). This is an "algorithm only" performance, as the device itself makes the determination without human interpretation of the final signal output. The clinical study specifically states that the instrument performs the necessary steps, reads the signal, and calculates/prints the result.

7. Type of Ground Truth Used

• The ground truth primarily used for evaluating the Biocircuits IOS™ Serum Pregnancy Test was the results from a legally marketed predicate device: the Hybritech ICON II hCG ImmunoConcentration Assay.
• For the analytical sensitivity, the ground truth was established by comparing results from known spiked serum samples (containing specific, known concentrations of hCG) and a zero calibrator.

8. Sample Size for the Training Set

• No explicit training set size is provided. This device is a diagnostic assay, and the "algorithm" is more a function of fixed reaction kinetics and a set cut-off value, rather than a machine learning algorithm that undergoes a distinct "training" phase on a large dataset in the way modern AI/ML systems do. The development process would have involved internal validation and optimization, but a "training set" in the context of recent AI guidances isn't applicable here.

9. How the Ground Truth for the Training Set Was Established

• As there's no explicitly defined "training set" in the context of machine learning, this question isn't directly applicable. The device's "training" would have involved the R&D process to optimize reagents, reaction parameters, and the detection cut-off value to achieve the desired analytical sensitivity and specificity, likely using internal reference standards, spiked samples, and comparison to established methods during its development.

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