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The IOS Prostate Specific Antigen Test Cartridges are to be used for the quantitative determination of prostate specific antigen levels in serum as an aid in the management of patients diagnosed with prostate cancer. They are 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 PSA Controls are to be used to assist in monitoring accuracy and precision in the IOS PSA Test Cartridges.

Prostate Specific Antigen Test Cartridges:

Prostate specific antigen (PSA) is a serine protease first discovered in seminal plasma which has a molecular weight of approximately 30,000 Daltons. 14 PSA is secreted by normal prostatic epithelial cells as well as by diseased prostatic tissue. When PSA is released into the blood, it is inactivated by the major extracellular serine protease inhibitors, alpha-2-macroglobulin and alpha-1-antichymotrypsin. The portion of PSA that is inactivated by alpha-2-macroglobulin is undetectable by immunoassays measuring total PSA.46 The fraction of PSA bound to alpha-1-antichymotrypsin (~90 kDa) is detectable and is the predominate form of PSA in human serum, constituting 73 -95% of circulating PSA. The remaining 5 - 27% of detectable PSA exists in a "free" enzymatically inactive state (~30 kDa), and is found to be at higher proportions in patients with benign prostatic hyperplasia. The IOS PSA assay measures free and total PSA in an equimolar fashion.

Longitudinal determinations of PSA have been shown to be useful when monitoring prostate cancer patients. Serial PSA measurements are indicative of recurrence of disease or metastatic progression if PSA levels continue to rise after surgical or medical treatment. Serial PSA measurements that decrease to undetectable levels indicate successful treatment of disease.8-11

PSA levels have also been shown to be elevated in patients with benign prostatic hyperplasia (BPH) and prostatitis. 10 PSA levels are not elevated in cancers of the breast, lung, colon, rectum, stomach, pancreas, or thyroid.

PSA testing alone is not be used as a screening test for prostate cancer or in the staging of prostatic cancer. PSA testing is accepted as an adjunctive test in managing the treatment of patients with prostate cancer. 12,13

Principle of the Test

The IOS PSA test is a two-site sandwich immunoassay. PSA in the patient serum binds to an enzyme-labeled monoclonal anti-PSA conjugate. This PSA:conjugate complex is captured by polyclonal anti-PSA antibody immobilized on the plastic surface, forming a capture-antigen-conjugate sandwich. After an incubation period, excess sample and conjugate are washed away and substrate is added. The substrate reacts with the conjugate: PSA complex captured on the surface and produces a fluorescent signal. The rate of the enzyme-substrate reaction is directly proportional to the amount of conjugate bound, which is directly proportional to the amount of PSA present in the patient sample. All reagents necessary to perform the test are dried on the IOS test cartridge, and are rehydrated by the addition of patient sample, or by the addition of IOS buffer by the instrument.

To perform the test, the operator inserts an IOS PSA cartridge into the IOS instrument. When prompted, the operator adds sample to the sample well and starts the test sequence. The instrument draws the cartridge inside to mix the patient sample, which also rehydrates the anti-PSA conjugate. A short incubation period allows the serum and conjugate to react. The PSA:conjugate complex then flows into the incubation/reaction chamber where binding to the solid phase occurs. At the end of this incubation time, excess patient sample and conjugate are aspirated out of the incubation/reaction chamber and the incubation/reaction chamber is washed using buffer added by the instrument. Buffer is also used to rehydrate the substrate necessary for signal generation and quantitation of PSA in another reagent chamber; rehydrated substrate is then allowed to enter the incubation/reaction chamber. The fluorescent signal produced is read as a rate by front-surface fluorometry, compared to the rates produced by a series of calibrators stored in the instrument memory, and the amount of PSA present in the patient sample is calculated from the stored calibration curve.

IOS PSA 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 PSA Controls are two levels of bloodbased material for use with Biocircuits IOS PSA 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 an analysis of the provided text to extract the acceptance criteria and study details for the Biocircuits IOS® PSA Test Cartridges:

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document explicitly states the "Performance Data" which includes precision and accuracy. While the document presents these as "results" rather than explicit "acceptance criteria," in the context of a 510(k) summary, these are the performance metrics the manufacturer submits to demonstrate the device's capability and equivalence to a predicate. The predicate device's performance would generally set the benchmark for these implicit acceptance criteria.

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

• Sample Size for Test Set: 319 patient samples were used for the accuracy study (comparison of methods).
• Data Provenance: The studies were "performed in the manufacturer's laboratories." The document does not specify the country of origin of the data or whether it was retrospective or prospective, but the context of an in vitro diagnostic device for PSA testing suggests that these were likely collected clinical samples.

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

This information is not provided in the document. For in vitro diagnostic devices like this PSA test, the "ground truth" for accuracy is typically established by comparison to a recognized reference method or a legally marketed predicate device, rather than expert consensus on interpretive tasks. In this case, the accuracy was determined by comparing the IOS PSA assay to "a commercially available enzyme immunoassay." The qualifications of those who ran the comparative assay are not detailed.

4. Adjudication Method for the Test Set

This information is not applicable to this type of in vitro diagnostic device study. Adjudication methods (like 2+1, 3+1) are typically used in clinical imaging studies or other diagnostic areas where human interpretation can be subjective and independent expert review is needed to establish a consensus ground truth. For an immunoassay, the result is quantitative and directly measured by a machine.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

This information is not applicable to this device. An MRMC study is relevant for evaluating the impact of AI on diagnostic tasks performed by human readers (e.g., radiologists, pathologists). The Biocircuits IOS® PSA Test Cartridges are an in vitro diagnostic assay that provides a quantitative measurement of PSA; it does not involve human readers interpreting AI output.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, the performance data presented (Precision and Accuracy) represent the standalone performance of the IOS PSA assay system. The device itself performs the measurement and calculates the PSA level. There is no human-in-the-loop component for the measurement of PSA by the device, although a human operates the device and interprets the numerical result in the context of a patient's clinical management.

7. The Type of Ground Truth Used

For the accuracy study, the ground truth was effectively established by comparison to a "commercially available enzyme immunoassay." This predicate or reference method served as the comparative "truth" against which the new device's measurements were evaluated. The range of samples tested was from 0.2 to 95.8 ng/mL.

8. The Sample Size for the Training Set

This information is not provided in the document. The Biocircuits IOS® PSA Test Cartridges are a chemical immunoassay, not an AI/machine learning algorithm that requires a "training set" in the conventional sense. The "training" in this context would refer to method development, reagent optimization, and calibration curve generation, which is a different paradigm than AI model training.

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

As noted above, the concept of a "training set" with established "ground truth" in the AI sense does not directly apply here. For immunoassays, the equivalent would be the development of calibrators and quality control materials. The document states that the calibration is "Factory-generated" and calibrated against "a series of calibrators stored in the instrument memory." The ground truth for these calibrators would typically be established through highly accurate reference methods or certified reference materials, but the specifics are not detailed in this summary.

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The IOS Free Thyroxine Test Cartridges are intended to be used for the quantitative determination of free (not protein bound) thyroxine (thyroid hormone) in serum for the diagnosis and treatment of thyroid diseases. They are intended to be used with the Biocircuits IOS® instrument in clinical laboratories, physician office laboratories, and other alternate sites of use close to the point of patient care.

The IOS Controls are to be used to assist in monitoring accuracy and precision in the IOS immunoassay test cartridges.

The IOS Free T4 assay is a sequential immunoassay in which free T4 in the patient serum sample first binds to a monoclonal anti-T4 antibody; this free T4:anti-T4 complex is then captured by polyclonal goat-anti-mouse immobilized on the plastic surface. Excess ('uncomplexed') anti-T4 antibody also binds to the surface. After an incubation period, any excess sample and unbound anti-T4 antibody are removed. In the second step, alkaline phosphatase-labeled T4 ('conjugate') is added, and the conjugate binds to T4 binding sites on the uncomplexed anti-T4 antibody. After another incubation period, excess conjugate is washed away and substrate is added. The substrate reacts with the conjugate bound to uncomplexed anti-T4 antibody and produces a fluorescent signal. The level of fluorescence is directly proportional to the amount of conjugate bound to the uncomplexed anti-T4 antibody and inversely proportional to the amount of free T4:T4 antibody complex, and thus inversely proportional to the amount of free T4 present in the serum sample. All the reagents necessary to perform the test are dried in the IOS Free T4 Test Cartridge, and are rehydrated by 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 Free T4 Test Cartridge into the IOS instrument. When prompted, the operator adds sample to the sample well and starts the test sequence. The instrument draws the cartridge inside and adds buffer to dilute the serum. The diluted serum rehydrates the dried reagent (mouse anti-T4 antibody) in the sample well. A short incubation period allows the serum and reagents to react. This mixture then flows into the incubation/ reaction chamber, where binding to the solid phase occurs. At the end of the incubation time, excess mixture is aspirated out of the incubation/reaction chamber by the instrument. Buffer is used to rehydrate conjugate in a separate chamber; rehydrated conjugate is allowed to enter the reaction chamber to bind to uncomplexed T4 antibody. At the end of this incubation time, excess conjugate is washed away by buffer dispensed by the instrument. Buffer is also used to rehydrate the substrate necessary for signal generation and quantitation in a third chamber: rehydrated substrate is then allowed to enter the incubation/reaction chamber. The signal produced is read as a rate by front-surface fluorometry, compared to the signal produced by a series of calibrators stored in instrument memory, and the amount of free T4 present in the patient sample is calculated from the stored calibration curve.

IOS 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 Controls are two levels of blood-based 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 Cartidge barcode, and then ejects the Control Cartidge. 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 an analysis of the provided 510(k) summary regarding the Biocircuits IOS® Free Thyroxine Test Cartridges and IOS Controls, focusing on the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct pass/fail thresholds in this summary. However, the performance data presented is implicitly compared to what would be considered acceptable for a diagnostic device of this type, especially in relation to the predicate device. The primary performance metrics presented are precision and accuracy (correlation with a predicate device).

Note: The summary states: "It is self-evident from the data and information presented here that the Biocircuits IOS Free Thyroxine Test Cartridges are as safe, effective, and perform as well as the Dade Stratus Free Thyroxine Fluorometric Immunoassay manufactured and distributed by Dade International, Inc." This implies the reported performance met the unstated acceptance criteria for substantial equivalence.

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

• Accuracy (Manufacturer's Lab): 119 patient samples.
  • Data Provenance: "manufacturer's laboratories." Includes "pooled human serum spiked with T4 to obtain high concentrations of free T4." (Likely retrospective, but not explicitly stated if all 119 were patient-derived or if spiked samples were included in that count.)
• Accuracy (Physician's Office Lab): 68 patient samples.
  • Data Provenance: "clinical testing performed in a typical physicians' office laboratory." Samples were "split and sent to the manufacturer's laboratory for testing by both the IOS and a commercially available fluorescent enzyme immunoassay." Includes "pooled human serum spiked with T4 to obtain high concentrations of free T4." (Likely retrospective patient samples, with spiked samples used for wider range coverage.)
• Precision (Manufacturer's Lab): "n=10" for within-day, "n=40" for between-day for 3 control levels. This refers to the number of replicates tested.
• Precision (Physician's Office Lab): "number of replicates 44" for control level 1, "40" for control level 2.
• Control Range Establishment (Manufacturer's Lab): Each control level was tested in "80 cartridges, over at least 3 days, using several IOS instruments."

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

This type of immunoassay (Free Thyroxine Test) relies on comparison with a predicate device and established laboratory methods. No human experts were used to establish ground truth for the test set in the traditional sense (e.g., radiologists interpreting images). The "ground truth" for accuracy was established by comparing the results of the new device to those obtained from a "commercially available fluorescent enzyme immunoassay" (the Dade Stratus Free Thyroxine Fluorometric Enzyme Immunoassay, and later generalized to "a commercially available fluorescent enzyme immunoassay").

4. Adjudication Method for the Test Set

Not applicable. The ground truth was based on a laboratory reference method, not expert consensus requiring adjudication.

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

Not applicable. This is an in-vitro diagnostic device (immunoassay) and does not involve human readers for interpretation in the context of imaging or similar tasks where MRMC studies are typically employed. "AI" is not mentioned in the context of assisting human interpretation in this document.

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

Yes, the performance studies presented (precision and accuracy) are of the standalone device performance. The device (IOS Free Thyroxine Test Cartridges with the IOS instrument) provides quantitative results directly. The human "in-the-loop" is the operator performing the test and adding samples, but not interpreting the raw signal in a way that requires AI assistance or a complex human-algorithm interaction for diagnostic output.

7. The Type of Ground Truth Used

The ground truth used for accuracy was comparison against a legally marketed predicate device (the Dade Stratus Free Thyroxine Fluorometric Enzyme Immunoassay and "a commercially available fluorescent enzyme immunoassay"). This is a common approach for establishing substantial equivalence for in-vitro diagnostic devices. For precision, the ground truth is simply the statistical distribution of repeated measurements on control materials.

8. The Sample Size for the Training Set

No explicit training set is mentioned. For in-vitro diagnostic assays, "training" in the machine learning sense is not typically applicable. Instead, the device's calibration curve and operational parameters are established during development and manufacturing. The document mentions "Factory-generated" calibration and "stored standard curves" which would be developed using known concentrations of analytes, but no sample size for this internal process is provided.

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

As above, there isn't a "training set" in the machine learning context. The calibration for the device (what it would 'learn' in a broad sense) is "Factory-generated" and "stored standard curves." This process would involve running samples with precisely known concentrations of free T4 (standards or calibrators) to establish the relationship between the fluorescent signal and the analyte concentration. This is a fundamental part of developing any quantitative assay. The known concentrations of these calibrators serve as the 'ground truth' for the instrument's internal calibration.

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The IOS™ Quantitative hCG Test Cartridges are to be used for the quantitative determination of human chorionic gonadotropin (hCG) in serum for the early detection of pregnancy. They are 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 IOS™ immunoassay test cartridges.

Quantitative hCG Test Cartridges: Human chorionic gonadotropin is a glycoprotein that is synthesized by the placenta during pregnancy and 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. (1) Quantitation of hCG can aid in the determination of ectopic pregnancy and spontaneous abortion (2, 3). hCG is also secreted by a wide variety of tumors: gestational trophoblastic tumors, testicular and prostatic tumors, and some breast cancers. (4,5).

Human chorionic gonadotropin is composed of two noncovalently linked polypeptides: the alpha and beta subunits. The individual subunits lack biological activity, but become active when combined to form the intact hormone. The alpha subunit of hCG is structurally homologous to the alpha subunits of LH (luteinizing hormone), FSH (follicle stimulating hormone), and TSH (thyroid stimulating hormone). The beta subunit of each of the hormones is structurally unique and confers 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.

Principle of the Test: The IOS™ Quantitative hCG test is a two-site sandwich immunoassay which utilizes two antibodies directed against 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, unbound 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 IOS™ 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™ Quantitative hCG cartridge in the IOS™ instrument. When prompted, the operator adds sample well. A second portion of patient sample is diluted off-line, using the dilution vial supplied with the kit, and pipetted into the second well of the test cartridge. 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, unbound sample-conjugate is washed away by buffer. Buffer is used to rehydrate the dried substrate necessary for signal generation and quantitation of hCG, and the rehydrated substrate is then delivered to the incubation/reaction chamber. The fluorescent signal produced is read as a rate by front-surface fluorometry, compared to the rates produced by a series of calibrators stored in the instrument memory, and the amount of hCG present in the patient sample is calculated from the stored calibration curve. If the signal from the first track (undiluted patient serum) is higher than that of the highest calibrator, the instrument will take a reading from the second track (user-diluted sample) to obtain a quantitative value for the patient sample. This increases the assay range 2500 mIU/mL (undiluted track) to 250,000 mIU/mL (diluted track).

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 study details for the Biocircuits IOS™ Quantitative hCG Test Cartridges and IOS™ Immunoassay Controls, based on the provided text:

Acceptance Criteria and Reported Device Performance

Note: The document states that "it is self-evident from the data and information presented here that the Biocircuits IOS™ Quantitative hCG Test Cartridges are as safe, effective, and perform as well as the Dade Stratus hCG Fluorometric Immunoassay." This implies that the observed performance of the Biocircuits device, as presented in the tables above, is considered acceptable due to its comparability to the legally marketed predicate device (Dade Stratus). Specific numerical acceptance thresholds were not explicitly given in the provided text beyond the comparison itself.

Study Details

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

   • Non-Clinical (Manufacturer's Laboratories):
     • Precision:
       • Within-day: n ≥ 19 for each of 3 control levels.
       • Between-day: n ≥ 60 for each of 3 control levels.
     • Accuracy: 165 patient samples (107 neat sera, 58 diluted samples).
     • Data Provenance: Manufacturer's laboratories (implies in-house testing, likely US-based as the company is in Sunnyvale, CA). Retrospective (patient samples were tested, not explicitly clear if newly collected for the study or pre-existing).
   • Clinical (Physicians' Office Laboratories):
     • Precision: n = 39 (Level 1 control), n = 31 (Level 2 control).
     • Accuracy: 121 patient samples.
     • Data Provenance: Three typical physicians' office laboratories (OB/GYN, Internal Medicine, Reproductive Endocrinology/Fertility practice). Samples were "split and sent to the manufacturer's laboratory for retesting on the predicate device," indicating the original testing was done in these clinical sites. Likely US-based. Retrospective (patient samples).
   • Immunoassay Controls (Manufacturer's Laboratories): At least 40 cartridges each for Level 1 and Level 2 controls.
     • Data Provenance: Manufacturer's laboratories.

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

   • The "ground truth" for the accuracy studies was established by comparison to a "commercially available fluorescent enzyme immunoassay" (Dade Stratus) at the manufacturer's laboratory for the non-clinical study, and by the predicate device at the manufacturer's lab for the clinical study.
   • For the clinical study, "medical technologists, medical assistants, and front-office personnel" performed the tests using the IOS™ device. However, the ground truth was essentially the result from the predicate device in the manufacturer's laboratory, not an expert panel.
   • No specific number of experts or their qualifications for establishing ground truth (other than the implied expertise being embedded in the predicate device's performance which was the comparator) is provided.

3. Adjudication method for the test set:

   • Not applicable. The ground truth was established by comparison to a single predicate device (Dade Stratus) or a commercially available fluorescent enzyme immunoassay, not through a consensus or adjudication process of multiple human readers.

4. 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 study was not done. This device is an automated immunoassay system, not an AI-assisted diagnostic tool that would involve human readers interpreting images or data with and without AI. It directly measures hCG levels.

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

   • Yes, the device operates in a standalone manner. The IOS™ instrument performs the tests, reads the signal, and calculates/prints the result. Human operators interact by inserting cartridges, adding samples, and starting the test sequence, but the analytical process itself is automated. The performance data presented (precision, accuracy) represents the standalone performance of the device.

6. The type of ground truth used:

   • Comparative Reference: The ground truth for accuracy was established by comparing the results of the Biocircuits IOS™ device to those obtained from a "commercially available fluorescent enzyme immunoassay" (Dade Stratus) which is the predicate device. This is a form of comparative ground truth against a well-established and legally marketed method.

7. The sample size for the training set:

   • The document does not explicitly mention a "training set" in the context of a machine learning or AI algorithm. This device is an immunoassay, not a system that uses a trained AI model in the conventional sense. The "training" in this context would implicitly refer to the internal development and calibration of the assay.
   • For the Immunoassay Controls calibration, the ranges were determined by testing in "at least 40 cartridges each, over several days, using several IOS™ instruments." While this isn't a "training set" for an AI, it represents data used to establish the device's operational parameters for controls.

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

   • As noted above, there's no explicit "training set" in the AI sense. For the Immunoassay Controls, the "ranges" were established internally by the manufacturer through repeated testing, implying consistency and accuracy with their own established standards and processes. The document suggests that "Your laboratory should establish its own range for these controls over time," indicating a process of ongoing internal validation.

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TSH: The IOS™ TSH Test Cartridge is to be used for the quantitative determination of thyroid stimulating hormone (TSH, thyrotropin) levels in serum using the Biocircuits IOS™ system.

Thyroid Controls: The IOS™ Thyroid Controls Kit is to be used to assist in monitoring accuracy and precision in the IOS™ thyroid assays.

Thyroid stimulating hormone (TSH) is a glycoprotein with a molecular weight of about 28,000 daltons that is secreted by the anterior pituitary gland. TSH interacts with a specific receptor on the thyroid gland cell surface, stimulating production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Secretion of TSH is regulated by two factors: 1) a hormone secreted by the hypothalamus called thyrotropin releasing hormone (TRH) which stimulates the pituitary to produce and release TSH; and 2) the concentration of unbound thyroid hormones T4 and T3 in the interstitial fluid of the brain. An increase of the concentrations of T4 and T3 inhibits the production and secretion of TSH, while a decrease in T4 and T3 levels stimulates production and secretion of TSH, forming a negative feedback mechanism. Failure at any level of regulation of the hypothalamic-pituitary-thyroid axis will result in either under-production (hypothyroidism) or over-production (hyperthyroidism) of T4 and/or T3.

Primary hypothyroidism is associated with low thyroid hormone levels and elevated TSH levels, while secondary (pituitary) and tertiary (hypothalamic) forms of hypothyroidism are associated with both low levels of T4 and/or T3 and low-to-undetectable levels of TSH. All three forms of hypothyroidism can be differentiated by the patient's TSH response to TRH.

Primary hyperthyroidism is associated with high levels of thyroid hormones and very low or undetectable levels of TSH. The TRH challenge test has been used to confirm primary hyperthyroidism. More recently, sensitive TSH assays have been developed which can differentiate overtly thyrotoxic patients from euthyroid individuals.

TSH is composed of two noncovalently linked subunits, designated "alpha" and "beta". The alpha portion is essentially identical to the alpha subunits of human luteinizing hormone (hLH), human follicle stimulating hormone (hFSH), and human chorionic gonadotropin (hCG), differing only in carbohydrate moieties. The beta subunits of each of these hormones is structurally unique and contains the biologic and immunologic specificity. Both subunits are needed for biological activity.

The Biocircuits IOS™ TSH assay uses a monoclonal antibody against the beta subunit of TSH to specifically capture the patient TSH, and a polyclonal antibody also against the beta subunit for the enzyme conjugate. This allows specific determination of the concentration of TSH without cross-reactivity with other glycoprotein hormones.

Principle of the Test:

TSH: The IOS™ TSH test is a two-site sandwich immunoassay. TSH in the patient sample binds to monoclonal anti-TSH antibody in the test cartridge. After a short incubation time, excess sample is washed away and enzyme-labeled polyclonal anti-TSH antibody (conjugate) is added, which binds to any antibody-bound TSH, forming an antibody-antigen-labeled antibody sandwich. After another short incubation time, excess conjugate is washed away and substrate is added. The rate of the enzyme-substrate reaction is directly proportional to the amount of conjugate bound, which is directly proportional to the amount of TSH 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™ TSH cartridge into the IOS™ instrument. When prompted, the operator adds sample to the sample well and starts the test sequence. The instrument draws the cartridge inside to be incubated. Patient sample flows into the incubation/reaction chamber where patient TSH binds to anti-TSH antibody. At the end of the sample incubation time, excess patient sample is washed away using buffer added by the instrument. Buffer is also added by the instrument to rehydrate dried conjugate in a separate reagent chamber for the next step; the rehydrated conjugate is then allowed to enter the incubation/reaction chamber and bind to antibody-bound TSH. At the end of the conjugate incubation time, excess conjugate is washed away by buffer. Buffer is used to rehydrate the substrate necessary for signal generation and quantitation of TSH in a second reagent chamber; rehydrated substrate is then allowed to enter the incubation/reaction chamber. The fluorescent signal produced is read as a rate by front-surface fluorometry, compared to the rates produced by a series of calibrators stored in instrument memory, and the amount of TSH present in the patient sample is calculated from the stored calibration curve.

Thyroid 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. (1) The Biocircuits IOS™ Thyroid Controls are two levels of blood-based material for use with Biocircuits IOSTM thyroid assays test cartridges (T4/TU, T4, or TSH),

To run a control, the operator inserts the Thyroid 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.

This looks like a 510(k) premarket notification for a TSH assay rather than an AI/ML powered device. While it contains performance data and a comparison to a predicate device, it does not involve the typical elements of an AI/ML study such as training sets, ground truth establishment by experts, or MRMC comparative effectiveness studies. Therefore, many of the requested fields cannot be filled.

Here's an analysis based on the provided text, focusing on the available information:

Acceptance Criteria and Device Performance for Biocircuits IOS™ TSH Test Cartridges

Device Name: Biocircuits IOS™ TSH Test Cartridges

Predicate Device: Stratus ultra-sensitive hTSH test (Dade International)

Intended Use: Quantitative determination of thyroid stimulating hormone (TSH, thyrotropin) levels in serum using the Biocircuits IOS™ system.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the document. Instead, the study aims to demonstrate substantial equivalence to the predicate device and acceptable precision and accuracy for diagnostic use. The reported performance is as follows:

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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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