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The ABL90 FLEX PLUS analyzer is an in vitro diagnostic, portable, automated analyser that quantitatively measures, pH, blood gases, electrolytes, glucose, lactate and oximetry in heparinized whole blood, and neonatal bilirubin in heparinized capillary whole blood.

The ABL90 FLEX PLUS analyzer is intended for use by trained technologists, nurses, physicians and therapists.

It is intended for use in a laboratory environment, near patient or point-of-care setting.

These tests are only performed under a physician's order.

Bilirubin measurements on the ABL90 FLEX PLUS analyzer are intended to aid in assessing the risk of kernicterus in neonates.

pH, pO2 and pCO2: pH, pCO2 and pO2 measurements are used in the diagnosis and treatment of life-threatening acid-base disturbances.

Potassium (cK+): potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels.

Sodium (cNa+); sodium measurements are used in the diagnosis and treatment of aldosteronism. diabetes insipidus, adrenal hypertension, Addison's disease, dehydration,inappropriate antidiuretic secretion, or other diseases involving electrolyte imbalance.

Calcium (cCa2+): calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease and tetany.

Chloride (cCl-): chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such a cystic fibrosis and diabetic acidosis.

Glucose (cGlu): qlucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoqlycemia, and of pancreatic islet cell carcinoma.

Lactate (cLac): The lactate measurements measure the concentration of lactate in plasma. Lactate measurements are used to evaluate the acid-base status and are used in the diagnosis and treatment of lactic acidosis (abnormally high acidity of the blood.)

Total Hemoglobin (ctHb): total hemoglobin measurements are used to measure the hemoglobin content of whole blood for the detection of anemia.

sO2: oxygen saturation, more specifically the ratio between the concentration of oxyhemoqlobin and oxyhemoglobin plus reduced hemoqlobin.

FO2Hb: oxyhemoqlobin as a fraction of total hemoqlobin.

FCOHb: carboxyhemoglobin measurements are used to determine the carboxyhemoglobin content of human blood as an aid in the diagnosis of carbon monoxide poisoning.

FMetHb: methemoglobin as a fraction of total hemoglobin.

FHHb: reduced hemoqlobin as a fraction of total hemoglobin.

Fraction of Fetal Hemoglobin (FHbF): FHbF indicates the amount of fetal hemoglobin. FHbF is seldom used clinically.

The ABL90 FLEX PLUS is a portable, automated system intended for in vitro testing of samples of whole blood for the parameters pH, pO2, pCO2, potassium, sodium, chloride, glucose, lactate, neonatal bilirubin, and co-oximetry parameters (total hemoglobin, oxygen saturation, and the hemoglobin fractions FO-Hb, FCOHb, FMetHb, FHHb and FHbF).

The manufacturer of the ABL90 FLEX PLUS is Radiometer Medical ApS.

The ABL90 FLEX PLUS consists of an instrument with a sensor cassette and a solution pack as the main accessories. Multiple models of sensor cassettes are available.

The various sensor cassette models for different parameter combinations. For each parameter combination, models allowing for different test load are available. The solution pack is available in two models differing in the number of tests available.

The provided text describes the ABL90 FLEX PLUS analyzer, an in vitro diagnostic device. The submission is for a design change to an existing device, the ABL90 FLEX, with the introduction of the ABL90 FLEX PLUS which includes a mechanized inlet module (AutoInlet) and a Short Probe Mode.

Here's the breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The core of the performance evaluation is a "Method comparison of ABL90 FLEX PLUS Short Probe mode versus ABL90 FLEX syringe mode with inlet clip" and "Imprecision" studies. The reported device performance is that all acceptance criteria were met.

Method Comparison Acceptance Criteria & Performance:

Imprecision Acceptance Criteria & Performance:

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

• Method Comparison Test Set: "more than 40 samples (N) per parameter"
• Data Provenance: Samples were "heparinized, leftover whole blood samples (analyzed 2-3 hours post draw)." The specific country of origin is not explicitly stated, but the submission is from Radiometer Medical ApS in Denmark, suggesting the study likely occurred in a European context or by their internal methods. The study is retrospective as it uses "leftover whole blood samples".

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

Not applicable to this type of in vitro diagnostic device and study. The ground truth for this device is based on measurements from a predicate device (ABL90 FLEX) or a reference instrument, not expert consensus.

4. Adjudication method for the test set

Not applicable. The study compares quantitative measurements between two devices, not subjective interpretations 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 for quantitative measurements, not an AI-assisted diagnostic imaging or interpretation device that would involve human readers.

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

Yes, the performance studies described (Method Comparison and Imprecision) evaluate the standalone analytical performance of the ABL90 FLEX PLUS device (ABL90 FLEX PLUS Short Probe mode and ABL90 FLEX PLUS for imprecision). The comparisons are against a predicate device or reference instrument, not involving human interpretation.

7. The type of ground truth used

• Method Comparison: The predicate device, ABL90 FLEX syringe mode with inlet clip, served as the comparative "truth". The study assessed if the new ABL90 FLEX PLUS Short Probe mode yields equivalent results to this established method.
• Imprecision: "The total imprecision for all parameters except neonatal bilirubin was calculated as the imprecision of the bias towards a reference value determined for each sample on an ABL90 FLEX reference instrument." For neonatal bilirubin, the ground truth source is not explicitly defined beyond "aqueous solutions," but implies a known concentration.

8. The sample size for the training set

Not explicitly stated. For in vitro diagnostic devices, "training set" is not a standard term as it is in machine learning. The studies described are performance verification studies for a medical device. If there was an internal development phase for calibration or algorithm adjustment, that data is not detailed here.

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

Not applicable directly as this is not an ML/AI model with a "training set" in the conventional sense. For the performance studies, ground truth (or reference values) for comparison were established by:

• Method Comparison: Measurements from the predicate device (ABL90 FLEX syringe mode with inlet clip).
• Imprecision: Measurements on an "ABL90 FLEX reference instrument" for most parameters, and "aqueous solutions" for neonatal bilirubin (implying known concentrations).

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The ABL90 FLEX analyzer is a portable, automated analyzer that measures pH, blood gases, electrolytes, glucose, lactate, and oximetry in heparinised whole blood. The ABL90 FLEX analyzer is intended for use by trained technologists, nurses, physicians and therapists. It is intended for use in a laboratory environment, near patient or point-of-care setting. These tests are only performed under a physician's order.

Indications for use:

pH, pO2 and pCO2: pH, pCO2 and pO2 measurements are used in the diagnosis and treatment of life-threatening acid-base disturbances.

Potassium (cK*): potassium measurements are used to monitor electrolyte balance in the diagnosis and treatment of disease conditions characterized by low or high blood potassium levels.

Sodium (cNa*): sodium measurements are used in the diagnosis and treatment of aldosteronism, diabetes insipidus, adrenal hypertension, Addison's disease, dehydration, inappropriate antidiuretic secretion, or other diseases involving electrolyte imbalance.

Calcium (cCa2+): calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease and tetany.

Chloride (cCl¯): chloride measurements are used in the diagnosis and treatment of electrolyte and metabolic disorders such a cystic fibrosis and diabetic acidosis.

Glucose (cGlu): glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.

Lactate (cLac): The lactate measurements measure the concentration of lactate in plasma. Lactate measurements are used to evaluate the acid-base status and are used in the diagnosis and treatment of lactic acidosis (abnormally high acidity of the blood.)

Total Hemoglobin (ctHb): total hemoglobin measurements are used to measure the hemoglobin content of whole blood for the detection of anemia.

sO2: oxygen saturation, more specifically the ratio between the concentration of oxyhemoglobin and oxyhemoqlobin plus reduced hemoglobin.

FO2Hb: oxyhemoqlobin as a fraction of total hemoglobin.

FCOHb: carboxyhemoqlobin measurements are used to determine the carboxyhemoglobin content of human blood as an aid in the diagnosis of carbon monoxide poisoning.

FMetHb: methemoqlobin as a fraction of total hemoglobin.

FHHb: reduced hemoglobin as a fraction of total hemoglobin.

Fraction of Fetal Hemoglobin (FHbF): FHbF indicates the amount of fetal hemoglobin. FHbF is seldom used clinically.

The ABL90 FLEX is a portable, automated system intended for in vitro testing of samples of whole blood for the parameters pH, pO2, pCO2, potassium, sodium, chloride, glucose, lactate, and co-oximetry parameters (total hemoqlobin, oxygen saturation, and the hemoglobin fractions FO2Hb, FCOHb, FMetHb, FHHb and FHbF).

This document describes modifications to the ABL90 FLEX device, specifically software changes to suppress glucose results under certain low pO2 conditions. The following is a summary of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The results are valid under the conditions that:

• all glucose results are suppressed when the pO2 level of the sample is below 10 mmHg.
• all glucose results are suppressed when pO2 level of the sample is between 10 mmHg and 25 mmHg and the glucose level is above 270 mg/dL.
  All acceptance criteria are met: Bias 90 mmHg | 18.1 | 0.1 | 0.7 | 4.1 | 240 |
  | Glu Mid $98.7 \pm 9 mg/dL$ | 10 mmHg | 101.7 | 1.1 | 3.8 | 3.7 | 240 |
  | | 30 mmHg | 101.0 | 0.7 | 3.3 | 3.3 | 240 |
  | | >90 mmHg | 101.2 | 0.5 | 3.3 | 3.2 | 240 |
  | Glu High $270 \pm 6 mg/dL$ | 10 mmHg | 254.1 | 1.6 | 10.8 | 4.2 | 240 |
  | | 30 mmHg | 262.3 | 1.1 | 8.8 | 3.4 | 240 |
  | | >90 mmHg | 271.9 | 1.7 | 7.4 | 2.7 | 240 | | Passed |
  | 48/Unacceptable bias on Glucose results obtained from samples with pO2 levels above 25 mmHg | (Covered by Interference Study) | (Covered by Interference Study) | (Covered by Interference Study) | Passed |
  | (General Performance) Method Comparison | Method comparison study versus a comparative analyzer (ABL735). | Slope: 0.9 - 1.1
  Intercept: 0
  Correlation Coefficient: ≥ 0.95 | Linear regression of the pooled data gives a slope of 0.9206, intercept of 0.084 and an R² ≥ 0.95. | Passed |

2. Sample Sizes and Data Provenance

Interference Study (Test Set):

• Sample Size:
  • 6 different pO2 levels (including a control at ≥90 mmHg)
  • 7 different glucose levels
  • 3 analyzers
  • 6 tests of each sample on each analyzer
  • 2 runs
  • Total: 1512 measurements
• Data Provenance: Fresh heparinized whole blood samples. The document does not specify the country of origin but implies an in-house study ("Radiometer Medical ApS"). The samples are likely prospective as they are "fresh heparinized whole blood samples" and "untreated donor samples in combination with spiked donor blood."

Precision Study (Test Set):

• Sample Size:
  • 20 days
  • 3 different pO2 levels
  • 3 different glucose levels
  • 2 tests of each sample each day
  • 2 runs
  • Total: 2160 measurements
• Data Provenance: Serum pool sample of glucose. The document does not specify the country of origin but implies an in-house study ("Radiometer Medical ApS"). likely prospective.

Method Comparison Study:

• Sample Size: A total of 52 different donors and approximately 500 samples.
• Data Provenance: In-house study using untreated donor samples in combination with spiked donor blood where necessary. Likely prospective.

3. Number of Experts and Qualifications for Ground Truth

The studies described are for an in vitro diagnostic device measuring blood analytes. The ground truth for such devices is typically established through a reference method or comparator device, not clinical expert consensus in the way image analysis or clinical diagnosis algorithms would.

• Interference Study: The ground truth for bias calculation was established by comparing results to a "control" pO2 level (≥90 mmHg). This relies on the established accuracy of the glucose measurement at optimal pO2.
• Precision Study: The ground truth is inherent in the known concentrations of glucose levels in the serum pool samples used.
• Method Comparison Study: The ground truth was established by comparison to results from a "comparative analyzer (ABL735)," which is a predicate device.

Therefore, the concept of "number of experts" and their "qualifications" for establishing ground truth in the context of clinical interpretation (e.g., radiologists for images) is not applicable here. The ground truth is based on laboratory-defined reference measurements or a well-established predicate device.

4. Adjudication Method for the Test Set

Adjudication methods like "2+1" or "3+1" are typically used for subjective assessments where multiple human readers disagree (e.g., interpreting medical images or clinical notes). This document describes performance studies for an in vitro diagnostic device, where results are quantitative measurements. Discrepancies would be resolved through re-testing, calibration, or investigation of instrument malfunction, not clinical adjudication by experts. Therefore, no formal adjudication method of this type is mentioned or expected.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is relevant for assessing the impact of AI on human reader performance, typically in diagnostic imaging or similar fields where human interpretation is central. This document focuses on the analytical performance of an in vitro diagnostic device, specifically the impact of a software modification on glucose measurement accuracy under certain pO2 conditions. The comparisons are between the device's results and reference methods/predicate devices, not between human readers with and without AI.

6. Standalone Performance

Yes, standalone performance was done. The entire submission describes the standalone analytical performance of the ABL90 FLEX device, particularly its glucose measurement under varying pO2 conditions, after the proposed software modification. The studies (Interference, Precision, Method Comparison) evaluate the device's inherent measurement capabilities and the impact of the software suppression logic without human intervention in the continuous measurement process. The modification itself involves the device automatically suppressing results based on pO2 and glucose levels.

7. Type of Ground Truth Used

• Interference Study: The ground truth for bias calculation was primarily reference measurements at optimal pO2 (≥90 mmHg) and the known concentrations of spiked glucose.
• Precision Study: The ground truth was based on the known concentrations of glucose in the serum pool samples used.
• Method Comparison Study: The ground truth was established through comparison with a predicate device (ABL735) and likely involved reference methods for its initial validation.

In essence, the ground truth for these analytical performance studies is rooted in established reference values, comparator devices, and controlled experimental conditions where "true" concentrations or performance characteristics are either known or determined by a validated reference standard.

8. Sample Size for the Training Set

The document does not explicitly state a separate "training set" sample size. This is common for analytical performance studies of this nature, especially when the modification is primarily a software rule change based on understanding of the underlying chemistry (glucose oxidase co-reaction with oxygen). The "training" in such cases might involve development and initial testing against known samples to define the suppression rules, which is not typically formalized as a distinct "training set" in the context of a 510(k) submission for IVDs. The "test set" described above (1512 measurements for interference, 2160 for precision) serves as the primary validation data.

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

As noted above, a formal "training set" with ground truth establishment in the machine learning sense is not explicitly described or necessarily applicable here. The software modification (suppression rules) likely emerged from:

• Understanding of the underlying scientific principle: The document states, "The linearity of the glucose is dependent on the oxygen tension of the sample. This dependence is due to the co-reaction of glucose and oxygen by the enzyme glucose oxidase." This foundational knowledge guides the need for suppression.
• Prior internal R&D data/experiments: Radiometer would have conducted extensive internal studies to characterize the glucose sensor's performance across various pO2 and glucose concentrations to determine the thresholds (e.g., 270 mg/dL) at which accuracy is compromised. This data, if it exists, would have informed the development of the suppression logic.

Therefore, the "ground truth" for developing these rules would be based on analytical measurements from controlled experiments using samples with known glucose and pO2 concentrations, helping to define the performance boundaries.

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The Caltag Fetal Hemoglobin Test, containing either FITC, R-PE or TRI-COLOR® conjugated monoclonal antibodies to fetal hemoglobin (hemoglobin F), is intended for the identification followed by enumeration of fetal red blood cells. Fetal red cells are identified by the presence of fetal hemoglobin by a flow cytometric method. Fetal cells, when found in the maternal circulation, may be an indication of fetal or maternal complications. The hemorrhage of Rh+ fetal blood into Rh- maternal blood may result in the formation of sensitizing Rh antibodies in the mother. This Rh immunization may be prevented by the administration to the mother of Rh immune globulin (RhIg) soon after delivery. The Caltag Fetal Hemoglobin Test may be used as an aid in detecting incompatible fetal-maternal hemorrhage and determining the need for immunoprophylaxis with Rh immune globulin.

An anticoagulated peripheral blood sample is drawn from an appropriate donor. The erythrocyte count is determined and adjusted, followed by brief fixation of the cells in gluteraldehyde. Fixed and washed cells are permeabilized with a detergent in a manner that is frequently used to enable macromolecules such as monoclonal antibodies to penetrate cellular membranes. Caltag HbF FITC, HbF R-PE and HbF TRI-COLOR monoclonal antibodies bind to fetal hemoglobin in fetal red cells. To identify cells containing fetal hemoglobin, fixed and permeabilized cells are incubated with the monoclonal antibody, and washed to remove unbound antibody. Antibody stained cells are subsequently analyzed by flow cytometric methods. Positive and negative control samples must be used with sample analysis, to establish that all reagents are performing in a consistent manner and that the positive fluorescence attributed to antibody-stained fetal red cells is differentiated from unstained normal red blood cells, leukocytes and any cellular debris. If cord blood is not available for the performance of positive controls, the assay cannot be performed reliably. The recommended positive control samples consist of both 1% and 5% fetal erythrocyte-containing placental cord blood in normal adult blood. The recommended negative control sample consists of 1% anticoagulated sample from a normal male or non-pregnant adult female.

Here's a breakdown of the acceptance criteria and the study details for the Caltag Fetal Hemoglobin Test, based on the provided text:

Acceptance Criteria and Device Performance

The core of the acceptance criteria for this device revolves around demonstrating substantial equivalence to the predicate device (Sure-Tech Fetal Hemoglobin Test, K892241). This is primarily shown through correlation studies and assessments of expected values and reproducibility.

1. Table of Acceptance Criteria and Reported Device Performance

Given that this is a 510(k) summary for a diagnostic device, the acceptance criteria are not explicitly stated as pass/fail thresholds in the same way they might be for a therapeutic device. Instead, the performance is demonstrated by showing strong correlation with the predicate device and acceptable levels of specificity, reproducibility, and linearity.

2. Sample Size and Data Provenance

• Correlation Studies (Test Set):

  • Site 1: 50 prepared samples, 30 patient samples.
  • Site 2: 15 prepared samples, 38 patient samples.
  • Site 3: 15 prepared samples, 13 patient samples.
  • Total: 80 prepared samples, 81 patient samples (summing across sites, noting some overlap in prepared samples).
  • Provenance: "patient samples were obtained from women having clinical indications that were consistent with fetal-maternal hemorrhage and prepared samples consisted of mixtures of fetal cord blood in normal adult blood." The studies were conducted in three independent laboratories in geographically diverse areas within the United States. This implies retrospective for patient samples with specific clinical indications, and prospectively prepared for mixed samples.

• Expected Values Data:

  • Sample Size: 161 adult female normal donors.
  • Provenance: Collected from "adult female normal donors" across "three independent laboratories" in "geographically diverse areas within the United States, including the Northern, South-central and Western regions." Donors were of "differing ethnic origins, including adult Caucasians, Blacks, Orientals and Hispanics." This data is prospective.

• Specificity Data:

  • Sample Size: Not explicitly stated but "blood samples were obtained from healthy normal donors of Caucasian, Black, Hispanic and Oriental ethnic origins." (likely a subset of the 161 from expected values, or similar cohort).
  • Provenance: Healthy normal donors, likely prospective.

• Reproducibility Data (Intra-lab & Inter-lab):

  • Sample Size: 6 replicated determinations for each antibody at high, medium, and low levels, performed across three independent laboratories. The samples were "varying mixtures of placental cord blood in normal adult blood." For inter-lab, "unstained and unfixed samples containing mixtures of cord blood in normal adult blood representing the appropriate ranges were prepared by one of the participating laboratories for staining and analysis by each of the participating laboratories." This involved prepared samples, likely prospective.

• Linearity of Measurement:

  • Sample Size: 10 samples (mixtures of cord blood cells in normal adult blood).
  • Provenance: Prepared samples, prospective.

• Detection of 100% Cord Blood:

  • Sample Size: 5 different cord blood samples.
  • Provenance: Cord blood samples, likely prospective.

3. Number of Experts Used to Establish Ground Truth and Qualifications

• The document does not explicitly mention "experts" being used to establish ground truth for this device in the sense of trained clinicians making diagnoses that the device is then compared against.
• Instead, the Kleihauer-Betke (KB) test is used as the comparative "ground truth" to which the Caltag device is correlated. The KB test is an established, widely used microscopic staining method for detecting fetal hemoglobin. The interpretation of KB tests typically involves trained laboratory technicians or pathologists.
• The document states that the correlation study was conducted in 3 independent laboratories, implying that personnel trained in both flow cytometry and the KB method were involved in generating the data. No specific qualifications (e.g., "Radiologist with 10 years of experience") are provided for these individuals, as the device measures a quantitative biological marker rather than interpreting images.

4. Adjudication Method for the Test Set

• No explicit adjudication method (e.g., 2+1, 3+1) is mentioned.
• The "ground truth" for the correlation studies was the result from the Kleihauer-Betke (KB) test. This is a laboratory test with an established protocol, and the agreement is between the Caltag device's quantitative output and the KB test's quantitative output, rather than human expert interpretations requiring adjudication.

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

• No MRMC comparative effectiveness study was done.
• This device is a diagnostic assay that directly quantifies fetal hemoglobin. It is not an AI-assisted interpretation tool for human readers, so comparing human readers with and without AI assistance is not applicable to this type of device.

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

• Yes, the performance presented for the Caltag Fetal Hemoglobin Test is its standalone performance. The flow cytometric analysis is an automated process after sample preparation and staining with the monoclonal antibodies. The reported percentages of positive cells (e.g., mean % positive, r² values) represent the device's output. While human technicians perform the sample preparation and operate the flow cytometer, the measurement itself is performed by the instrument and its associated software, making it a standalone quantitative measurement.

7. Type of Ground Truth Used

• The primary ground truth used for comparison and validation is the Kleihauer-Betke (KB) microscopic staining method. This is a laboratory-based, established diagnostic test for quantifying fetal red blood cells.
• For the 100% cord blood samples, the "ground truth" is the known composition of the sample (i.e., that it should be 100% fetal cells), effectively using known sample composition.
• For expected values and specificity, healthy normal donors were the "ground truth" for what constitutes a normal, non-pregnant sample result.

8. Sample Size for the Training Set

• The document describes studies for validation and substantial equivalence, not a machine learning "training set" in the modern sense. Therefore, there isn't a "training set" sample size like one would find for an AI/ML algorithm.
• The "expected value" data (161 donors) and "specificity" data implicitly contribute to defining the normal operating parameters and behavior of the test, which could be considered analogous to internal validation or establishing reference ranges.

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

• As mentioned, there isn't a "training set" in the AI/ML context.
• For the data that helps define the device's characteristics (e.g., expected values, specificity), the ground truth was established by:
  • Using healthy normal donors to determine normal ranges and confirm specificity (i.e., no fetal cells expected, or very low baseline).
  • Using known prepared samples (mixtures of cord blood and adult blood) to assess linearity and reproducibility. These samples have a known, pre-determined percentage of fetal cells.

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