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The NeoLSD™ MSMS kit is intended for the quantitative measurement of the activity of the enzymes acid-9glucocerebrosidase (ABG), acid-sphingomyelinase (GAA), 8 galactocerebrosidase (GALC), agalactosidase A (GLA) and a-L-iduronidase (IDUA) in dried blood spots (DBS) from newborn babies. The analysis of the enzymatic activity is intended as an aid in screening newborns for the following lysosomal storage disorders (LSD) respectively; Gaucher Disease, Niemann-Pick A/B Disease, Krabbe Disease, Fabry Disease, and Mucopolyaccharidosis Type I (MPS I) Disease.

The NeoLSD MSMS test system uses mass spectrometry to quantitatively measure the activity of six lysosomal enzymes simultaneously from a dried blood spot sample. The NeoLSD MSMS test system is comprised of:

1. NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
2. The QSight Instrument is comprised of:
   QSight® 210 MD Mass Spectrometer O
   QSight HC Autosampler MD Instrument Software O
   QSight Binary Pump MD O
   Simplicity Instrument control software: O
   Simplicity Data Processing software (by sample): O
   O PerkinElmer MSMS Workstation Data Processing Software

The NeoLSD MSMS kit evaluates enzyme activities by measuring the product generated when an enzyme reacts with a synthesized substrate to create a specific end product. The activities of the six lysosomal enzymes present in a 3.2 mm punch from a dried blood spot (DBS) are simultaneously measured by the NeoLSD MSMS kit. The punches are incubated with the assay reagent mixture which contains;

• six substrates, one corresponding to each lysosomal enzyme
• six stable-isotope mass-labeled internal standards (IS) each designed to chemically resemble each product generated
• . a buffer to maintain the reaction pH, and to carry inhibitors to limit activity from competing enzymes if present and additives to enhance the targeted enzyme reactions.

Here's a breakdown of the acceptance criteria and study information for the NeoLSD MSMS Kit, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state acceptance criteria in a dedicated table for screening performance per se, but it details the analytical performance and implies that meeting the predicate device's performance characteristics for screening, along with established analytical limits, constitutes acceptance. The "Comparison Chart" on page 6 includes some comparable metrics between the proposed and predicate device.

Below is a table summarizing the reported analytical performance, with implied acceptance criteria that the device's performance should be within acceptable clinical/analytical ranges and comparable to the predicate device.

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

• Sample Size for Screening Performance Study: 2489 routine newborn samples + 12 archived confirmed LSD positive newborn Dried Blood Spot (DBS) specimens = 2501 samples.
• Data Provenance:
  • Country of Origin: The study was conducted at a "US newborn screening laboratory (Site A)".
  • Retrospective/Prospective: Primarily retrospective for the routine samples as they were "routine newborn samples". The 12 positive samples were "archived confirmed LSD positive newborn DBS specimens", making them retrospective as well. The device also mentions testing samples from newborns ≤ 48 hours old, common for newborn screening.

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

The document does not explicitly state the number of experts or their qualifications. It refers to the 12 archived confirmed LSD positive newborn DBS specimens as having a "confirmed" diagnosis. This implies clinical confirmation, likely by medical specialists and further diagnostic testing, but the specific process for establishing this ground truth (e.g., expert panel review of clinical, biochemical, and genetic data) is not detailed.

4. Adjudication Method for the Test Set

The document does not describe a formal adjudication method for the test set in terms of expert review for AI output. Instead, the study compares the screening results of the new device (QSight) against a predicate device (Waters Acquity TQD) and against retrospectively confirmed positive samples. The "ground truth" for the 12 positive samples was their established "confirmed" LSD status, not an adjudication process by experts specifically for this study.

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 is not applicable. The device is an in-vitro diagnostic kit for quantitative measurement of enzyme activity using mass spectrometry (MSMS), not an image-based AI system that assists human readers. The study involves comparing the performance of the new kit on one MSMS instrument (QSight) against its predicate on a different MSMS instrument (Waters Acquity TQD).

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

Yes, this study represents a standalone performance evaluation of the "NeoLSD MSMS Kit" on the "QSight Instrument" system. The kit/instrument system performs the quantitative measurement of enzyme activity. While a human laboratory technician operates the instrument and interprets the numerical results based on cut-off values, the core diagnostic output (enzyme activity) is determined by the automated system without subjective human interpretation of raw data fields that would typically be associated with "standalone AI" vs "human-in-the-loop" in other diagnostic contexts (e.g., radiology). The comparison is between two automated systems (QSight vs. TQD).

7. The Type of Ground Truth Used

The ground truth for the 12 positive samples was confirmed LSD diagnoses, which implies a combination of:

• Clinical diagnosis: Based on patient symptoms.
• Biochemical confirmation: Enzyme assays, metabolite analysis.
• Genetic confirmation: DNA sequencing to identify pathogenic variants.

For the 2489 routine newborn samples, the ground truth is implied to be their "routine" healthy status, where no LSD was suspected or later confirmed, and their performance was used to establish median values and cut-offs.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. The term "training set" is typically used for developing AI models. This device is a diagnostic kit based on mass spectrometry, not a machine learning algorithm that is "trained." Performance characteristics like expected values (means, medians, percentiles) were derived from a large population of 2488 (or 2489) routine newborn samples, which could be considered a reference population for establishing normal ranges and cut-offs.

• Expected Values (Reference Population): 2488 or 5041 (depending on the enzyme) de-identified residual DBS samples from routine newborn screening. (Page 7, Table "Expected Values")

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

As noted above, there's no explicit "training set" in the AI sense. However, the "Expected Values" table on page 7 lists statistics derived from "N=2488" and "N=5041" samples, which are described as de-identified residual DBS samples from routine newborn screening. These would represent a population assumed to be largely unaffected (normal controls) in terms of LSDs, allowing for the establishment of normal enzyme activity ranges, medians, and percentiles. The ground truth for these samples would be their implicit "normal" or "no confirmed LSD" status based on routine screening outcomes or lack of follow-up diagnoses.

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The NeoLSD MSMS Kit is intended for the quantitative measurement of the activity of the enzymes acid-pglucocerebrosidase (ABG), acid-sphingomyelinase (ASM), acid-a-glucosidase (GAA), B-galactocerebrosidase (GALC), α-galactosidase A (GLA) and α-L-iduronidase (IDUA) in dried blood spots (DBS) from newborn babies. The analysis of the enzymatic activity is intended as an aid in screening newborns for the following lysosomal storage disorders (LSD) respectively; Gaucher Disease, Nieman-Pick A/B Disease, Pompe Disease, Fabry Disease, and MPS I Disease.

The NeoLSD MSMS test system uses mass spectrometry to quantitatively measure the activity of six lysosomal enzymes simultaneously from a dried blood spot sample. The NeoLSD MSMS test system is comprised of:

1. NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
2. Waters TQD MSMS instrument comprised of,
   a. Waters 1525 sample pump
   b. Waters 2777c autosampler
   c. Waters MassLynx v4.1 firmware C.
   d. Power cables, tubing, syringes, connection cables
3. Waters NeoLynx v4.1 software and computer with monitor
4. PerkinElmer MSMS Workstation Software

The NeoLSD MSMS kit evaluates enzyme activities by measuring the product generated when an enzyme reacts with a synthesized substrate to create a specific end product. The activities of the six lysosomal enzymes present in a 3.2 mm punch from a dried blood spot (DBS) are simultaneously measured by the NeoLSD MSMS kit. The punches are incubated with the assay reagent mixture which contains;
. six substrates, one corresponding to each lysosomal enzyme
. six stable-isotope mass-labeled internal standards (IS) each designed to chemically resemble each product generated
. a buffer to maintain the reaction pH, and to carry inhibitors to limit activity from competing enzymes if present and additives to enhance the targeted enzyme reactions.

The NeoLSD MSMS Kit is intended for the quantitative measurement of the activity of six lysosomal enzymes (acid-β-glucocerebrosidase (ABG), acid-sphingomyelinase (ASM), acid-α-glucosidase (GAA), β-galactocerebrosidase (GALC), α-galactosidase A (GLA), and α-L-iduronidase (IDUA)) in dried blood spots (DBS) from newborn babies. The analysis of enzymatic activity serves as an aid in screening newborns for Gaucher Disease, Niemann-Pick A/B Disease, Pompe Disease, Krabbe Disease, Fabry Disease, and MPS I Disease.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics reported, such as linearity ranges, precision (reproducibility %CV), and LoQ values. The screening performance, particularly sensitivity and specificity, are key for a screening tool.

Note: The document provides performance metrics, implying these are the acceptance criteria that the device has met or is expected to meet for its intended use as a newborn screening aid.

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

• Sample Size for Screening Performance Study:

  • Routine Samples: 4011 newborn specimens (retrospective, 4 years old, used for follow-up of clinical status).
  • Confirmed LSD Positive Samples (enriched): 30 newborn DBS specimens (from the site's biobank, ranging from 5.8 to 17.6 years of age).
  • Total Test Set: 4041 specimens (4011 routine + 30 confirmed positive).

• Data Provenance:

  • Routine Samples: Retrospective routine newborn screening samples, 4 years old, from an EU (European) newborn screening laboratory.
  • Confirmed LSD Positive Samples: From the site's biobank (likely the same EU lab), with ages ranging from 5.8 to 17.6 years.

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

The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.

Instead, the ground truth for the 4011 routine samples was established based on:

• Clinical outcome: "Clinical outcome was used as a comparator for all samples, including the 4011 routine screening samples, as derived from the civil registry status and national hospital registry. Subject´s survival at 4 years of age without LSD diagnosis or clinical signs suggestive of an LSD was used as clinical confirmation of an unaffected newborn."
• For the 30 confirmed LSD positive samples: Their status was "known" as "confirmed LSD positive newborn DBS specimens."

Therefore, the ground truth relies on clinical follow-up data and prior confirmed diagnoses, rather than a panel of experts adjudicating each case for the study.

4. Adjudication Method for the Test Set

No explicit "adjudication method" in the sense of expert review (e.g., 2+1, 3+1) is described for the test set. The ground truth was established by:

• Clinical outcome and registry data for routine samples to determine "unaffected" status.
• Known (prior confirmed) diagnoses for the "confirmed positive" samples.
• Screening algorithm: For routine samples, those below the initial cut-off were re-tested in duplicate to classify as normal, presumptive positive, or invalid.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is a diagnostic kit that quantitatively measures enzyme activity, not an interpretative imaging AI tool that assists human readers. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply here.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was done

Yes, the screening performance study essentially represents a standalone (algorithm only) performance for the NeoLSD MSMS kit. The device measures enzyme activity, and the "screening results" (positive, negative, invalid) are derived directly from these quantitative measurements compared against predefined cut-off values and a re-testing algorithm. While a human laboratory technician performs the assay, the interpretation of the results as "screen positive" or "screen negative" is determined by the device's output and the established algorithm, without human interpretative judgment affecting the individual sample classification.

7. The Type of Ground Truth Used

The ground truth used was primarily:

• Outcomes data/Clinical Confirmation: For the 4011 routine samples, "Subject´s survival at 4 years of age without LSD diagnosis or clinical signs suggestive of an LSD was used as clinical confirmation of an unaffected newborn." This is a form of clinical outcome data.
• Pathology/Confirmed Diagnosis: For the 30 enriched samples, they were "confirmed LSD positive" specimens, indicating a definitive medical diagnosis.

8. The Sample Size for the Training Set

The document describes studies for establishing reference ranges and calibration, but it does not explicitly describe a "training set" in the context of machine learning model development. The development of this assay likely involved extensive analytical validation (e.g., linearity, LoQ, interference) and establishing reference ranges using large sample sets, which might be considered analogous to a training or development phase for defining assay parameters and cut-offs.

• Reference Range Establishment:
  • EU site: 5041 newborn samples were tested to establish cut-off values. These were "retrospective routine newborn screening samples" from newborns 0-30 days of age.
  • US Site A: 5251 newborn DBS specimens, newborns ≤ 4 days.
  • US Site B: 5053 newborn DBS specimens, newborns ≤ 7 days.

These large cohorts were used to determine population distributions, medians, and percentiles to set initial and retest cut-off values. While not a "training set" for an AI algorithm, they serve a similar purpose in defining the operational parameters for the device's classification logic.

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

Given that there isn't a "training set" for an AI model, the "ground truth" for establishing the reference ranges and cut-offs was based on:

• Population Distribution: Statistical analysis of enzyme activity levels in large cohorts of presumably healthy newborns (5041 from EU, 5251 from US Site A, 5053 from US Site B).
• Expert-defined Percentiles: The initial cut-off values were based conservatively on "0.1 - 0.3 percentile of enzyme activity distribution and converted to a percentage of population median activity," which reflects expert consensus on appropriate thresholds for screening. The "retest cut-off values were set 5% lower from the initial cut-off percentage."

This process is standard for establishing normal ranges and screening cut-offs for diagnostic assays and involves statistical methods and clinical expert judgment in setting initial thresholds.

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