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.

Device Description

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:

NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
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.

AI/ML Overview

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.

Performance Metric	Acceptance Criteria (Implied/General)	Reported Device Performance (QSight System)
Reportable Range (µmol/L/h)	Generally, a sufficiently broad and clinically relevant range.	IDUA: 0.19 – 22.3GAA: 0.31 – 25.3ABG: 0.79 – 20.0GLA: 0.80 – 20.4ASM: 0.16 – 13.8GALC: 0.20 – 7.75
Lower Limits of Measure (LoB, LoD, LoQ) (µmol/L/h)	Limits should be clinically relevant and allow for detection of low enzyme activity associated with LSDs. Imprecision at LoQ within specified CV% limits (ABG, GLA, IDUA <40%; ASM, GAA <30%; GALC <50%).	IDUA: LoB=0.044, LoD=0.13, LoQ=0.19GAA: LoB=0.080, LoD=0.31, LoQ=0.31ABG: LoB=0.114, LoD=0.79, LoQ=0.79GLA: LoB=0.519, LoD=0.80, LoQ=0.80ASM: LoB=0.046, LoD=0.16, LoQ=0.16GALC: LoB=0.120, LoD=0.20, LoQ=0.20 Imprecision (CV%) at LoQ: ABG (LoQ 0.79): No specific CV% provided at LoQ, but precision data for sample 1 (mean 1.05) shows Total variation CV% of 22.8% (within <40% target).ASM (LoQ 0.16): No specific CV% provided at LoQ. GALC (LoQ 0.20): No specific CV% provided at LoQ, but precision data for sample 1 (mean 0.27) shows Total variation CV% of 13.4% (within <50% target).IDUA (LoQ 0.19): No specific CV% provided at LoQ, but precision data for sample 1 (mean 0.76) shows Total variation CV% of 15.8% (within <40% target).GLA (LoQ 0.80): No specific CV% provided at LoQ, but precision data for sample 1 (mean 1.03) shows Total variation CV% of 16.1% (within <40% target).GAA (LoQ 0.31): No specific CV% provided at LoQ, but precision data for sample 1 (mean 0.95) shows Total variation CV% of 12.8% (within <30% target).
Linearity (Linear Range µmol/L/h)	Data should fulfill acceptance criteria of the study.	IDUA: 0.08 – 22.3GAA: 0.11 – 25.3ABG: 0.39 – 20.0GLA: 0.60 – 20.4ASM: 0.09 – 13.8GALC: 0.18 – 7.75
Precision (Total Variation CV%)	Within acceptable analytical variability for newborn screening, generally below specific thresholds (e.g., <40% for ABG, GLA, IDUA; <30% for ASM, GAA; <50% for GALC). Ranges given in Comparison Chart hint at typical performance, e.g., 8.9%-15.8% for IDUA.	ABG: 10.7%-22.8%GALC: 7.4%-13.4%IDUA: 8.9%-15.8%GLA: 7.3%-16.1%GAA: 7.3%-12.8%ASM: 8.1%-14.5%
Screening Performance (Agreement with Predicate)	High agreement (e.g., all confirmed positive samples identified, minimal false positives/negatives)	Gaucher (ABG): 100% agreement (3 Positive with QSight, 3 Positive with TQD; 2487 Negative with both)Niemann-Pick A/B (ASM): 100% agreement (2 Positive with QSight, 2 Positive with TQD; 2488 Negative with both)Krabbe (GALC): 100% agreement (4 Positive with QSight, 4 Positive with TQD; 2486 Negative with both)MPS I (IDUA): 100% agreement (6 Positive with QSight, 6 Positive with TQD; 2484 Negative with both)Fabry (GLA): 100% agreement (6 Positive with QSight, 6 Positive with TQD; 2484 Negative with both)Pompe (GAA): 100% agreement (1 Positive with QSight, 1 Positive with TQD; 2489 Negative with both)

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.

Summary

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May 3, 2019

PerkinElmer Inc. Brian Ciccariello Sr. Manager Regulatory Affairs 940 Winter Street Waltham, MA 02451

Re: K190266

Trade/Device Name: NeoLSD MSMS Kit Regulation Number: 21 CFR 862.1488 Regulation Name: Lysosomal storage disorder newborn screening test system Regulatory Class: Class II Product Code: PQW, PQT, PQU, PQV, QCL, QCM Dated: February 6, 2019 Received: February 8, 2019

Dear Brian Ciccariello:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part

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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K190266

Device Name NeoLSD MSMS Kit

Indications for Use (Describe)

Type of Use (Select one or both, as applicable):

☑ Prescription Use (Part 21 CFR 801 Subpart D)
☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary

This summary of safety and effectiveness information is supplied in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned number is K190266

Date: February 06, 2019

Submitted by:	PerkinElmer Inc940 Winter StreetWaltham MA 02451
Contact Person:	Brian CiccarielloTel: 781-663-5651
Trade Name:	NeoLSD MSMS Kit
Common Name:	NeoLSD MSMS Kit
Regulation:	21 CFR 862.1488
Classification Name:	Lysosomal storage disorder newborn screening test system
Classification:	75 Chemistry
Product Code:	PQW, PQT, PQU, PQV, QCL, QCM
Predicate device:	NeoLSD MSMS Kit (K173829)

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Intended Use:

The NeoLSD MSMS Kit is intended for the quantitative measurement of the activity of the enzymes acid-ß- glucocerebrosidase (ABG), acid-sphingomyelinase (ASM), acid-a-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 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, Pompe Disease, Krabbe Disease, and Mucopolysaccharidosis Type I (MPS I) Disease.

Device Description:

1. NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
  The NeoLSD MSMS Kit will contain sufficient reagents and consumables to perform 960 assays (10 x 96-well plates) as listed in the following table.

Component	Description
Kit insert	Instructions for use
QC certificate	QC certificate showing the kit lot specific Kit Control results determined bythe manufacturer, and the 1 SD limits.
Internal Standards Substrate Mix	1 vial or several vials of stable-isotope standards and designed substrates,the dried substrates and internal standards are a mixture of the 6 syntheticsubstrates, the corresponding 6 stable-isotope labeled internal standards,and sodium oleate
DBS controls	C1, C2, C3 control levels on DBS cassettes, manufactured from human bloodwith a hematocrit value of 45-50%.
Assay buffer	1 bottle of 40 mL buffer, ready-for-use succinate buffered (pH 4.7) saltsolution
Extraction Solution	Ethyl acetate
Flow Solvent reconstitution solvent	The ready-for-use Flow Solvent contains acetonitrile, water, and formicacid.
Incubation/Sampling plate	20 x 96-well microplate, U-bottomed
Extraction plate	10 x 96-deep well microplate
Aluminum foil microplate covers	20 adhesive aluminum foil microplate covers
Microplate covers	10 x adhesive microplate covers
Plate barcode labels	30 plate barcodes

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1. 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

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.

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Comparison Chart:

Comparison of the NeoLSD MSMS Kit with the predicate.

Characteristics	Proposed Device	Predicate (K173829)
Intended Use/Indications forUse	The NeoLSD MSMS Kit is intended for thequantitative measurement of the activity of theenzymes 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 theenzymatic activity is intended as an aid inscreening newborns for the followinglysosomal storage disorders (LSD) respectively;Gaucher Disease, Niemann-Pick A/B Disease,Pompe Disease, Krabbe Disease, Fabry Disease,and Mucopolysaccharidosis Type I Disease.	Same
TestMethodology	Quantitative mass spectrometric enzymaticactivity assay	Same
Instrument /SoftwarePlatform	PerkinElmer QSight 210MD SMSScreening System: CTC PAL RSI SampleManager, Spark Holland SPH1240Binary Pump. Instrument Software:Simplicity, Data Processing softwareand with the PerkinElmer MSMSWorkstation Software	Waters Acquity TQD instrument with MassLynxv4.1 firmware, with Waters 1525 sample pump,with Waters 2777c autosampler, with WatersNeoLynx v4.1 software and with thePerkinElmer MSMS Workstation Software
Sample Type	Punch from dried blood spot specimen	Same
Reportable Range(μmol/L/h)	IDUA: 0.19 – 22.3GAA: 0.31 – 25.3ABG: 0.79 – 20.0GLA: 0.80 – 20.4ASM: 0.16 – 13.8GALC: 0.20 – 7.75	IDUA: 0.34 – 17.2GAA: 0.44 – 24.2ABG: 0.69 – 20.1GLA: 0.97 – 20.9ASM: 0.90 – 20.5GALC: 0.63 – 6.3
Lower Limits ofMeasure(μmol/L/h)	IDUA: LoB=0.044, LoD=0.13, LoQ=0.19GAA: LoB=0.080, LoD=0.31, LoQ=0.31ABG: LoB=0.114, LoD=0.79, LoQ=0.79GLA: LoB=0.519, LoD=0.80, LoQ=0.80ASM: LoB=0.046, LoD=0.16, LoQ=0.16GALC: LoB=0.120, LoD=0.20, LoQ=0.20	IDUA: LoB=0.059, LoD=0.24, LoQ=0.34GAA: LoB=0.073, LoD=0.39, LoQ=0.44ABG: LoB=0.165, LoD=0.63, LoQ=0.69GLA: LoB=0.476, LoD=0.97, LoQ=0.97ASM: LoB=0.110, LoD=0.27, LoQ=0.90GALC: LoB=0.106, LoD=0.34, LoQ=0.63

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Calibrators /Standards	Molecular Weights & Concentrations of InternalStandards:IDUA: 430.26 / 15.0 μΜGAA: 502.32 / 24.0 μΜABG: 390.38 / 20.0 μΜGLA: 488.31/ 24.0 μΜASM: 404.40/ 15.0 μΜGALC: 416.40 / 10.0 μΜ						Same
Controls	3 levels of control material, human blood based						Same
Expected Values(µmol/L/h)		N	0.1%	0.2%	0.3%	2.5%	97.5%
	IDUA	2488	1.36	1.51	1.86	3.31	12.55
	GAA	2488	2.32	2.54	2.79	4.23	19.55
	ABG	2488	1.40	1.78	1.96	3.66	18.95
	GLA	2488	3.83	4.74	5.44	7.59	41.99
	ASM	2488	1.32	1.43	1.57	2.32	8.01
	GALC	2488	0.80	1.01	1.07	1.62	14.90
	IDUA	5041	2.06	2.55	2.62	3.82	13.2
	GAA	5041	2.33	2.69	2.92	4.28	17.5
	ABG	5041	2.85	3.16	3.33	4.74	20.1
	GLA	5041	3.04	3.37	3.62	4.81	25.8
	ASM	5041	2.12	2.21	2.37	3.15	12.9
	GALC	5041	0.43	0.52	0.56	0.95	9.34
Precision	Sample ActivityRange			Sample CV%Range
	IDUA	0.76-16.4			8.9%-15.8%
	GAA	0.95-24.7			7.3%-12.8%
	ABG	1.05-14.7			13.9%-22.8%
	GLA	1.03-17.6			7.3%-16.1%
	ASM	0.56-12.2			8.1%-14.5%
	GALC	0.27-7.75			6.4%-13.4%
	IDUA	0.92-15.7			8.7%-18.7%
	GAA	1.29 - 22.4			6.9%-16.7%
	ABG	1.15-19.3			12.5%-23.2%
	GLA	1.23-19.3			9.1%-16.1%
	ASM	0.92-21.5			10.4%-16.7%
	GALC	0.45-5.58			11.4%-22.7%

Summary of Studies:

Precision:

The NeoLSD kit precision was determined based on the recommendations of the CLSI guideline EP5-A2 and presented in the tables below. The variation of the NeoLSD MSMS kit is based on 108 determinations: 54 plates measured over 22 working days, each plate having 2 replicates per sample. The samples were measured on 3 QSight systems using 3 kit lots.

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ABG	n	Meanµmol/L/h	RepeatabilitySD	RepeatabilityCV%	Within-labSD	Within-labCV%	Between-lotSD	Between-lotCV%	Total variationSD	Total variationCV%
1	108	1.05	0.11	10.7	0.24	22.7	0.02	2.4	0.24	22.8
2	108	2.33	0.30	13.0	0.38	16.5	0.11	4.8	0.40	17.2
3	108	6.56	0.71	10.8	0.93	14.1	0.19	2.8	0.95	14.4
4	108	13.0	1.21	9.30	1.73	13.3	0.50	3.9	1.80	13.9
5	108	14.7	2.35	15.9	2.97	20.2	0.29	2.0	2.99	20.3

NeoLSD QSight 22-day precision results.

GALC	n	Meanµmol/L/h	Repeatability		Within-lab		Between-lot		Total variation
			SD	CV%	SD	CV%	SD	CV%	SD	CV%
1	108	0.27	0.03	10.1	0.04	13.2	0.01	2.1	0.04	13.4
2	108	0.56	0.05	8.3	0.07	12.6	0.02	3.6	0.07	13.1
3	108	2.58	0.18	7.1	0.19	7.3	0.02	0.8	0.19	7.4
4	108	4.74	0.24	5.1	0.30	6.4	0.03	0.6	0.30	6.4
5	108	7.75	0.78	10.0	0.82	10.5	0.34	4.4	0.89	11.4

IDUA	n	Meanµmol/L/h	Repeatability		Within-lab		Between-lot		Total variation
			SD	CV%	SD	CV%	SD	CV%	SD	CV%
1	108	0.76	0.11	15.1	0.12	15.6	0.02	2.3	0.12	15.8
2	108	1.33	0.12	9.1	0.18	13.5	0.03	2.4	0.18	13.7
3	108	2.71	0.20	7.2	0.25	9.2	0.09	3.3	0.26	9.7
4	108	7.75	0.55	7.0	0.69	8.9	0.04	0.5	0.69	8.9
5	108	16.4	1.78	10.8	2.01	12.2	0.34	2.1	2.04	12.4

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GLA	n	Meanµmol/L/h	Repeatability		Within-lab		Between-lot		Total variation
			SD	CV%	SD	CV%	SD	CV%	SD	CV%
1	108	1.03	0.11	10.7	0.16	15.9	0.03	2.6	0.17	16.1
2	108	2.46	0.19	7.5	0.26	10.4	0.04	1.7	0.26	10.5
3	108	6.44	0.49	7.6	0.64	9.9	0.01	0.2	0.64	9.9
4	108	12.2	0.58	4.8	0.95	7.8	0.20	1.6	0.97	7.9
5	108	17.6	1.15	6.5	1.27	7.2	0.15	0.8	1.28	7.3

GAA	n	Meanµmol/L/h	Repeatability		Within-lab		Between-lot		Total variation
			SD	CV%	SD	CV%	SD	CV%	SD	CV%
1	108	0.95	0.08	8.4	0.12	12.7	0.02	1.7	0.12	12.8
2	108	2.80	0.22	7.8	0.24	8.5	0.05	1.7	0.24	8.7
3	108	8.01	0.55	6.9	0.58	7.2	0.11	1.4	0.59	7.3
4	108	17.1	1.76	10.3	1.95	11.4	0.29	1.7	1.97	11.5
5	108	24.7	1.54	6.2	1.81	7.3	0.23	0.9	1.82	7.4

Limit of Blank, Detection and Quantification:

The limits of blank and detection were determined according to the CLSI guideline EP17-A2 and presented in the table below. The limit of blank (LoB) for the NeoLSD MSMS kit is defined as the 95th percentile of a distribution of blank samples determinations. The limit of detection (LoD) of the kit is based on 75 determinations done with low level samples for the QSight 210 MD Screening System.

Enzyme	LoB	LoD
ABG	0.114	0.79
ASM	0.046	0.16
GALC	0.120	0.20
IDUA	0.044	0.13
GLA	0.519	0.80
GAA	0.080	0.31

NeoLSD limit of blank (LoB) and limit of detection (LoD) with QSight.

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Image /page/10/Picture/1 description: The image shows the logo for PerkinElmer. The logo consists of a blue abstract shape resembling a stylized "P" and an arrow pointing to the right. To the right of the shape is the text "PerkinElmer" with "Perkin" in black and "Elmer" in gray. Below the company name is the text "For the Better" in blue.

The Limit of Quantitation (LoQ) is defined as the lowest activity fulfilling the total CV% requirement of the assay. For ABG, GLA and IDUA the CV% requirement is <40%. For ASM and GAA <30% and for GALC <50%. If the imprecision criterion was met for activities below LoD, the LoQ was set to be equal to the LoD. The table shows the LoQ results and imprecision observed at these activities:

Enzyme	QSight
	LoQ$(µmol/L/h)$
ABG	0.79
ASM	0.16
GALC	0.20
IDUA	0.19
GLA	0.80
GAA	0.31

NeoLSD Limit of Quantitation
------------------------------

Linearity:

Linearity was determined in accordance with CLSI guideline EP06-A. The data fulfills the acceptance criteria of the study for the PerkinElmer QSight 210 MD Screening System. The linear range for NeoLSD MSMS kit using the QSight is summarized in below.

Enzyme	QSight	QSight
	Linear RangeLower Limit(µmol/L/h)	Linear RangeUpper Limit(µmol/L/h)
ABG	0.39	20.0
ASM	0.09	13.8
GALC	0.18	7.75
IDUA	0.08	22.3
GLA	0.60	20.4
GAA	0.11	25.3

NeoLSD linear range

Interference:

Refer to the kit insert for interference information.

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Image /page/11/Picture/1 description: The image shows the logo for PerkinElmer. The logo consists of a blue stylized "P" with an arrow shape to the right of it. Below the symbol is the name "PerkinElmer" in a bold, sans-serif font, with "Perkin" in black and "Elmer" in gray. Underneath the name is the tagline "For the Better" in a smaller, blue font.

Screening Performance:

The screening performance of the NeoLSD MSMS kit on QSight and Waters Acquity TQD was compared in a clinical study at US newborn screening laboratory (Site A). In the study 2489 routine newborn samples were tested. Samples tested were from newborns ≤ 48 hours old. The study population was enriched with 12 archived confirmed LSD positive newborn DBS specimens.

The initial cut-off values were based on a percentage of population median activity. The retest cut-off values were set 5% lower from the initial cut-off percentage. The cut-off percentages were applied to daily medians established based on the initial routine sample results for the initial and retest cut-off percentages used in the study are shown below. The final results for the screening performance including confirmed positive specimens are presented below. Two retrospective confirmed positive Krabbe specimens and one routine specimen were categorized as "invalid result". In routine newborn screening, if a specimen result is categorized as invalid result, a new dried bloodspot specimen should be obtained, and retesting performed using age-specific cut-off values. Invalid results are excluded from the tabulations.

QSight
		Enzyme activity (µmol/L/h)						Initialcut-off	Retestcut-off
Enzyme	n	Range*	Mean	Median	Lower percentiles
					0.1%	0.2%	0.3%
ABG	2489	1.06 – 102	9.47	8.83	1.40	1.78	1.96	25%	20%
ASM	2489	1.09 – 23.7	4.55	4.30	1.32	1.43	1.57	35%	30%
GALC	2489	0.48 – 50.0	5.57	4.70	0.80	1.01	1.07	25%	20%
IDUA	2489	0.34 – 21.0	7.30	7.05	1.36	1.51	1.86	25%	20%
GLA	2489	2.21 – 133	17.5	15.3	3.83	4.74	5.44	35%	30%
GAA	2489	1.87 – 31.8	10.1	9.53	2.32	2.54	2.79	25%	20%

Descriptive statistics for the US Site A.

TQD
Enzyme activity (µmol/L/h)
Enzyme	n						Initialcut-off	Retestcut-off
		Range*	Mean	Median	0.1%	0.2%	0.3%
ABG	2489	1.09 – 104	9.17	8.50	1.36	1.70	1.88	25%	20%
ASM	2489	1.11 – 24.2	4.63	4.39	1.36	1.43	1.60	35%	30%
GALC	2489	0.43 – 47.0	5.08	4.25	0.68	0.85	0.92	25%	20%
IDUA	2489	0.32 – 21.3	7.24	6.99	1.34	1.44	1.83	25%	20%
GLA	2489	1.84 – 144	16.9	14.6	3.64	4.27	4.79	35%	30%
GAA	2489	1.92 – 35.6	10.9	10.2	2.40	2.65	2.88	25%	20%

Some results were outside the measuring range and cannot be considered accurate (see section "REPORTING RESULTS").

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Image /page/12/Picture/1 description: The image displays the logo for PerkinElmer. The logo features a blue abstract shape resembling a stylized "P" with an arrow-like extension. The text "PerkinElmer" is written in bold, black letters, with the "Elmer" portion in a lighter shade. Below the company name, the tagline "For the Better" is written in a smaller, italicized font.

Screening performance using percentage of daily median cut-off (Invalid results and samples with no repeat result excluded).

	TQD
Gaucher (ABG)	Screening Positive	Screening Negative	Total
QSight	Screening Positive	3*	0	3
	Screening Negative	0	2487	2487
Total		3	2487	2490

*Includes 2 retrospective confirmed positive samples

Niemann-Pick A/B (ASM)		TQD
		Screening Positive	Screening Negative	Total
QSight	Screening Positive	2*	0	2
	Screening Negative	0	2488	2488
Total		2	2488	2490

*Includes 1 retrospective confirmed positive sample

Krabbe (GALC)		TQD
		Screening Positive	Screening Negative	Total
QSight	ScreeningPositive	4*	0	4
	ScreeningNegative	0	2486	2486
	Total	4	2486	2490

*Includes 1 retrospective confirmed positive sample

MPS I (IDUA)		TQD
		Screening Positive	Screening Negative	Total
QSight	ScreeningPositive	6*	0	6
	ScreeningNegative	0	2484	2484
	Total	6	2484	2490

*Includes 1 retrospective confirmed positive sample

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Image /page/13/Picture/1 description: The image shows the PerkinElmer logo. The logo consists of a blue abstract shape resembling a stylized "P" with an arrow pointing to the right. Below the shape is the company name "PerkinElmer" in a bold, dark font. Underneath the company name is the tagline "For the Better" in a smaller, lighter blue font.

Fabry (GLA)		TQD
		Screening Positive	Screening Negative	Total
QSight	Screening Positive	6*	0	6
	Screening Negative	0	2484**	2484
	Total	6	2484	2490

Includes 2 retrospective confirmed positive samples

**Includes 2 retrospective confirmed positive female samples

	Pompe (GAA)		TQD
		Screening Positive	Screening Negative	Total
QSight	ScreeningPositive	1*	0	1
	ScreeningNegative	0	2489	2489
	Total	1	2489	2490

*Includes 1 retrospective confirmed positive sample

Conclusion:

The NeoLSD MSMS kit demonstrates analytical and screening performance that supports its substantial equivalency with the predicate device, NeoLSD MSMS kit (K173829).

Regulation Number and Section

§ 862.1488 Lysosomal storage disorder newborn screening test system.

(a)
Identification. A lysosomal storage disorder newborn screening test system is intended to measure lysosomal enzyme levels obtained from dried blood spot specimens on filter paper from newborns as an aid in screening newborns for a lysosomal storage disorder.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include information that demonstrates the performance characteristics of the device, including:
(i) Study results that adequately demonstrate the clinical validity of the device, which must include information supporting the link between the analyte being measured and the condition being screened. The clinical validity of the device must be demonstrated in a clinical validation study using either well-characterized prospectively or retrospectively obtained clinical specimens from the intended use population. Testing in the clinical validation study must be performed by operators representative of the types of operators intended to use the test. The study design of the clinical validation study must assess the effects of sample collection and processing steps on test performance. Confirmed positive specimens must have a diagnosis based on confirmatory diagnostic methods or clinically meaningful information regarding the status of the subject must be obtained.
(ii) The reference interval in the normal newborn population for the analyte or analytes measured by the device.
(iii) Study results demonstrating the level of carryover or drift affecting the device performance.
(iv) Study results demonstrating the concentrations of the limit of blank, limit of detection, and limit of quantitation of the device. Sample concentrations below the limit of quantitation must not be reported by the device.
(v) Study results, which must be collected using sample panels from at least three reagent lots and at least three instruments over more than 20 testing days, demonstrating the imprecision of the device. The sample panels must consist of blood spot specimens with a range of analyte concentrations that span the reportable range of the device and must include samples with concentrations in the screen positive range, samples with concentrations at each cutoff, and samples with concentration in the normal range.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) A warning that indicates that the test is not intended to diagnose lysosomal storage disorders.
(ii) A warning that indicates that test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, and clinical evaluation as appropriate.
(iii) Detailed information on device performance, including the false positive rate and the false negative rate observed in the clinical study.
(iv) Information on device performance in any relevant subgroup (
e.g., age of newborn at time of sample collection, birth weight, sex, gestational age, race, ethnicity) observed in the clinical study.