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The SEEKER System, including the SEEKER Instrument and the SEEKER LSD Reagent Kit-IDUA|GAA|GBA|GLA for use on the SEEKER Instrument, is intended for quantitative measurement of the activity of a-L-iduronidase, a-D-glucosidase, Bglucocerebrosidase and a-D-galactosidase A from newborn dried blood spot specimens as an aid in screening newborns for Mucopolysaccharidosis Type I, Pompe, Gaucher and Fabry diseases. Reduced activity of these enzymes may be indicative of these lysosomal storage diseases. The enzymes measured using the SEEKER LSD Reagent Kit-IDUA|GAA|GBA|GLA and their associated lysosomal storage diseases are listed below.

Enzyme (abbreviation)	Disease
α-L-iduronidase (IDUA)	Mucopolysaccharidosis Type I (MPS I)
α-D-glucosidase (GAA)	Pompe
β-glucocerebrosidase (GBA)	Gaucher
α-D-galactosidase A (GLA)	Fabry

Device Description

The SEEKER System employs digital microfluidic technology to measure multiple lysosomal enzymatic activities quantitatively from newborn dried blood spot specimens. The following components are provided:

1. SEEKER Instrument (including USB and power cables), Desktop PC with monitor, keyboard, mouse, and the Spot Logic software.
1. SEEKER LSD Reagent Kit IDUA|GAA|GBA|GLA containing enzyme specific substrate reagents, dried blood spot extraction buffer, reaction stop buffer, 4 levels of calibrators and quality control dried blood spots containing 4 levels of quality control (OC) material. Each Reagent Kit contains sufficient consumables for 1440 tests. The contents of the kit are listed below:

Component	Contents	Quantity
Quality control
dried blood spots	QC-Base Pool (QCBP)	1x15 spots
	QC-Low (QCL)	1x15 spots
	QC-Medium (QCM)	1x15 spots
	QC-High (QCH)	1x15 spots
Enzyme substrates	IDUA	9x100 µL
	GAA	9x100 µL
	GBA	9x100 µL
	GLA	9x100 µL
Calibrators	Calibrant A (CALA)	9x50 µL
	Calibrant B (CALB)	9x50 µL
	Calibrant C (CALC)	9x50 µL
	Calibrant D (CALD)	9x50 µL

Other components needed to run tests include the following:

Component	Contents	Quantity
Other Reagents	Extraction Buffer (EXT)	9 x 30 mL
	Filler Fluid	9 x 10 mL
Cartridge	SEEKER cartridge	1 x 36

The composition of the enzyme reagents and buffers are summarized below:

Reagent (Description)	Composition
IDUA
(α-L-iduronidase substrate)	2 mM 4-MU-α-L-iduronide sodium salt
3mM D-saccharolactone
0.04 M acetate buffer, pH 3.5
20 mM methyl β-cyclodextrin
0.01% Tween20
GAA
(α-D-glucosidase substrate)	5 mM 4-MU-α-glucopyranoside
12 µM acarbose
0.04 M acetate buffer, pH 3.8
20 mM methyl β-cyclodextrin
0.01% Tween20
GBA
(β-glucocerebrosidase substrate)	16 mM 4-MU-β-glucopyranoside
0.05 M/0.1M citrate phosphate buffer, pH 5.2
0.01% Tween20
1.5% sodium taurocholate
GLA
(α-D-galactosidase A substrate)	10 mM 4-MU-α-galactopyranoside
145 μM N-acetyl galactosamine
0.04 M acetate buffer, pH 4.6
20 mM methyl β-cyclodextrin
0.01% Tween20
Stop Buffer STB
(reaction stopping buffer)	0.6 M NaHCO3, pH 11.0 in 0.04% Tween 20
Extraction Buffer EXT
(dried blood spot extraction buffer)	0.1% Tween 20 in water
Filler Fluid
(medium for droplet movement)	0.1% Triton X-15 in 5cSt silicone oil

The Seeker Calibrators are supplied as part of the SEEKER LSD Reagent Kit -IDUA|GAA|GBA|GLA. The calibrators consist of 4 levels of aqueous preparation of 4methylumbelliferone sodium salt (4-MU) in 0.6M sodium bicarbonate buffer, pH 11.0 with 0.01% Tween 20. The concentration of 4-MU in each of the 4 calibrators is indicated in the table below:

Calibrator Level	Concentration of 4-MU
Calibrant A (CAL A)	0.0375 µM
Calibrant B (CAL B)	0.0750 µM
Calibrant C (CAL C)	0.1500 µM
Calibrant D (CAL D)	0.3000 µM

The quality control dried blood spots include 4 levels of control material: OC Low (QCL), QC Medium (QCM) and QC High (QCH). The composition of the 4 quality control dried blood spot (DBS) is summarized below. QCBP is used to fill empty wells on a cartridge.

Quality Control Level	Composition
QCBP	Heat inactivated human serum, adjusted to ~50% hematocrit
using human red blood cells
QCL	5% cord blood and 95% heat inactivated serum, adjusted to
~50% hematocrit using human red blood cells
QCM	50% cord blood and 50% heat inactivated serum adjusted to
~50% hematocrit using human red blood cells
QCH	Human umbilical cord blood, adjusted to ~50% hematocrit
using human red blood cells

The enzymatic activity values for the quality control DBS measured by the manufacturer are given on the lot specific quality control certificate included in each assay kit for all levels except QCBP. Each laboratory should establish its own mean and acceptable ranges for the quality control materials.

3. SEEKER Cartridges

1. Finnipipette Novus 8-channel automatic pipette 1-10 uL
1. Finnipipette Novus 1-channel automatic pipette 10-100 uL

AI/ML Overview

The SEEKER System is a device designed for quantitative measurement of the activity of α-L-iduronidase (IDUA), α-D-glucosidase (GAA), β-glucocerebrosidase (GBA), and α-D-galactosidase A (GLA) from newborn dried blood spot specimens. This serves as an aid in screening newborns for Mucopolysaccharidosis Type I (MPS I), Pompe, Gaucher, and Fabry diseases.

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

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for the SEEKER System are implicitly defined by the analytical and clinical performance standards required for its De Novo classification as a Class II device with special controls. These controls mandate thorough demonstration of performance characteristics, including clinical validity, reference intervals, carry-over, detection limits, and imprecision. The clinical validity is primarily demonstrated by the false positive and false negative rates observed in the pivotal clinical study.

Table: Acceptance Criteria (Implied by Regulatory Requirements) and Reported Device Performance

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance (Pivotal Phase Study)
Clinical Validity (False Positive Rate)	Acceptable false positive rates to minimize unnecessary confirmatory testing and emotional burden.	IDUA: 0.035%
GAA: 0.092%
GBA: 0.047%
GLA: 0.097%	These rates are considered acceptable, particularly given the benefits of early detection and the fact that newborns with "presumed normal" results after risk assessment were not followed up, potentially leading to an overestimation of the false positive rate.
Clinical Validity (False Negative Rate)	Acceptable false negative rates to ensure affected newborns are detected and receive timely therapy.	IDUA: 0%
GAA: 0%
GBA: 0%
GLA: 0% (Note: 2 newborns that would have been FN at 7.0µmol/L/hr cutoff were TP at 8.0µmol/L/hr cutoff. Labeling specifies known limitations for female Fabry and late-onset Pompe).	The reported 0% false negative rate for IDUA, GAA, and GBA is based on active surveillance and the assumption that early-onset cases would be reported. However, some limitations are disclosed in the labeling, acknowledging potential false negatives due to clinical variability (e.g., late-onset Pompe, female Fabry patients). The adjustment of cutoffs over time also indicates complexities in achieving a perfect 0% FN rate. The note about GLA false negatives suggests that the 0% reported might be dependent on the specific cutoff used at the time.
Imprecision (Reproducibility)	Reproducibility across different instruments, reagent lots, and days, within acceptable limits.
(No explicit %CV target stated, but general medical device standards suggest low CVs for reliable quantitative assays).	IDUA: 14.2% - 28.5% CV (depending on concentration)
GAA: 12.0% - 17.0% CV
GBA: 15.7% - 38.0% CV
GLA: 9.4% - 16.3% CV	These CVs are generally considered acceptable for screening assays, especially at lower concentrations where biological variability or technical limitations might be higher. The CLSI EP5-A3 guideline was followed.
Linearity/Reportable Range	Linear response over the intended measurement range, covering normal and disease-associated values.	IDUA: 2.77 to 50.75 µmol/L/h
GAA: 2.18 to 94.66 µmol/L/h
GBA: 2.14 to 73.24 µmol/L/h
GLA: 4.88 to 153.74 µmol/L/h. Max deviation from linearity 88 mg/mL and hematocrit at 66% caused significant negative bias; heparin increased imprecision.	Generally good, but specific interferences identified for IDUA (high protein, high hematocrit, heparin) are crucial for laboratories to consider. These are included in the package insert.
Carry-over	Demonstrate minimal or no significant impact from carry-over.	Most assays showed minimal bias (

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