← Product Code [PFX](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PFX) · K163367
# GenetiSure Dx Postnatal Assay (K163367)
_Agilent Technologies, Inc. · PFX · Aug 11, 2017 · Immunology · SESE_
**Canonical URL:** https://fda.innolitics.com/submissions/MG/subpart-f%E2%80%94immunological-test-systems/PFX/K163367
## Device Facts
- **Applicant:** Agilent Technologies, Inc.
- **Product Code:** [PFX](/submissions/IM/subpart-f%E2%80%94immunological-test-systems/PFX.md)
- **Decision Date:** Aug 11, 2017
- **Decision:** SESE
- **Submission Type:** Traditional
- **Regulation:** 21 CFR 866.5920
- **Device Class:** Class 2
- **Review Panel:** Immunology
- **Attributes:** Pediatric
## Intended Use
GenetiSure Dx Postnatal Assay is a qualitative assay intended for the postnatal detection of copy number variations (CNV) and copy-neutral loss of heterozygosity (cnLOH) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. GenetiSure Dx Postnatal Assay is intended for the detection of CNVs and cnLOH associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended to be performed only by healthcare professionals, board certified in clinical cytogenetics or molecular genetics. The assay is intended to be used on the SureScan Dx Microarray Scanner System and analyzed by CytoDx Software. This device is not intended to be used for standalone diagnostic purposes, preimplantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.
## Device Story
In vitro diagnostic assay for molecular karyotyping using array comparative genomic hybridization (aCGH) and SNP analysis; inputs are gDNA from peripheral whole blood; patient sample and sex-matched reference sample are restriction-digested, fluorescently labeled (Cy5/Cy3), and co-hybridized to 4x180K aCGH+SNP microarray slides; slides are washed and scanned via SureScan Dx Microarray Scanner; CytoDx Software performs feature extraction, computes relative abundance of target sequences, and identifies CNVs and cnLOH; results are interpreted by board-certified cytogeneticists or molecular geneticists; output is a report of chromosomal aberrations; used in clinical laboratories to assist in diagnosing patients with developmental delay, intellectual disability, or congenital anomalies; benefits include identification of clinically relevant genomic abnormalities to guide clinical management and counseling.
## Clinical Evidence
Retrospective clinical study of 800 patient samples and 100 normal samples. Diagnostic yield for CNVs was 15%, increasing to 20% with cnLOH. PPA was 76.8% (CNV only) and 76.7% (CNV+cnLOH); NPA was 95.5% (CNV only) and 89.8% (CNV+cnLOH). Accuracy assessed against two independent microarray platforms; confirmation rates varied by aberration size and probe count. Bench testing confirmed stability, precision, and limit of detection (375ng).
## Technological Characteristics
Array comparative genomic hybridization (aCGH) + SNP microarray. 4x180K slides (approx. 107k CNV probes, 59k SNP probes). In-situ ink-jet probe synthesis. Fluorescence-based detection (Cy3/Cy5). SureScan Dx Microarray Scanner. CytoDx 1.0 software for analysis. Requires 500ng gDNA input. Sterilization/materials: standard laboratory reagents/glass slides.
## Regulatory Identification
A postnatal chromosomal copy number variation detection system is a qualitative assay intended for the detection of copy number variations (CNVs) in genomic DNA obtained from whole blood in patients referred for chromosomal testing based on clinical presentation. It is intended for the detection of CNVs associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended to be performed by qualified healthcare professionals such as clinical cytogeneticists or molecular geneticists. This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.
## Special Controls
*Classification.* Class II (special controls). The special controls for this device are:(1) Design verification and validation must include the following information:
(i) A detailed description of all components in the test system that includes:
(A) A description of the assay components, array composition and layout, all required reagents, instrumentation, and equipment, including illustrations or photographs of non-standard equipment or methods;
(B) A description of the design of the array in terms of chromosomal coverage and probe density for different regions;
(C) An identification of the number of probes and size of the CNVs reported at the lower range of the assay;
(D) Detailed documentation of the device software, including standalone software applications and hardware-based devices that incorporate software;
(E) Methodology and protocols for detecting copy number and visualizing results;
(F) A description of the result outputs along with sample reports, and a description of any links to external databases provided by the device to the user or accessed by the device;
(G) Specifications for the methods to be used in specimen collection, extraction (including DNA criteria for DNA quality and quantity to perform the assay), and storage; and
(H) A description of appropriate internal and external controls that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure.
(ii) Information that demonstrates the performance characteristics of the system, including:
(A) Device reproducibility data generated, at a minimum, using three sites, with two operators at each site, for three non-consecutive days using at least three instruments. A well-characterized panel of samples that provide a wide range of CNVs (
*i.e.,* gains, losses, adequate size coverage across the range of sizes claimed by the device, adequate chromosomal coverage, challenging regions in the genome, CNVs reported at the lower range of the assay, interstitial, subtelomeric, and pericentromeric rearrangements, aneuploidy, unbalanced translocations, mosaicism, and known syndromic regions) must be used. The results must be itemized for all CNVs detected in each sample across all replicates and summarized in a tabular format stratified by size range and range of probe numbers for gains and losses separately and calculated for overall. The results must be analyzed using pairwise replicate agreement, and summarized as overall pairwise replicate agreement as well as pairwise replicate agreement conditional on replicates having a positive copy number state call (gains or losses), call rate, CNV size variation, and endpoint agreement;(B) Device accuracy data using cell lines and clinical samples representing a variety of CNVs and syndromes. In this analytical study, accuracy must be determined for every CNV detected in a particular sample. The accuracy data provided must include the copy number state determination and endpoint accuracy. The accuracy samples must cover different genomic variations across the genome (
*i.e.,* gains, losses, adequate CNV size coverage across the range of sizes claimed by the device, adequate chromosomal coverage, challenging regions in the genome, CNVs reported at the lower range of the assay, interstitial, subtelomeric, and pericentromeric rearrangements, aneuploidy, unbalanced translocations, mosaicism, and known syndromic regions). CNVs identified by the device must be compared to comparator method(s). Agreement between the CNVs detected by the array and the comparator must be summarized in a tabular format that includes the positive percent agreement and false positive rate stratified by size range and range of probe numbers for gains and losses separately and calculated for overall;(C) Assay performance data for CNVs reported at the lower range of the assay for both gains and losses;
(D) Device analytical sensitivity data, including DNA input and limit of detection for mosaicism, if applicable;
(E) Device analytical specificity data, including interference, carryover, and cross-contamination data;
(F) Device stability data, including real-time stability under various storage times, temperatures, and freeze-thaw conditions;
(G) Specimen matrix comparison data if more than one specimen type or anticoagulant can be tested with the device;
(H) Data that demonstrates the clinical validity, including diagnostic yield, of the device using a minimum of 800 retrospective clinical samples that were collected prospectively and obtained from three or more clinical laboratories, with results interpretation equally divided between two or more qualified healthcare professionals (
*e.g.,* cytogeneticists). Patients must be representative of the intended use population and not limited to common syndromes. Diagnostic yield data must be summarized in tabular format and stratified by the comparison methodologies. Data must also be summarized comparing interpretation of results, with description of reasons for variability in calls between the device and the standard of care methods. Data to support the accuracy of calls for known syndromes must be included; and(I) Data that demonstrates device results when a minimum of 100 apparently healthy, phenotypically normal individuals are tested and interpreted by one or more cytogeneticists blinded to the patient status.
(iii) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(2) The labeling required under § 809.10 of this chapter must include:
(i) A warning statement that the device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations;
(ii) Limitations regarding the assay's performance with respect to validated CNVs reported at the lower range of the assay, stratified by size range and range of probe numbers for gains and losses separately; and limitations regarding problematic (hypervariable) regions, loss of heterozygosity, mosaicism, and inability to detect balanced translocations, as appropriate;
(iii) A warning statement that interpretation of assay results is intended to be performed by qualified healthcare professionals such as clinical cytogeneticists or molecular geneticists; and,
(iv) A description of the performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.
## Predicate Devices
- Affymetrix CytoScan Dx Assay ([K130313](/device/K130313.md))
## Submission Summary (Full Text)
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
August 11, 2017
Agilent Technologies, Inc. Bill Kurani, Ph.D. Director of Regulatory Affairs and Ouality Assurance 5301 Stevens Creek Blvd. Santa Clara, CA 95051
Re: K163367
Trade/Device Name: GenetiSure Dx Postnatal Assay Regulation Number: 21 CFR 866.5920 Regulation Name: Postnatal chromosomal copy number variation detection system Regulatory Class: Class II Product Code: PFX Dated: July 11, 2017 Received: July 12, 2017
Dear Bill Kurani:
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. 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 801 and Part 809); medical device reporting (reporting of
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medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and Part 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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 the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely.
# Reena Philip -S
Reena Philip, Ph.D. Director Division of Molecular Genetics and Pathology 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) K163367
#### Device Name GenetiSure Dx Postnatal Assay
#### Indications for Use (Describe)
GenetiSure Dx Postnatal Assay is a qualitative assay intended for the postnatal detection of copy number variations (CNV) and copy-neutral loss of heterozygosity (cnLOH) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. GenetiSure Dx Postnatal Assay is intended for the detection of CNVs and cnLOH associated with developmental delay, intellectual disability, congenital anomalies or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended only by healthcare professionals, board certified in clinical cytogenetics. The assay is intended to be used on the SureScan Dx Microarray Scanner System and analyzed by CytoDx Software.
This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.
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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## 5. 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92(c).
## A. 510(k) Number:
K163367
## B. Purpose for Submission:
Clearance of new device
### C. Submitter Information:
- Submitter: Aqilent Technologies, Incorporated 5301 Stevens Creek Boulevard Santa Clara, CA 95051
Establishment Registration No: 2916205
| Contact: | Lois Nakayama Sr. Regulatory Affairs Specialist |
|----------|----------------------------------------------------|
| Phone: | +1 408 553 2715 |
| E-mail: | lois.nakayama@agilent.com |
Contact: Bill Kurani Director, Regulatory Affairs and Quality Assurance Phone: +1 408 553 2007 E-mail: bill.kurani@agilent.com
Contact: Philip Klimbal Program Manager Phone: +1 858 373 6490 E-mail: phil.klimbal@agilent.com
Date Prepared: November 28, 2016
## D. Name of Device and Classification
#### Name: GenetiSure Dx Postnatal Assay
Classification: Class II, 21 CFR § 866.5920 Postnatal chromosomal copy number variation detection system
Product Code: PFX
Panel: Immunology (82)
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## E. Predicate Device
Affymetrix CytoScan Dx Assay (K130313)
The Agilent GenetiSure Dx Postnatal Assay (the device) is substantially equivalent to the Affymetrix CytoScan Dx Assay (the predicate) as described in the premarket notification K130313.
## F. Type of Test or Tests performed:
Chromosomal microarray
### G. System Description:
### 1. Device Description
### a) Overview
The GenetiSure Dx Postnatal Assay is a clinical laboratory in vitro diagnostic assay for performing molecular karyotyping based on array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) analysis from blood samples of post-natal patients who are suspected of having a genomic abnormality. This molecular karyotyping is a modified in situ hybridization technique that allows detection and mapping of DNA sequence copy difference(s) between two genomes in a single experiment. In molecular karyotyping analysis, two differentially labeled genomic DNAs (subject/test sample and a reference sample) are co-hybridized to complementary nucleic acid sequences synthesized in situ on a microarrav slide.
Locations of copy number variation (CNVs) and copy-neutral loss of heterozygosity (cnLOH) in the DNA segments of the subject sample genome are revealed by variable fluorescence intensity on the microarray.
The assay compares the patient sample against a sex-matched reference sample. Genomic DNA (gDNA) is extracted from the patient's whole blood and then is fluorescently labeled in parallel with the reference sample using two different fluorescent dyes. The two labeled samples are hybridized to complementary sequences (probes) that are printed on a CGH+SNP microarray.
After hybridization, the microarrays are washed and then scanned. The data from the microarray images are converted to numeric data. The relative abundance of the target sequences is computed based on the relative intensities of the fluorophores in the patient and reference samples hybridized to each of the probe sequences.
The numeric data is then processed using software specifically designed to report CNVs by chromosomal location. The reported CNVs are interpreted by a Board Certified Cytogeneticist, Molecular Geneticist, Molecular Pathologist, or similarly qualified clinician who has been trained to identify the clinically relevant CNVs,
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determine clinical significance, and report out these findings. cnLOH in patient samples is also reported to the clinician.
### b) Components of the Product
- i. Microarray
```
K1201A GenetiSure Dx Postnatal Assay
K1201-64500 GenetiSure Dx Postnatal Array
K1201-64600 GenetiSure Dx Postnatal Gasket
```
Agilent will provide to customers 4x180K aCGH+SNP microarray slides, manufactured under QSR, as the microarray component of this kit. Each single-use microarray slide carries four identical microarrays.
The microarray contains approximately 107,000 probes optimized for CNV analysis, and approximately 59,000 bi-allelic SNP probes. Each probe is approximately 60 bases long.
The CNV probes are distributed across the entire genome with a higher density of probes in regions designated by the International Standards for Cytogenomic Arrays (ISCA) consortium to be of clinical interest. These regions include:
- telomere and selected centromere regions, .
- . microdeletion / duplication regions,
- dosage sensitive regions, and ●
- · regions associated with X-linked disorders.
Overall, 94% of the genome is targeted with at least 5 CNV probes per 400 kb. The ISCA regions are targeted with a median probe spacing of approximately 1 CNV probes per 3.5 kb.
The SNP probes are designed to known SNPs that overlap restriction digestion sites (Alu I/Rsa I). These probes allow for identification of cnLOH.
Overall, 91% of the genome is targeted with at least 100 SNP probes per 10 Mb.
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#### ii. Gasket slides
The gasket slides are single-use, silicone gasket backing slides that hold the samples during hybridization to the microarrays.
#### iii. Reagent
| K1201-64100 | GenetiSure Dx DNA Labeling Kit |
|-------------|-------------------------------------------|
| K1201-64105 | GenetiSure Dx Labeling Kit, -20C Part |
| K1201-64110 | GenetiSure Dx Labeling Kit, RT Components |
| K1201-64200 | GenetiSure Dx Hybridization Kit |
| K1201-64300 | GenetiSure Dx Wash Buffer Set |
| K1201-64305 | GenetiSure Dx Wash Buffer 1, 4L |
| K1201-64310 | GenetiSure Dx Wash Buffer 2, 4L |
| K1201-64400 | GenetiSure Dx Cot-1 Human DNA |
A complete list of laboratory equipment and reagents required is provided in the GenetiSure Dx Postnatal Assay Instructions for Use (IFU).
#### iv. Software
K1203-10000 CytoDx 1.0 Software
Agilent CytoDx Software performs feature extraction, CNV and cnLOH identification and reporting on the microarray TIF images generated by the SureScan Dx Microarray Scanner.
The software application has three functional components, described briefly below.
- 1) Feature Extraction uses image files created by the scanner, verifies the quality of the scanned image, extracts the intensity information and calculates signal and background for each feature/probe on the array, applying appropriate normalization.
- 2) CNV and Allele Identifier uses the data produced during the Feature Extraction step to evaluate the intensity of each probe, applying algorithms that identify aberrations, SNPs, CNVs and cnLOH compared to the reference sample.
- 3) Chromosome Viewer uses the CNV Table and LOH Intervals Table produced during CNV and Allele Identification to overlay the chromosomal aberrations or LOH detected onto an image of the chromosomes to provide a graphical representation of the results.
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#### c) Components Required but Not Included in the System
- Special Instrument Requirements i.
SureScan Dx Microarray Scanner G5761A
#### d) Specimen Processing
The Agilent GenetiSure Dx Postnatal Kit Instructions for Use (IFU) provides instructions to enable the user to process DNA obtained from blood specimens. The illustration and text below provide an overview.
Image /page/7/Figure/5 description: This image shows a flowchart of the microarray process. The process starts with DNA isolation, quantitation, and qualitative analysis, followed by sample fragmentation, and sample labeling. The process ends with microarray processing, which includes 24-hour hybridization, microarray washing, microarray scanning, and aberration reporting.
Image /page/7/Figure/6 description: The image is titled, "Figure 1-Agilent GenetiSure Dx Postnatal Kit Sample Processing Workflow from gDNA to Report Generation." The title describes the image as a figure that shows the sample processing workflow of the Agilent GenetiSure Dx Postnatal Kit. The workflow starts with gDNA and ends with report generation. The figure is labeled as Figure 1.
#### i. Specimen requirements
The GenetiSure Dx Postnatal Assay is for use with gDNA from whole blood specimens collected in tubes using EDTA as the anticoagulant. Blood specimens may be stored at 2-8°C for up to 7 days prior to DNA extraction. Two hundred (200) microliters of whole blood are used for DNA extraction, and 0.5 micrograms (500 ng) of DNA are required to perform the GenetiSure Dx Postnatal Assay.
#### ii. Workflow sequence, from sample to report
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The Agilent GenetiSure Dx Postnatal Kit starts with purified gDNA isolated from EDTA whole blood samples using the Qiagen QIAmp DSP DNA Blood Mini Kit (part number 61104).
- 1) gDNA is quantified using a double-stranded DNA-based fluorometric method. For each sample to be tested, 0.5 µg of the subject's DNA is processed in parallel with 0.5 uq of the sex-matched reference DNA included in the GenetiSure Dx DNA Labeling Kit.
- 2) Both the gDNA of the subject and the sex-matched reference are restriction digested with Alu I and Rsa I restriction enzymes included in the Labeling Kit.
- 3) After digestion, the samples are labeled in parallel with the reference sample using the fluorescent dyes provided in the Labeling Kit. The subject sample is labeled with cyanine 5 (Cy5) dye and the sex-matched reference sample is labeled with cyanine 3 (Cy3) dye.
- 4) The two labeled samples are hybridized onto a single microarray of a 4x180k aCGH+SNP slide using the reagents in the GenetiSure Dx Hybridization Kit, GenetiSure Dx Gasket 4xArray Slides (part of the Postnatal Assay) and Hybridization Chamber Kit. Prepared slides are hybridized for 24 hours at 67℃ in a light eliminating Hybridization Oven rotating at 20 rpm.
- 5) After hybridization, the microarrays are washed using the GenetiSure Dx Wash Buffer Set and transferred into a SureScan Microarray Scanner slide holder.
- 6) The microarray slides are then scanned in the SureScan Dx Microarray Scanner.
- 7) The scanner generated image is then processed using the Agilent CytoDx Software, and the image data are converted to numeric data using the Feature Extraction module of the software. The relative abundance of the target sequences is computed by the Analytics module, based on the relative intensities of the fluorophores in the patient and reference samples hybridized to each of the probe sequences. CNVs and cnLOH are reported by chromosomal location.
- 8) The reported CNVs and cnLOH are interpreted by a Board Certified Cytogeneticist, Molecular Geneticist, Molecular Pathologist, or similarly qualified clinician who has been trained to identify the clinically relevant CNVs, determine clinical significance, and report out these findings.
#### iii. Quality Control (QC)
Internal control probes on each array are used to calculate array QC metrics and assess the quality of data. As external controls, Agilent Male and Agilent Female reference DNA (provided with the Labeling Kit) are sexmatched, processed alongside, and co-hybridized with each test sample. These reference DNAs are used for data normalization and aberration detection on a per test sample basis, and to aid in troubleshooting, if necessary.
The following QC checks are required to assure reliable results:
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- 1) Sample input: only samples with sufficient amount of gDNA obtained by DNA extraction/purification procedures proceed to labeling: minimum of 500 ng is required.
- 2) Labeling/In-Process QC: only samples passing DNA yield and specific activity measurements proceed to array hybridization. The required amount of fluorescently labeled DNA obtained after labeling/purification procedures is 8-15 ug, and the specific activity, i.e. the amount of dye (Cy3 or Cy5) incorporated into DNA after labeling and purification is 20-45 pmol Cv3 dye/ug of DNA or 20-40 pmol Cy5 dye/ug of DNA.
- 3) Array QC metrics: The software uses the signal from probes on the microarray to perform a series of data verifications that detect laboratory processing anomalies. These include automated grid finding, probe-toprobe noise, signal-to-noise ratios and SNP call rates. Only arrays passing the QC metrics proceed to analysis. If the assay fails any of the array QC metrics, the software will generate a report for review of the QC metrics, but "sign-off" will not be allowed for the report.
### 2. Description of Test Report
The aberrations identified in a patient sample by the CytoDx algorithms can be viewed from the Triage View screen of the CytoDx software. The final Cyto Report is generated when the Lab Director signs off on the sample results, and lists the aberrations.
Clinical interpretation is performed by a Board Certified Cytogeneticist, Molecular Geneticist, Molecular Pathologist, or similarly qualified clinician who has been trained to identify the clinically relevant CNVs and cnLOH intervals, determine clinical significance, and report out these findings. Clinical interpretation of the aberration results takes place during classification of the aberrations (e.g., as Pathogenic, Likely pathogenic, VOUS, Likely benign, or Benign) in the CytoDx software. To select the appropriate classification, the clinician can rely on prior knowledge, comparisons to tracks or to other samples, and references to gene ontology database that describe the functions and disease associations for genes impacted by the aberrations. The classification assignments appear in the Cyto Report in the Classifications section.
Details of the report are available in the IFU.
### H. Intended Use:
### 1. Intended Use:
GenetiSure Dx Postnatal Assay is a qualitative assay intended for the postnatal detection of copy number variations (CNV) and copy- neutral loss of heterozygosity (cnLOH) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. GenetiSure Dx Postnatal Assay is intended for the detection of CNVs and cnLOH associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate.
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Interpretation of assay results is intended to be performed only by healthcare professionals, board certified in clinical cytogenetics or molecular genetics. The assay is intended to be used on the SureScan Dx Microarray Scanner System and analyzed by CytoDx Software.
This device is not intended to be used for standalone diagnostic purposes, preimplantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.
### 2. Indications for Use:
Same as above.
### 3. Special Condition for Use Statement(s):
For prescription use only.
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## I. Standard/Guidance Document Referenced (if applicable):
#### Table 1 – Documents referenced
| No | Standard Developing Organization | Standard Designation Number and Date | Title of Standard |
|----|-------------------------------------|-----------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|
| 1 | ISO | 14971 Second edition 2007-03-01;14971:2012 | Medical devices - Application of risk management to medical devices |
| 2 | ISO | ISO 23640:2011 | In vitro diagnostic medical devices -- Evaluation of stability of in vitro diagnostic reagents |
| 3 | AAMI ANSI ISO | 15223-1:2012 | Medical devices - Symbols to be used with medical devices labels, labeling, and information to be supplied - Part 1: General requirements |
| 4 | AAMI ANSI IEC | 62304:2006 | Medical device software - Software life cycle processes |
| 5 | AAMI ANSI IEC | 62366-1 Edition 1.0 2015-02 | Medical devices - Part 1: Application of usability engineering to medical devices |
| 6 | CLSI | EP07-A2 - 05/21/2007 | Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition |
| 7 | CLSI | EP12-A2 - 01/30/2014 | User Protocol for Evaluation of Qualitative Test Performance |
| 8 | CLSI | EP25-A - 01/15/2013 | Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline |
| 9 | CLSI | MM13-A - 12/01/2005 | Collection, Transport, Preparation, and Storage of Specimens for Molecular Methods; Approved Guideline |
| 10 | CLSI | MM21: 1st Edition – Aug 2015 | Genomic Copy Number Microarrays for Constitutional Genetic and Oncology Applications |
## J. Substantial Equivalence Discussion
The predicate device for the GenetiSure Dx Postnatal Assay is the Affymetrix CytoScan Dx Assay, cleared in January, 2014 under K130313.
Comparisons between the GenetiSure Dx Postnatal Assay and its predicate device are presented in the following tables.
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#### Table 2-Similarities between assay and predicate
| | GenetiSure Dx Postnatal Assay | Affymetrix CytoScan Dx Assay |
|------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | (Device) | (Predicate)K130313 |
| Indications for Use | GenetiSure Dx Postnatal Assay is a qualitative assay intended for the postnatal detection of copy number variations (CNV) and copy-neutral loss of heterozygosity (cnLOH) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. GenetiSure Dx Postnatal Assay is intended for the detection of CNVs and cnLOH associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended to be performed only by healthcare professionals, board certified in clinical cytogenetics or molecular genetics. The assay is intended to be used on the SureScan Dx Microarray Scanner System and analyzed by CytoDx Software. This device is not intended to be used for standalone diagnostic purposes, pre- implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations. | CytoScan® Dx Assay is a qualitative assay intended for the postnatal detection of copy number variations (CNV) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. CytoScan® Dx Assay is intended for the detection of CNVs associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay 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, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended to be performed only by healthcare professionals, board certified in clinical cytogenetics or molecular genetics. The assay is intended to be used on the GeneChip® System 3000Dx and analyzed by Chromosome Analysis Suite Dx Software (ChAS Dx Software). This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations. |
| Special Conditions | For prescription use | Same. |
| Sample Type | Peripheral whole blood | Same. |
| Technology | Microarray for comparative genomic hybridization | Same. |
| Software | Assay-specific software is used to perform feature extraction, CNV and cnLOH identification and reporting on the microarray images. | Same. |
| Assay steps | Starts with purified genomic DNA (gDNA) and ends with microarray intensity data. | Same. |
| Quality Controls | In-process QC checks, external controls and array QC metrics are used to monitor and assess the quality of results. | Same. |
| Report | The device reports the copy number change (gain, loss) and loss of heterozygosity aberrations, and position/location of the aberrant segment across the queried genome. | Same. |
| Limitations | This device is not intended to be used for standalone diagnostic purposes, pre- implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations. | Same. |
| Clinical Validation | Compare test results with available diagnosis for sample. | Same. |
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#### Table 3-Differences between assay and predicate
| | GenetiSure Dx Postnatal Assay (Device) | Affymetrix CytoScan Dx Assay (Predicate) |
|-----------------------------------------|----------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Array Format | 60-mer probes Four microarrays on a single 1"x 3" glass slide | 25-mer oligos Individual microarrays housed in a GeneChip cartridge |
| Method of Array Manufacture | On slide (in-situ) synthesis of probes using ink-jet printing | On-wafer synthesis of probes using photolithography |
| DNA Fragmentation/ Labeling | Fragmented DNA is directly labelled with fluorescent dye (Cy3 and Cy5) before hybridization. | Fragmented DNA is PCR amplified and then labelled with biotin before hybridization. |
| | Data is produced in two intensity channels which are then compared to generate a LogRatio | Single channel data is produced which is later compared to an in silico reference to produce a LogRatio. |
| Hybridization | Cohybridization of labeled sample and reference for direct on-array comparison | Hybridization of single labeled sample which is compared to an in silico reference. |
| Washing / Staining of Microarrays | Manual washing process in accordance with instruction for the validated diagnostic assay | Automated processing with FS450Dx fluidics station for both washing and staining steps |
| Equipment | SureScan Dx Microarray Scanner | GeneChip System 3000Dx Scanner |
## K. Performance Characteristics
### 1. Analytical Performance
### a) Reproducibility
The aim of the Reproducibility Study was to demonstrate that GenetiSure Dx Postnatal Assay achieves acceptable, reproducible results when performed at multiple laboratory sites by multiple operators over multiple days. Replicates of forty-eight (48) test samples were processed by two separate operators, at each of
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three individual clinical laboratories, in three (3) one-week intervals for a total of 864 data points.
The forty-eight (48) test samples were selected from cell-lines with a wide range of known aberrations (copy number gains, losses, and copy neutral loss of heterozygosity (cnLOH)). The aberrations met the following criteria: common syndromes ('known syndromic regions'), analytically challenging regions, claimed minimal resolution, varying aberration size ranges, and genomic coverage of aberrations. Multiple samples had multiple aberrations spanning multiple criteria. Test sample selection criteria encompasses aberrations expected to be found in normal whole blood samples.
All individual aberrations reported within each processed test sample, regardless of expected pathogenicity, were compared to their respective replicates (18 replicates for each aberration, operator by site by week) by pairwise replicate analysis (PRA), requiring at least 50% overlap of chromosomal coordinates for confirmation. Positive agreement was assessed separately for small copy number variants (CNVs, 5-20 probes contained with the aberration), larger CNVs (>20 probes), or cnLOH regions. The results demonstrate that the pre-defined acceptance criteria were met for each category with a pairwise replicate agreement of 80.22%, 95.83%, and 89.08%, respectively. Using a more stringent 80% overlap criteria for pairwise replicate agreement, acceptance criteria were also met.
Data are further refined by size, probe number, aberration type, and study variable (e.g. operator, site, test sample). Alternative metrics of positive percent agreement, call rate, and breakpoint accuracy/endpoint deviation are presented.
To provide additional insight into the reproducibility of the test as a function of reported aberration size (in kb), the data were categorized into more refined size bins (see Table 4). The results demonstrated that when comparing all replicates of all test samples across all days, sites, and operators, using a 50% aberration overlap criteria, the overall pairwise replicate agreement across all sizes of CN gains and losses was 85.0%. Pairwise replicate agreement across the various kb bins ranged from 75.9% to 100%. For copy number gains, the overall agreement was 85.7%; for losses, the overall agreement was 84.6%. For cnLOH, the overall pairwise replicate agreement was 89.1%. Applying a more stringent 80% overlap criteria produced overall agreements of 82.3% for CN gains and losses combined, 84.4% for gains, 81.3% for losses, and 87.9% for cnLOH.
When assessing specifically the agreement between replicates for positive aberration calls by PPA analysis, the agreement was 89.3% for all copy number calls and 92.7% for cnLOH using the 50% overlap criteria.
Call rate averaged 78.1% for CNVs, and 74.9% for cnLOH.
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Table 4-Reproducibility of Aberrations Categorized by Size (in kb) and Type
| Aberration Type | Aberration Range (kb) | # Aberrations | Call Rate (%) | Pairwise Replicate Agreement (%) | | PPA (%) | |
|------------------------------|--------------------------|---------------|---------------|----------------------------------------|-------|---------|-------|
| | | | | 50% | 80% | 50% | 80% |
| CN Gain | 10 - 50 | 5 | 51.2 | 82.5 | 82.5 | 82.9 | 82.9 |
| | 50 - 100 | 3 | 68.7 | 96.3 | 96.3 | 97.3 | 97.3 |
| | 100 - 200 | 13 | 50.5 | 79.9 | 79.8 | 80.1 | 80.0 |
| | 200 - 500 | 26 | 82.7 | 86.3 | 84.6 | 91.5 | 89.4 |
| | 500 - 1000 | 9 | 79.7 | 80.2 | 78.9 | 87.6 | 86.0 |
| | 1000 - 2000 | 7 | 72.1 | 90.7 | 82.8 | 92.4 | 81.6 |
| | 2000 - 5000 | 11 | 65.1 | 75.9 | 75.9 | 79.7 | 79.7 |
| | 5000 + | 13 | 93.2 | 98.4 | 98.4 | 99.1 | 99.1 |
| | Total | 87 | 73.8 | 85.7 | 84.4 | 89.9 | 88.2 |
| CN Loss | 10 - 50 | 14 | 51.6 | 76.8 | 76.1 | 77.6 | 76.2 |
| | 50 - 100 | 2 | 100.0 | 100.0 | 89.5 | 100.0 | 89.5 |
| | 100 - 200 | 23 | 81.4 | 82.3 | 78.1 | 88.1 | 82.9 |
| | 200 - 500 | 31 | 82.6 | 81.8 | 75.5 | 86.3 | 78.7 |
| | 500 - 1000 | 55 | 72.8 | 81.2 | 76.2 | 85.2 | 78.5 |
| | 1000 - 2000 | 30 | 83.3 | 86.4 | 85.9 | 91.5 | 91.0 |
| | 2000 - 5000 | 18 | 88.9 | 87.4 | 85.1 | 89.9 | 87.3 |
| | 5000 + | 20 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| | Total | 193 | 80.1 | 84.6 | 81.3 | 89.0 | 84.8 |
| All CNVs (Gain & Loss) | Total | 280 | 78.1 | 85.0 | 82.3 | 89.3 | 85.8 |
| cnLOH | 5000 - 10000 | 21 | 50.6 | 77.1 | 76.8 | 77.4 | 76.8 |
| | 10000 - 20000 | 11 | 91.5 | 99.0 | 96.4 | 99.4 | 96.7 |
| | 20000 + | 13 | 100.0 | 100.0 | 98.4 | 100.0 | 98.4 |
| | Total | 45 | 74.9 | 89.1 | 87.9 | 92.7 | 91.1 |
When results were binned by the number of probes in an aberration, rather than size in kb, using the 50% overlap criteria, the overall pairwise replicate agreement was similar to the above (see Table 5): 86.2% for combined CN gains and losses
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(ranging from 70.6% to 100%), 86.1% for gains alone, 86.3% for losses alone, and 89.1% for cnLOH.
Using the 80% overlap criteria, overall agreements were 84.6% for CN gains and losses combined, 85.3% for gains, 84.2% for losses, and 88.4% for cnLOH. PPA for the 50% overlap criteria was 90.9% and 92.7% for CNVs and cnLOH, respectively. Call rate averaged 78.1% for CNVs, and 74.9% for cnLOH.
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| Table 5-Reproducibility of Aberrations Categorized by Probe Number and Type | | | |
|-----------------------------------------------------------------------------|--|--|--|
| | | | |
| Aberration Type | Aberration Range (# Probes) | # Aberrations | Call Rate (%) | Pairwise Replicate Agreement (%) | | PPA (%) | |
|-----------------------------|-----------------------------------|---------------|---------------|-------------------------------------|-------|---------|-------|
| | | | | Overlap | | 50% | 80% |
| CN Gain | 5 - 7 | 11 | 38.0 | 76.5 | 76.5 | 69.0 | 69.0 |
| | 7 - 10 | 15 | 54.1 | 70.6 | 69.4 | 72.8 | 70.6 |
| | 10 - 15 | 23 | 87.9 | 89.4 | 88.3 | 94.0 | 92.7 |
| | 15 - 20 | 11 | 66.5 | 82.4 | 79.9 | 86.8 | 83.1 |
| | 20 - 30 | 9 | 89.6 | 97.5 | 97.5 | 97.9 | 97.9 |
| | 30 - 100 | 3 | 70.3 | 93.0 | 93.0 | 95.0 | 95.0 |
| | 100 - 500 | 3 | 72.3 | 90.2 | 90.2 | 93.2 | 93.2 |
| | 500 + | 12 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| | Total | 87 | 73.8 | 86.1 | 85.3 | 90.5 | 89.4 |
| CN Loss | 5 - 7 | 36 | 61.1 | 76.6 | 75.6 | 80.9 | 79.1 |
| | 7 - 10 | 39 | 65.5 | 77.6 | 75.4 | 82.8 | 79.6 |
| | 10 - 15 | 42 | 81.9 | 85.5 | 81.0 | 90.5 | 85.0 |
| | 15 - 20 | 18 | 96.9 | 95.9 | 94.0 | 97.6 | 95.7 |
| | 20 - 30 | 16 | 87.5 | 89.1 | 85.7 | 91.6 | 87.9 |
| | 30 - 100 | 10 | 92.2 | 93.2 | 92.9 | 96.3 | 96.0 |
| | 100 - 500 | 17 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| | 500 + | 15 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| | Total | 193 | 80.1 | 86.3 | 84.2 | 91.1 | 88.5 |
| AII CNV (Gain & Loss) | Total | 280 | 78.1 | 86.2 | 84.6 | 90.9 | 88.8 |
| cnLOH | 100 to 200 | 25 | 54.8 | 80.3 | 80.3 | 82.0 | 82.0 |
| | 200 to 500 | 13 | 100.0 | 100.0 | 97.7 | 100.0 | 97.7 |
| | > 500 | 7 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
| | Total | 45 | 74.9 | 89.1 | 88.4 | 92.7 | 91.8 |
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CONCLUSIONS: More refined categorization of aberrations by size and probe number, and further analyses of these confirmations using PPA and call rate calculations, support the reproducibility conclusions established for small (5-20 probes), large (>20 probes), and cnLOH categories by pairwise confirmation. In general, pairwise replicate agreement, PPA, and call rate increase with aberration size and probe number, although the aberration numbers within each bin varies.
### b) Precision
#### i. Between-Lot Reagent and Scanner Precision
The aim of the Between-Lot Reagent and Scanner Precision Study was to demonstrate that GenetiSure Dx Postnatal Assay achieves acceptable, precise results when performed using multiple reagent manufacturing lots and when analyzed on multiple scanner instruments. Forty-eight (48) test samples containing a range of chromosomal aberrations (copy number gains, losses, and copy-neutral loss of heterozygosity (cnLOH)) were processed by multiple operators, using combinations of three (3) reagent lots and three (3) scanner instruments across three (3) processing weeks at a single site for a total of 432 data points.
Individual aberrations called within each processed test sample were compared to their respective replicates (9 replicates for each aberration, representing 3x3 reagent-lot/scanner combinations) by pairwise replicate analysis (PRA), requiring at least 50% overlap of chromosomal coordinates for confirmation. Agreement was assessed separately for small copy number variants (CNVs, 5-20 probes contained within the aberration), larger CNVs (>20 probes), or cnLOH regions. The results demonstrate that the pre-defined acceptance criteria were met for each category with a pairwise replicate agreement of 83.33%, 98.39%, and 80.80%, respectively. Results were similar when using a more stringent 80% overlap criteria for pairwise replicate agreement. In addition, no substantial differences were observed when the pairwise replicate agreement was assessed separately for inter-lot vs. intra-lot replicate pairs, or for inter-scanner vs. intra-scanner replicate pairs.
Data were further refined by size, probe number, aberration type, and study variable (e.g. reagent lot, scanner, processing week). Alternative metrics of positive percent agreement, call rate, and breakpoint accuracy/endpoint deviation are presented.
To provide additional insight into the precision of the test as a function of reported aberration size (in kb), the data were categorized into more refined size bins (see Table 6). The results demonstrated that when comparing all replicates of all test samples across all lots, scanners, and weeks, using a 50% aberration overlap criteria, the overall pairwise replicate agreement across all sizes of copy number qains and losses was 89.0%. Pairwise
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replicate agreement across the various kb bins rang…
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**Source:** [https://fda.innolitics.com/submissions/MG/subpart-f%E2%80%94immunological-test-systems/PFX/K163367](https://fda.innolitics.com/submissions/MG/subpart-f%E2%80%94immunological-test-systems/PFX/K163367)
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