The YO™ Home Sperm Test is a smartphone based home test which provides a qualitative assessment of motile sperm concentration (MSC) in human semen. MSC is one aspect of a male semen examination. The YO™ Home Sperm Test does not provide a comprehensive evaluation of a male's fertility status and is intended for over-the-counter, in vitro use only.

Device Description

YO™ is an over-the-counter device that provides a qualitative assessment of motile sperm concentration (MSC) in human semen. Results are reported as "LOW MSC RANGE" or "MODERATE/NORMAL MSC RANGE," requiring no user interpretation. The YO™ software application is downloaded onto the users' own smartphone and on-screen menus and instructions are shown on the phone's display so that the user is taken through the process step by step. The YO™ kit (purchased on the website) provides all the supplies necessary to evaluate two semen samples: two semen collection cups, two vials of liquefying powder (chymotrypsin), two pipettes for sample aspiration, two fixed coverslip slides for sample testing, one QC slide, and one YOT™ Clip that attaches to the smartphone and houses the fixed coverslip slide.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the YO™ Home Sperm Test, based on the provided document:

Acceptance Criteria and Reported Device Performance

Criteria	Acceptance Metric	Reported Performance (iPhone and Galaxy Combined)
Reproducibility/Repeatability (Non-clinical)	%CV < 20%	Intra-device, inter-phone type, inter-operator/Clip/slide lot %CVs < 20%
Detection Limit (Non-clinical)	Limit of detection: <= 3 M/mL MSC; Limit of blank: 0 M/mL MSC	Achieved: 3 M/mL MSC as LOD, 0 M/mL for LOB
Analytical Specificity (Non-clinical)	PPA and NPA = 100%	100% PPA and 100% NPA across all tested contaminants (yeast, bacteria, RBCs, WBCs, vitamin B12, testosterone, agglutinates, D-norgestrel, B-estradiol, urine, saliva) and intact controls.
MSC Cut-off Trial (Non-clinical)	PPA and NPA > 90%	PPA = 93.5% (iPhone & Galaxy combined) NPA = 96.7% (iPhone & Galaxy combined)
Clinical Agreement (Lay User vs. SQA-V)	PPA and NPA > 90%	PPA = 95.3% NPA = 96.1%
Clinical Agreement (Lay User vs. Trained User)	PPA and NPA > 90%	PPA = 96.7% NPA = 98.7%
Clinical Agreement (Trained User vs. SQA-V)	PPA and NPA > 90%	PPA = 97.6% NPA = 97.0%
Usability/Comprehension (Clinical)	High satisfaction and good comprehension of labeling	Over 81% rated directions as "Very clear and easy to follow" for all 5 questions.

Note: The acceptance criteria for the non-clinical and clinical studies are implicitly derived from the reported performance, as the document states that the results "exceeded 90%" and indicate the system is "safe and effective for its intended use."

Study Details

1. Sample sizes used for the test set and the data provenance:

Reproducibility/Repeatability (Non-clinical): At least 60 subjects per site (two sites, one internal and one external). Samples were grouped into three MSC categories (Positive <4 M/mL, Borderline 4-8 M/mL, Negative >8 M/mL), with approximately 20 samples per group. 480 measurements per site were performed. Data provenance is implied to be laboratory-generated samples at the internal (MES) and external (Ruppin College) sites. It is retrospective in the sense that laboratory-prepared samples were used to control specific variables.
Detection Limit (Non-clinical): Four semen samples prepared to represent four MSC levels (0 M/mL, 2-3 M/mL, 5-6 M/mL, 8-9 M/mL), assayed in duplicate. Data provenance similar to reproducibility study.
Analytical Specificity (Non-clinical): Three "LOW MSC RANGE" and three "MODERATE/NORMAL MSC RANGE" semen samples, each split into aliquots for various contaminants and controls. A separate study used three "LOW" and three "MODERATE/NORMAL" MSC samples for urine and saliva interference. Data provenance similar to reproducibility study.
MSC Cut-off Trial (Non-clinical): 100 fresh human semen samples (approximately 50/50 split above and below 6 M/mL MSC cutoff). 10% were prepared samples to better represent samples close to the cutoff. Data provenance similar to reproducibility study.
Clinical Study (Test Set): 316 samples across three clinical sites (one in Israel, two in the US). These were prospective samples from male subjects.

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

Non-clinical studies: The ground truth for MSC values in non-clinical studies (Reproducibility, Detection Limit, Analytical Specificity, MSC Cut-off) was established using the SQA-V sperm analyzer, which is a legally marketed predicate device cleared under K021746. No specific number of experts is mentioned as directly establishing these ground truths, but the SQA-V is an established laboratory-based instrument.
Clinical Study: The ground truth for the clinical study was established by two SQA-V systems (predicate device), with their results averaged. While not explicitly stated as "experts," the SQA-V is an established clinical laboratory method used by trained professionals to determine semen parameters. Additionally, "trained health care professionals (HCPs, trained users)" who performed a separate YO™ test served as a comparison point for the lay user results.

3. Adjudication method for the test set:

For non-clinical studies (MSC Cut-off Trial): The SQA-V generated numerical MSC data, which was then converted to qualitative results ("LOW MSC RANGE" or "MODERATE/NORMAL MSC RANGE") based on the 6 M/mL cutoff. This essentially serves as the adjudicator.
For clinical studies: The SQA-V results (averaged from two systems and then converted to qualitative categories) served as the comparator/ground truth against which both lay user YO™ results and trained user YO™ results were compared. There was no explicit "adjudication" in the sense of multiple human experts reviewing discrepancies; instead, the SQA-V was the reference standard.

4. 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 was not an MRMC comparative effectiveness study in the traditional sense of evaluating human reader improvement with AI assistance. The YO™ Home Sperm Test is designed for standalone over-the-counter use by lay users, with the device itself providing the qualitative assessment.
The study did compare lay users' performance with the device against a laboratory reference (SQA-V) and against trained users with the device. This assesses the device's accuracy when used by its target demographic. No "human reader improvement with AI vs without AI" effect size can be determined from this study design as there is no "without AI" human reading component.

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

Yes, a standalone performance was done for internal validation and non-clinical studies. The non-clinical studies (Reproducibility, Detection Limit, Analytical Specificity, MSC Cut-off Trial) assessed the YO™ system (device and algorithm) against the SQA-V without explicit human interpretation being part of the YO™ device's output. The YO™ device outputs "LOW MSC RANGE" or "MODERATE/NORMAL MSC RANGE" directly.
The clinical study primarily focused on the device's performance with a human user interaction (lay users following instructions). However, the underlying technology performing the sperm analysis and classification into MSC ranges is the standalone algorithm of the YO™ device.

6. The type of ground truth used:

Predominantly expert consensus via a legally marketed predicate device (SQA-V). For all quantitative evaluations, the SQA-V sperm analyzer served as the gold standard. The SQA-V itself is an instrument used by trained professionals and provides objective measurements, which are then categorized based on WHO guidelines.

7. The sample size for the training set:

The document does not explicitly state the sample size used for the training set for the YO™ device's algorithm. The non-clinical and clinical studies described are performance validation studies, not algorithm training studies.

8. How the ground truth for the training set was established:

Since the training set size is not provided, the method for establishing its ground truth is also not explicitly stated in this document. However, given that the SQA-V is used as the comparative method for all validation, it is highly probable that similar laboratory-based, SQA-V derived measurements and classifications would have been used to establish the ground truth for any training data.

Summary

{0}------------------------------------------------

Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three heads in profile, facing right. The eagle is enclosed in a circle with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" around the perimeter.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

November 8, 2016

Medical Electronic Systems, Ltd. c/o Erika B. Ammirati Ammirati Regulatory Consulting 575 Shirlynn Court Los Altos, CA 94022

Re: K161493

Trade/Device Name: YOTM Home Sperm Test Regulation Number: 21 CFR 864.5220 Regulation Name: Automated differential cell counter Regulatory Class: Class II Product Code: POV Dated: October 28, 2016 Received: October 31, 2016

Dear Ms. Ammirati:

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

{1}------------------------------------------------

CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of 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 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/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21CFR 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 yours.

Leonthena R. Carrington -S

Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

{2}------------------------------------------------

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known) K161493

Device Name YOTM Home Sperm Test

Indications for Use (Describe)

The YO™ Home Sperm Test is a smartphone based home test which provides a qualitative assessment of motile sperm concentration (MSC) in human semen. MSC is one aspect of a male semen examination. The YO™ Home Sperm Test does not provide a comprehensive · evaluation of a male's fertility status and is intended for over-the-counter, in vitro use only.

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

| Prescription Use (Part 21 CFR 801 Subpart D)

X Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

{3}------------------------------------------------

510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K161493.

807.92 (a)(1):

Name: Medical Electronic Systems, LTD

ALON HATAVOR ST. 20 ZONE 6 Address: CAESAREA INDUSTRIAL PARK CAESAREA, 38900, ISRAEL

Phone:	011 972 4 637-3981
FAX:	011 972 4 637-3984
Contact:	Ms. Marcia Deutsch

807.92 (a)(2): Device name- trade name and common name, and classification

Trade name:

YO™ Home Sperm Test

Common Name: YO™ Home Sperm Test for qualitative assessment of motile sperm concentration (MSC) using the user's smartphone, the YO™ software application, and the YO™ test kit.

Classification: Class II, POV 21 CFR 864.5220

807.92 (a)(3): Identification of the legally marketed predicate devices

YO™ Home Sperm Test (YO™) is substantially equivalent to an amalgam of two existing predicate devices, namely SpermCheck® Fertility (Princeton BioMeditech Corporation, Princeton, NJ), cleared under K100341, May 4, 2010, and the SQA-V sperm analyzer, (MES Ltd., Israel), cleared under K021746, September 20, 2002. All three test systems utilize fresh human sperm to measure various aspects of male fertility factors.

807.92 (a)(4): Device Description

{4}------------------------------------------------

The YO™ software recommends seeking medical advice if both YO™ test results report LOW MSC RANGE. The LOW cutoff has been established at <6M/mL motile sperm, based on the WHO 5th edition reference values for semen parameters, statistical modeling, and expert publications. The user is not required to perform interpretations and YO™ does not review, verify, or interpret the captured images. The user can only observe the stored images of his semen sample.

807.92 (a)(5): Intended Use

807.92 (a)(6): Technological Similarities and Differences to the Predicate

YO™ is substantially equivalent to two FDA-cleared predicate devices - SpermCheck® Fertility (Princeton BioMeditech Corporation, Princeton, NJ), cleared under K100341, May 4, 2010, and the SQA-V sperm analyzer, (MES Ltd., Israel), cleared under K021746, September 20, 2002. YO'" is substantially equivalent to both of these products in terms of general intended use, sample type, male fertility factor measurement and in vitro use. Further, YO ™ is substantially equivalent to the SQA-V in terms of the assessed parameter: motile sperm concentration (MSC), and is substantially equivalent to SpermCheck® Fertility in terms of both devices being qualitative, over-the-counter (OTC) sperm tests.

		Predicates:
Element	New product:YO™ home test	SQA-VK021746	SpermCheck® FertilityK100341
IntendedUse	The YO™ Home SpermTest is a smartphonebased home test whichprovides a qualitativeassessment of motilesperm concentration(MSC) in human semen.MSC is one aspect of amale semen examination.The YO™ Home SpermTest does not provide acomprehensive evaluationof a male's fertility statusand is intended for over-the-counter, in vitro useonly.	The SQA V is a point-of-care, electro-optical devicewith on-screen visualizationthat is used for semenanalysis. The SQA V reports:• total sperm concentration(TSC, millions/ml)• percent motility (%MOT)and % progressive motility(%PMOT)• % normal morphology(%MORPH)• motile sperm concentration(MSC, millions/mL) andprogressive MSC (PMSC)• functional spermconcentration (FSC,millions/mL)	SpermCheck® Fertility is aqualitative test that detectssperm concentration at orabove 20,000,000 sperm/mL.The test is intended for useas an aid in the determinationof a man's fertility status.For in vitro, over the counterhome use.
Sample	Human semen	Human semen	Human semen
MaleFertility	Yes	Yes	Yes

YO™ vs. SQA-V and SpermCheck® Fertility

{5}------------------------------------------------

Element	New product:YOTM home test	Predicates:	SQA-VK021746	SpermCheck® FertilityK100341
Factor
Technology	A specimen filled slide isinserted into amagnification "Clip" whichslides over the top of theSmart phone. Softwaredownloaded onto thephone is used to captureand analyze themagnified sperm video.		Desk-top unit consists of alight source, optical sensors,built-in video microscopy andan internal computercontaining algorithms for theassessment of semenparameters.	A one-step, immuno-chromatographic assay

807.92 (b)(1): Brief Description of Nonclinical Data

A series of studies were performed that evaluated traditional laboratory performance characteristics; a summary of each study follows.

Reproducibility/Repeatability

The study was conducted at two sites- one internal and one external. At least 60 subjects per site were included, with fresh semen samples allocated into three groups (approximately 20 samples per group, see 1-3 below). The three groupings were based on MSC values strictly from the YO system. The samples were assayed in duplicate by four operators using two phones of each type (iPhone and Galaxy), four lots of Clips, and four lots of slides (480 measurements per site). The summarized data are shown in the tables below.

1. Positive (MSC < 4 M/mL)
1. Close to cutoff (borderline, MSC 4 M/mL to 8 M/mL)
1. Negative (MSC >8 M/mL)

Site 1: MES	Positive	Negative	Total	% Positive	% Negative
Positive (<4 M/mL)	38	0	19x2 phonetypes = 38	100	0
Borderline (4-8M/mL)	20	16	18x2 phonetypes = 36	56	44
Negative(>8 M/mL)	0	60	30x2 phonetypes = 60	0	100

Site 2: RuppinCollege	Positive	Negative	Total	% Positive	% Negative
Positive (<4 M/mL)	62	0	31x2 phone types= 62	100	0
Borderline (4-8M/mL)	27	21	24x2 phone types= 48	56	44
Negative(>8 M/mL)	0	42	21x2 phone types= 42	0	100

{6}------------------------------------------------

Overall	Positive	Negative	Total	% Positive	% Negative
Positive (<4 M/mL)	100	0	50x2 phone types100	100	0
Borderline (4-8M/mL)	47	37	42x2 phone types= 84	56	44
Negative(>8 M/mL)	0	102	51x2 phone types= 102	0	100

It was demonstrated that the intra-device (iPhone and Galaxy separately), inter-phone type (iPhone vs. Galaxy), and inter-operator/Clip/slide lot repeatability, calculated via percents coefficients of variation (%CVs), were <20%.

Detection Limit (Limit of Blank)

The limit of blank and detection limits were established by assaying four MSC levels, in duplicate, with each of the two smartphones (n = 4 per level). The MSC levels were blank: 0 M/mL. low: 2-3 M/mL. close to cutoff: 5-6 M/mL. and high: 8-9 M/mL.

Four random semen samples were collected according to WHO 5ª manual laboratory procedure, liquefied and processed by standard procedure. The samples were pooled, centrifuged for 15 minutes and then the cell pellet was separated from the seminal plasma. The four semen samples were prepared using part of the pellet and 1 mL of the seminal plasma to tarqet the four levels (the 0 level was the neat seminal plasma). The levels were verified with the SQA-V. The limit of blank was established by assaying the seminal plasma sample (0 M/mL MSC) and the detection limit was established by the sample closest to zero. The %positive and negative results were calculated for each sample.

The results of the detection limit study, conducted by assaying the four MSC levels in duplicate by four operators using four phones of two types of smartphones (iPhone = Phones 1 and 2) and Galaxy= Phones 3 and 4) and four Clip lots, are presented in a table below.

Sample	Target	Assignedby SQA-V	YOTM Results				% Pos/Neg
			YOTMPhone 1	YOTMPhone 2	YOTMPhone 3	YOTMPhone 4
1	0	0	Low/Low	Low/Low	Low/Low	Low/Low	100% Pos
2	2-3	2.7	Low/Low	Low/Low	Low/Low	Low/Low	100% Pos
3	5-6	5.6	Low/MN	Low/Low	Low/Low	MN/MN	62.5% Pos37.5% Neg
4	8-9	8.1	MN	MN	MN	MN	100% Neg

All units MSC M/mL

Note: Low - LOW MSC RANGE; MN - MODERATE/NORMAL MSC RANGE

The data demonstrated 3 M/mL MSC as the limit of detection (2 times lower than 6 M/mL cutoff) and 0 for the limit of blank. The results for the sample with the MSC level close to the cutoff (5.6 M/mL) were split 62.5% positive and 37.5% negative.

Analytical Specificity (interference testing)

Three LOW MSC RANGE and three MODERATE/NORMAL MSC RANGE semen samples, 8 mL each, were prepared and each split into 8 aliquots of 1 mL. The following contaminants were added to 7 aliquots of each sample (1 per aliquot) at the level of 5%/95% (vol/vol) of the

{7}------------------------------------------------

following highly concentrated preparations that were centrifuged before their addition, if required): (1) yeast, (2) bacteria (E. coli), (3) erythrocytes (RBCs), (4) leukocytes (WBCs), (5) vitamin B12, (6) testosterone, and (7) agglutinates. The eighth aliquot of each sample level was supplemented with a volume of seminal plasma (5%, no sperm cells) equal to the volume of the contaminants (intact control sample). As viscosity impacts sperm motility, this contaminant was excluded from the trial.* The two female hormones D-norgestrel and B-estradiol were also evaluated in a separate study.

*NOTE: Naturally high viscosity may appear in some semen samples due to the intrinsic characteristics of semen. High viscosity impacts semen analysis results assessed by any method. The WHO recommends bringing the sample to normal viscosity prior to assessment. The liquefaction step obviates the need to assess high viscosity separately.

The contaminated and intact (neat) control samples were assayed by both the YO'" home test (candidate method) and the SQA-V method and the results were compared. Samples were tested in duplicate by the SQA-V with results averaged. YO™ testing was conducted including four smartphones, two of each type. The Positive (below the cutoff) and Negative (equal or greater than cut-off) Percent Agreement (PPA and NPA) were established according to EP12-A2 quidance as follows:

	Comparative Method
Candidate Method	Positive	Negative	Total
Positive	a	b	a+b
Negative	c	d	c+d
Total	a+c	b+d	n

% PPA = 100 x a/(a+c) % NPA = 100 x d/(b+d)

The summarized analytical specificity results are presented in the tables below.

Yeast
CandidateMethod	Comparative MethodPositive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

RBC
CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100%

% NPA = 100 x d/(b+d) = 100%

E. Coli
Candidate Method	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

WBC
Candidate Method	Comparative Method
Method	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100%

% NPA = 100 x d/(b+d) = 100%

{8}------------------------------------------------

Vitamin B12

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100%

% NPA = 100 x d/(b+d) = 100%

Agglutination

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% % NPA = 100 x d/(b+d) = 100%

		D-norgestrel

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

INTACT Control (non spiked)
-----------------------------	--

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

In a separate study assessing the impact of urine and saliva, three LOW (including one close to the cutoff) MSC and three MODERATE/NORMAL MSC semen samples, 3 mL each, were prepared and each split into 3 aliquots of 1 mL. The following contaminants were added to two LOW MSC and 2 MODERATE/NORMAL MSC aliquots of each sample (1 per aliquot): (1) urine at 5%, (2) saliva at 5%. The third aliquot of each sample level was supplemented with a volume of seminal plasma (no sperm cells) equal to the volume of the contaminants (non spiked control sample).

Testosterone

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100%

% NPA = 100 x d/(b+d) = 100%

Intact Control

Candidate	Comparative Method
Method	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% % NPA = 100 x d/(b+d) = 100%

B-estradiol

Candidate	Comparative Method
Method	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

{9}------------------------------------------------

The contaminated and control (neat) samples were assaved by both the YO™ home test (candidate method) and the SQA-V method and the results were compared. Samples were tested in duplicate by the SQA-V with results averaged. YO™ testing was conducted including four smartphones, two of each type. The positive (below the cutoff) and negative (equal or greater than cut-off) percent agreements (PPA and NPA) were established according to EP12-A2 quidance as follows:

Candidate Method	Comparative Method
	Positive	Negative	Total
Positive	a	b	a+b
Negative	c	d	c+d
Total	a+c	b+d	n

% PPA = 100 x a/(a+c)

% NPA = 100 x d/(b+d)

Analytical Specificity (interference testing)- Results

Urine
Candidate Method	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

Saliva
Candidate Method	Comparative Method
Method	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS % NPA = 100 x d/(b+d) = 100% PASS

INTACT Control (non spiked)

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	12	0	12
Negative	0	12	12
Total	12	12	24

% PPA = 100 x a/(a+c) = 100% PASS

% NPA = 100 x d/(b+d) = 100% PASS

MSC Cut-off Trial

One hundred (100) fresh human semen samples, approximately 50/50 with MSC values of above and below the 6M/mL MSC cutoff were tested using the YO™ home test and SQA-V as the comparator method. Ten percent (10%) of the samples were prepared samples to better represent samples close to the cutoff. The MSC range of the samples started at 0.2 M/mL (detection limit of the SQA-V). The study included two phones (1 of each type), four lots of Clips and four lots of fixed coverslips. All samples were assayed in parallel and within 2 minutes of each other on the SQA-V and YO™ to eliminate the impact of time on the sample MSC. In order to compare the YOTM test qualitative results with the SQA-V numeric data. the SQA-V data were converted to qualitative results based on the MSC cutoff as follows:

{10}------------------------------------------------

LOW MSC RANGE (MSC <6 M/mL) .
. MODERATE/NORMAL MSC RANGE (MSC >= 6 M/mL)

The YO™ and SQA-V results were compared based on the following categories: Positive (below cut-off) and Negative (equal to or greater than the cut-off). The comparison results were presented as positive and negative percents agreement (PPA & NPA).

iPhone				Galaxy
CandidateMethod	Comparative Method			Candidate	Comparative Method
	Positive	Negative	Total	Method	Positive	Negative	Total
Positive	51		52	Positive	50	2	52
Negative	3	45	48	Negative	ব	44	48
Total	54	46	100	Total	54	46	100
11A / Ph Ph A1 A AA 1 101A / Ph Ph A100AA AAI

% PPA = 100 x a/(a+c) = 94.4%

% NPA = 100 x d/(b+d) = 97.8%

% PPA = 100 x a/(a+c) = 92.6%

% NPA = 100 x d/(b+d) = 95.7%

CandidateMethod	Comparative Method
	Positive	Negative	Total
Positive	101	3	104
Negative	7	89	96
Total	108	92	200

iPhone and Galaxy Combined

$% PPA = 100 x a/(a+c) = 93.5%$
$% NPA = 100 x b/(b+d) = 93.7%$

% NPA = 100 x d/(b+d) = 96.7%

The results of the MSC cutoff study demonstrated that both the iPhone and Galaxy YO™ device platforms can discriminate MSC levels of fresh semen samples above and below 6 M/mL cutoff with PPA and NPA levels greater than 90% vs. the SQA-V comparative method.

807.92 (b)(2): Brief Description of Clinical Data

YO™ was clinically validated via a clinical study. The study was a cross-sectional, multi-site investigation conducted at three clinical sites, one in Israel and two in the US. All labeling was provided in English, and age and education levels across the sites were similar. Male subjects who provided the semen specimens comprised the groupings of: no known fertility issues (by self-reporting), a partner in a couple having difficulty conceiving, had been diagnosed with male factor infertility, post-vasectomy patients, or post-vasectomy reversal patients. The primary purpose of including subjects with fertility issues was to enrich the numbers of low MSC levels so that both positive and negative MSC samples were well represented. Additionally, "tester" lay-persons (men and women) were included to test semen specimens provided by a subset of the male subjects.

Following collection of the specimen by the subject either the subject and/or the tester analyzed the sample with the YOT™ system using only the instructions provided in the kit. A trained health care professional (HCP, trained user) performed a separate YOT™ test using the same ejaculate, phone type and lot of materials, and a third aliquot of the sample was assayed by two SQA-V systems where results were averaged and converted to the qualitative outcomes (see

{11}------------------------------------------------

below). All comparative testing was carried out within 10 minutes. A total of 316 samples were evaluated across the three sites, with a range of 82 to 136 samples at each site.

Samples were collected per instructions based on WHO 5" edition manual guidelines and maintained at room temperature until tested. All lav users (subjects and testers) provided demographic information and signed the informed consent form prior to study participation. Results were expressed as "LOW MSC RANGE" or "MODERATE/NORMAL MSC RANGE" by YO™, and the reference (SQA-V) results were translated to these two categories using the 6M/mL MSC cutoff; SQA-V results of >6M/mL were interpreted as "MODERATE/NORMAL MSC RANGE," and SQA-V results <6M/mL were interpreted as "LOW MSC RANGE". The clinical studies were conducted under the auspices a commercial IRB, and a summary of the study design is as follows:

. Sites 1, 2, and 3 tested 82, 136, and 98 subjects respectively. The larger participation at Site 2 was due to tremendous interest at this site not wishing to turn away volunteers.
. The diversity of the United States intended use population was reflected in the study. The following information was requested of each subject enrolled in the study: age, race, educational level, fertility status, and relevant medications.
. A subject (lay user) was supplied with a semen collection cup and collected the semen sample. Alternatively, subjects were provided with a previously collected sample (testers). One semen sample was used to generate three sets of data, A, B, and C.
. Subjects were provided with the smartphone type of their choice (iPhone or Galaxy), as this is representative of actual use; once the test is available, users will order the YO™ kit that is matched to the phone of choice.
Each lay user was supplied with the YO™ kit and performed a test based solely on the . instructions provided. The results were recorded (Result A).
. A trained person performed a second YO™ test on the same sample using the phone and same lot of the kit components as that of the lay user, and recorded the results (Result B).
. In parallel, the sample was tested on two SQA-V systems, and means were calculated and recorded (Result C.)
. A comparison of A to B demonstrated that lay users and trained users could perform YO™ tests and obtain the same/similar results.
. A comparison of A to C demonstrated that lay users could obtain the correct answer.
. A comparison of B to C demonstrated that HCPs could obtain the correct answer.
. All testing were done in a blinded fashion, and the results from YO™ were not used for clinical management.
. Each lay user was provided with a complete YO™ test kit containing a sperm collection container, one smartphone (iPhone or Galaxy), a Clip which attaches to the smartphone, a fixed coverslip slide, disposable plastic pipettes for sample aspiration and transfer, and a vial with liquefaction media. The Clips used for the clinical study were not used more than twice, in accordance with instructions for the end user.

{12}------------------------------------------------

The results were analyzed by the percent agreements between lay users and trained users of YO™; between lay users of YO™ and the SQA-V reference results, and between trained users of YOTM and the SQA-V reference results.
The test results were compared and analyzed as percent agreements between:
Lay Users (of YOTM) and the SQA-V averaged test results 1.
Lay Users and Trained Users of YO™ 2.
Trained Users of YO™ and the SQA-V 3.

The SQA-V MSC results were converted into LOW MSC RANGE or MODERATE/NORMAL MSC RANGE categories, based on the 6 M/mL cutoff, and the reported categories of the YO™ were compared to the SQA-V data.

The data for the 3-site study are shown below; data were similar among sites.

AGREEMENT: A vs. B				YOTM by LayUser (A)	SQA-V (C)
YOTM by LayUser (A)	YOTM by Trained User (B)				Positive	Negative	Total
	Positive	Negative	Total	Positive	81	9	90
Positive	87	3	90	Negative	4	222	226
Negative	3	223	226	Total	85	231	316
Total	90	226	316	$% PPA = 100 x a/(a+c)$		95.3%
% PPA = $100 x a/(a+c)$		96.7%		$% NPA = 100 x d/(b+d)$		96.1%
% NPA = $100 x d/(b+d)$		98.7%

AGREEMENT: A vs. C

	SQA-V (C)
YO™ byTrainedUser (B)	Positive	Negative	Total
Positive	83	7	90
Negative	2	224	226
Total	85	231	316
% PPA = $100 x a/(a+c)$		97.6%
% NPA = $100 x d/(b+d)$		97.0%

AGREEMENT: B vs. C

Questionnaire

Results from the 5-question questionnaire were summarized descriptively. Specifically, the percentage distributions of responses of the 5-point Likert scale are reported. The questions are shown below each question number, and the data are reported for all sites.

All Site Data, n = 316
Question # 1:
Were the directions and pictures in the YOTM TEST PROCEDURE
#	QUESTION	RESPONSE %
1	Very clear and easy to follow	81.70
2	Somewhat clear and fairly easy to follow	14.71
3	Neutral	1.96
4	Some unclear, but could be followed	1.31
5	Unclear and difficult to follow	0.33
Question # 2:

{13}------------------------------------------------

Were the instructions for SAMPLE PREPARATION
#	QUESTION	RESPONSE %
1	Very clear and easy to follow	84.97
2	Somewhat clear and fairly easy to follow	11.76
3	Neutral	1.96
4	Some unclear, but could be followed	1.31
5	Unclear and difficult to follow	0.00

Question # 3:Were the instructions for ATTACHING THE YO SPERM CLIP TO THEPHONE
#	QUESTION	RESPONSE %
1	Very clear and easy to follow	90.85
2	Somewhat clear and fairly easy to follow	5.88
3	Neutral	2.94
4	Some unclear, but could be followed	0.33
5	Unclear and difficult to follow	0.00

Question # 4:Were the instructions for FILLING THE YO SLIDE WITH SAMPLE
#	ANSWER	RESPONSE %
1	Very clear and easy to follow	66.89
2	Somewhat clear and fairly easy to follow	22.95
3	Neutral	6.23
4	Some unclear, but could be followed	3.93
5	Unclear and difficult to follow	0.00

Question # 5:Were the YO ANIMATIONS AND VIDEOS
#	ANSWER	RESPONSE %
1	Very clear and easy to follow	89.18
2	Somewhat clear and fairly easy to follow	8.52
3	Neutral	0.66
4	Some unclear, but could be followed	1.31
5	Unclear and difficult to follow	0.33

The results of the YO™ clinical testing showed the high levels of PPA and NPA between results of the lay and trained users, and lay users and SQA-V, exceeding 90%. High levels of PPA and NPA were also obtained between the trained user results and SQA-V. Lastly, lay users expressed good satisfaction with the procedural steps and good comprehension of the labeling.

807.92 (b)(3): Conclusions from Nonclinical and Clinical Testing

The data from the nonclinical and clinical testing indicate that the test system is safe and effective for its intended use.

Regulation Number and Section

§ 864.5220 Automated differential cell counter.

(a)
Identification. An automated differential cell counter is a device used to identify one or more of the formed elements of the blood. The device may also have the capability to flag, count, or classify immature or abnormal hematopoietic cells of the blood, bone marrow, or other body fluids. These devices may combine an electronic particle counting method, optical method, or a flow cytometric method utilizing monoclonal CD (cluster designation) markers. The device includes accessory CD markers.(b)
Classification. Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA.”