Predicate Devices

Wright-stain/Light Microscope, The Yellow IRIS® urinalysis workstation and body fluids cell counting system

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The document mentions "automated intelligent microscopy" and "color image analysis" but does not explicitly mention AI, ML, or related terms like neural networks or deep learning. The description focuses on image processing and classification that is reviewed and confirmed by a skilled human observer.

Therapeutic

No
The device is described as a leukocyte differential analyzer for in vitro diagnostic use, which analyzes blood specimens to determine proportional leukocyte counts. It is used in a laboratory setting to provide information for diagnosis, not to treat a disease or condition.

Diagnostic

Yes

The device is a leukocyte differential analyzer intended for in vitro diagnostic use, as stated in the "Intended Use / Indications for Use" section. It determines the proportional leukocyte count on peripheral blood specimens, which is a diagnostic function.

SaMD (Software as a Medical Device)

No

The device description explicitly mentions hardware components like a cytoprobe, compartments for sampling and preparation, a microscope, a camera sensor, and a 20-in touchscreen monitor. While it includes software for image analysis and presentation, it is not solely software.

IVD (In Vitro Diagnostic)

Based on the provided information, yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Explicit Statement in Intended Use: The "Intended Use / Indications for Use" section clearly states: "The White IRIS is a leukocyte differential analyzer intended for in vitro diagnostic use..." This is the most direct and definitive indicator.
Purpose of the Device: The device is designed to analyze peripheral blood specimens to determine the proportional leukocyte count (WBC differential). This is a laboratory test performed on biological samples outside of the body, which is the definition of an in vitro diagnostic.
Clinical Context: The device is intended for use in a clinical laboratory setting, either to review flagged specimens from automated hematology analyzers or to perform differentials when no automated differential has been done. This places it squarely within the realm of clinical diagnostics.
Performance Studies: The document describes performance studies comparing the device to a reference method (Wright-stain/Light Microscope) and another automated analyzer (Coulter STKS). These types of studies are standard for evaluating the performance of IVD devices.
Intended User: The intended users are described as "skilled competent observer" and "qualified laboratorian," indicating use in a professional laboratory environment for diagnostic purposes.

The presence of image processing, while relevant to the technology, does not negate its IVD status. Many IVD devices utilize image processing as part of their analytical process. The lack of explicit mention of AI, DNN, or ML also doesn't preclude it from being an IVD.

In summary, the primary purpose, intended use statement, and the context of its application all strongly indicate that The White IRIS is an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The White IRIS is a leukocyte differential analyzer intended for in vitro diagnostic use in determining the proportional leukocyte count (WBC differential) on peripheral blood specimens that have been flagged by an automated hematology analyzer performing differential counts as well as for peripheral blood specimens for which no automated differential has been performed.

Product codes (comma separated list FDA assigned to the subject device)

Not Found

Device Description

Combining unique cytoprobe, rapid hemacyte fractionation and novel color image analysis, The White IRIS extends automated intelligent microscopy to leukocyte differentiation. It provides flow cytometry precision and microscopical resolution to review specimens flagged by hematology analyzers with differential capabilities or to complement other analyzers without these capabilities. The system includes compartments for closed sampling, rapid leukocyte-rich plasma preparations, cytoprobeinduced metachromasia, and collection and color analysis of leukocyte images, and presents the results as a single-view 500-cell differential on a 20-in touchscreen monitor for examination by a skilled competent observer.

Mentions image processing

novel color image analysis

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Microscope images individual leukocytes on a camera sensor which produces a magnified video image for view and interpretation.

Anatomical Site

peripheral blood specimens

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Operator competence: The White IRIS is designed and intended for use by trained, competent operators well skilled in both the use of the instrument and in the recognition of leukocyte classes based on IRISpectracolor stained cell expressions displayed on the ViewStation video monitor. Although leukocyte images are classified presumptively by cell type, a competent technologist is required to confirm or modify the classification of each cell. Laboratories using The White IRIS should maintain adequate operator training and proficiency testing programs for instrument users.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Efficacy Demonstration:
Differential leukocyte composition determined using The White IRIS was compared to results obtained by visual interpretation of blood smears stained with Wright-stain as the reference method. Count accuracy, clinical sensitivity and precision were compared according to the NCCLS Approved Standard H20-A "Reference leukocyte differential count (proportional) and evaluation of instrumental methods," National Committee for Clinical Laboratory Standards, Villanova, PA, March 1992, hereinafter referred to as H20-A. Other suitable, well accepted statistical comparisons not prescribed in H2O-A were also performed to illustrate the effectiveness of The White IRIS even further. In addition, comparisons to proportional count and flagging results obtained with a Coulter STKS for the same group of specimens demonstrated the need for post primary analyzer review and the efficacy of The White IRIS in fulfilling this need as well as provided perspective with regards to current state-of-the-art hematology analyzers.

Key Results:

Inaccuracy, clinical sensitivity and imprecision studies according to H20-A have demonstrated substantial equivalence of leukocyte differential counts (proportional) derived from competent human interpretation of leukocyte images produced by The White IRIS to those from Wright-stained blood smears.
Additional statistical comparison (oneway ANOVA and paired t-test) of the results from the two instruments used in the study further demonstrated skilled competent observer inter-instrument as good or better than agreement between the two Wright-stain readers performing the predicate: method. Thus both agreement of the proposed new method with the established reference method and consistency within-run, instrument-to-instrument and over a few month period of intense use have been demonstrated in a way even more rigorous than specified by H2O-A.
Actual comparative performance measure in both review and primary procedural modes demonstrate how well The White IRIS can either complement or replace a 5part WBC differential capability on the Coulter STKS, the most popular such contemporary product in the market today.
Besides its demonstrated Wright-stain equivalency, and demonstrated superiority to the leading contemporary product in every leukocyte measure it makes, use of The White IRIS is also accompanied by significant safety and substantial labor saving benefits for the clinical laboratory.

Performance Characteristics on which Substantial Equivalence is Based:

Accuracy: Differential leukocyte counts for 1,202 normal and abnormal patient specimens were obtained using both manually prepared and observed Wright stained smears (200 cell differential), read by two skilled technologists, and automated analysis on The White IRIS (2 instruments x 500 cell differential), reviewed by the same two skilled technologists.
Precision: Short term standard deviations calculated according to H20-A are tabulated for The White IRIS and for the Wright stain reference method in Table 5. Short term imprecision is based on the root square of the differences between replicates. For The White IRIS, each replicate is the average of two determinations (specimen volume permitting) or a single determination for each instrument. For the reference method, each replicate is a 200 cell differential by one or the other reader.
The "within" run precision was established using 22 replicates of the same sample.
Clinical Sensitivity: The clinical sensitivity analysis is based on the evaluation of 1202 Leukocyte Differential Summaries performed on The White IRIS. All specimens were classified as normal (all parameters within normal range) or abnormal (any parameter outside of normal range) using the reference ranges from Table 8. The comparison after removing those cases for which parameters causing disagreement were within 95% confidence limits is shown in Table 9.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Agreement: 91.89% (93.51%)
False Positive: 15.36% (14.12%)
False Negative: 4.79% (2.98%)

Agreement (Table 11): 82.95%
False Positive (Table 11): 28.43%
False Negative (Table 11): 9.82%

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Wright-stain/Light Microscope, The Yellow IRIS® urinalysis workstation and body fluids cell counting system

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

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.”

Summary

0

ID :

INTERNATIONAL REMOTE IMAGING SYSTEMS, INC.

9162 Eton Avenue Chatsworth, CA 91311 Phone 818-709-1244 818-700-9661 FAX

K953116

13 139

510 (k) SUMMARY

June 29, 1995

Name of Contact Person:

Jimmie R. Kyle Vice President, Manufacturing and Product Reliability

Date of Submission:

Name of Device:

MAX - With House and Comments

Trade Name -.
Common Name -.
. Classification Name

Predicate Method and Legally Marketed Device to which Substantially Equivalent is claimed:

Intended Use of Device:

Instrument used in determining WBC Differential None Established

The White IRIS Leukocyte Differential Analyzer

Wright-stain/Light Microscope and The Yellow IRIS® urinalysis workstation and body fluids cell counting system

The White IRIS is a leukocyte differential analyzer intended for in vitro diagnostic use in determining the proportional leukocyte count (WBC differential) on peripheral blood specimens that have been flagged by an automated hematology analyzer performing differential counts as well as for peripheral blood specimens for which no automated differential has been performed.

Operator competence: The White IRIS is designed and intended for use by trained, competent operators well skilled in both the use of the instrument and in the recognition of leukocyte classes based on IRISpectracolor stained cell expressions displayed on the ViewStation video monitor. Although leukocyte images are classified presumptively by cell type, a competent technologist is required to confirm or modify the classification of each cell. Laboratories using The White IRIS should maintain adequate operator training and proficiency testing programs for instrument users.

1

141 47 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11

Limitations:

1. Competent human observer band neutrophil identification is generally limited to those cells with a distinct band-form nucleus. Band neutrophils with lobes connected by thin chromatin strands will generally not be distinguished from segmented neutrophils. Consequently, fewer band neutrophils and more polymorphonuclear neutrophils will be reported. However, the combined neutrophil (band plus segmented) proportional count obtained by a competent human observer using The White IRIS will closely match that obtained from a Wright-stain smear.
1. As with Wright-stain smears, distinctions between band and segmented neutrophil, metamyelocyte and myelocyte, myelocyte and promyelocyte will be subject to variation among individual observers.
1. IRISpectracolor stain is not designed for discrimination of nuclear details in leukocytes.
1. Nucleated RBC (NRBC) are generally removed from the leukocyte-rich plasma fraction analyzed by The White IRIS along with RBC. The White IRIS should not be used to determine presence or absence of NRBC.

Combining unique cytoprobe, rapid hemacyte fractionation and novel color image analysis, The White IRIS extends automated intelligent microscopy to leukocyte differentiation. It provides flow cytometry precision and microscopical resolution to review specimens flagged by hematology analyzers with differential capabilities or to complement other analyzers without these capabilities. The system includes compartments for closed sampling, rapid leukocyte-rich plasma preparations, cytoprobeinduced metachromasia, and collection and color analysis of leukocyte images, and presents the results as a single-view 500-cell differential on a 20-in touchscreen monitor for examination by a skilled competent observer.

Summary of Technological

Characteristics:

2

ールした 고려

| Brief Discussion of Non-
Clinical Factors supporting a
Determination of Substantial
Equivalence: | Involves a competent human observer to examine
microscopic images as does the predicate method
and other similar predicate devices.
See attached Substantial Equivalence comparisons. |
|-----------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Brief Discussion of Clinical
Tests Supporting a
Determination of Substantial
Equivalence: | Conformance to National Committee for Clinical
Laboratory Standards Reference leukocyte differential
count (proportional) and evaluation of instrumental
method: Approved Standard, NCCLS document
H20-A and other statistical comparisons to Wright-
stain/light microscope reference method. |
| Conclusions Drawn from
Clinical Tests: | Use of The White IRIS provides results equal to or
better than the reference method with less time
expenditure and less biohazard exposure. See
attached Efficacy Demonstration. |
| Safety of Device: | See attached Hazard Analysis. |

:

3

Substantial Equivalence.

Table 1- Similarities and differences between The White IRIS and the peripheral blood
smear stained with Wright-stain and viewed with a light microscope. (part 1 of 2)

| Substantial
Equivalence | The White IRIS | Peripheral Blood Smear Stained
with Wright Stain/Light
Microscope |
|--------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended use is the
same, | Production of images of cellular
components of peripheral blood
preparations to permit a skilled,
competent observer to
characterize these cells, enabling
the generation of a white blood cell
differential. | Production of images of cellular
components of peripheral blood
preparations to permit a skilled,
competent observer to
characterize these cells, enabling
the generation of a white blood cell
differential. |
| Specimen analyzed is
the same. | Whole blood collected in blood
specimen tube. | Whole blood collected in blood
specimen tube. |
| Stain used
differentially colors
different cell types in a
similar way. | Leukocytes stained supravitally in
suspension by 2-
Methylpolymethine which
produces unigue metachromasias
among different types of
leukocytes. | Leukocytes stained after cells
dried and fixed on slide by Wright-
stain (consisting of Methylene
Blue, Azures, and Eosin Y)
produces the Romanowsky effect,
differential coloration of cell
components. |
| Separation of WBC
from RBC background
is similar. | Leukocytes separated
gravitationally from erythrocytes to
allow mono-disperse presentation
for automatic randomized
selection. | Leukocytes separated by
spreading in the feather edge
portion of blood smear to allow
manual search and selection from
among monodispersed cells. |
| Mechanisms for
presenting individual
WBC images to
microscope objective
are comparable. | Non-overlapping individual cells, in
liquid suspension, in a flow cell are
automatically presented to and
imaged by a microscope objective. | Non-overlapping individual cells,
smeared and fixed on a glass slide
are manually presented to and
imaged by a microscope objective. |
| Optical means for
magnifying images of
WBCs for observation
and interpretation is
the same or similar. | A microscope images individual
leukocytes on a camera sensor
which produces a magnified video
image for view and interpretation. | A microscope directly images and
magnifies individual leukocytes for
view and interpretation through its
oculars. |

4

Table 1 - continued (part 2 of 2).

| Substantial
Equivalence | The White IRIS | Peripheral Blood Smear Stained
with Wright Stain/Light
Microscope |
|--------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|
| Viewing of images is
similar. | Individual cells are observed on a
video monitor in machine-ordered
and counted groups of like size
and color features. | Individual cells are observed
through the oculars one-at-a-time
while they are classified and
counted. |
| Overview scan
analysis is similar and
more easily
accomplished. | Scanning is accomplished at a
glance of 500-cells organized ir a
montage on a video monitor. | Scanning is accomplished by
moving the slide and manually
characterizing the kinds of cells
observed. |
| Features used to
distinguish among the
various WBC types are
the same or similar. | Cytoplasm of different leukocyte
types stained characteristically. | Cytoplasm of different leukocyte
types stained characteristically. |
| | While nucleus is not stained,
nuclear shape may often be
discerned. | Nuclear stain and shape used to
distinguish among different
leukocyte types. |
| | Size of nucleus (relative to cell
size) and cell size. | Size of nucleus (relative to cell
size) and cell size. |
| Image interpretation
requirements are the
same. | Differentiation of cells requires a
skilled competent observer. | Differentiation of cells requires a
skilled competent observer. |
| Result format is the
same and quality is
better. | The differential proportional count
is based on 500-cells. | The differential proportional count
is usually based on only 100-cells. |

5

Substantial	The White IRIS/Flow Microscope	Conventional Slide Microscope
Equivalence
Intended use is the
same.	To enable a skilled, competent
observer to examine, characterize
and differentiate WBC
compositions.	To enable a skilled, competent
observer to examine, characterize
and differentiate WBC
compositions.
Means for presenting
specimen to device is
the same principle.	Flow microscopy of leukocytes
monodispersed in suspension.
(Used in conjunction with video
camera, and monitor).	Slide microscopy of leukocytes
monodispersed in dried, stained
peripheral blood smear. (In some
instances, cells may be
suspended on the slide in a wet
mount).
Microscopic image
interpretation
requirements are
similar.	Differentiation of cells requires a
skilled competent observer.	Differentiation of cells requires a
skilled competent observer.
Results rely on
counting individual
cells and are based on
the same arithmetic
and quality is better.	The differential proportional count
is based on observing 500 cells.	The differential proportional count
is usually based on observing only
100 cells.

Table 2 - Similarities and Differences between The White IRIS Flow Microscope and the Conventional Light Microscope.

6

Table 3 - Similarities and Differences between The White IRIS and the Generic Flow
Microscope and The Yellow IRIS (part 1 of 2).

| Substantial
Equivalence | The White IRIS for WBC
Differentiation | Flow Microscope/The Yellow
IRIS for UA and Body Fluid
Blood Cell Examination and
Counting |
|----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended use is
parallel. | Production of images of cellular
components of peripheral blood
preparations to permit a skilled,
competent observer to
characterize and count these cells,
enabling the generation of a white
blood cell differential. | Production of images of formed
elements in urine including blood
and other cells, and blood cells in
other body fluids, to permit a
skilled, competent observer to
characterize and count these
components to compose a white
cell differential. |
| Stain used allows
microscopic objects to
be identified by
differential coloration in
a similar way. | Leukocytes stained with
2-Methylpolymethine while in
suspension. | Formed elements stained with
IRIStain, containing primarily
Crystal Violet while in suspension. |
| Mechanisms for
presenting individual
cell and other formed
element images to
microscope objective
are comparable. | Individual cells, in liquid
suspension, in a flow cell are
automatically selected and imaged
by a microscope objective. | Individual cells and other formed
elements, in liquid suspension, in a
flow cell are automatically selected
and imaged by a microscope
objective. |
| Presentation of images
for viewing are the
same. | Individual cells are presented or a
video monitor in machine-ordered
and counted groups of like size
and color features. | Individual cells and other formed
elements are presented on a video
monitor in machine-ordered and
counted groups of like size and
color features. |
| Features used to
distinguish among the
various leukocyte
types are the same or
similar. | Cytoplasm of different leukocyte
types stained characteristically.
While nucleus is not stained,
nuclear shape may often be
discerned.
Size of nucleus (relative to cell
size) and cell size | Cytoplasm of different cells
stained characteristically.
Nuclear stain and shape used to
distinguish among different cell
types.
Size of nucleus (relative to cell
size) and cell size |
| Substantial
Equivalence | The White IRIS for WBC
Differentiation | Flow Microscope/The Yellow
IRIS for UA and Body Fluid
Blood Cell Examination and
Counting |
| Presentation of images
to skilled, competent
observer is the same | Leukocytes in flow cell are viewed
through a microscope by a video
camera. Images are "captured"
and electronically presented to a
skilled, competent observer for
interpretation on a video monitor | Analytes in flow cell are viewed
through a microscope by a video
camera. Images are "captured"
and electronically presented to a
skilled, competent observer for
interpretation on a video monitor. |
| Image montage
organization is similar. | Cells are sorted into ranks of
comparable size and color. | Cells and other formed elements
are sorted into ranks of
comparable size. |
| Results are observed
and expressed in the
same way. | Scanning is accomplished at a
glance of 500-cells organized in a
montage on a video monitor. The
differential proportional count is
based on competent observer
acknowledged and assigned
classification of 500 cell images. | Scanning is accomplished by
observing a sequences of
montages on a video monitor.
Counts are based on competent
observer assigned classification of
cell images. |

7

Table 3 - continued (part 2 of 2).

8

Efficacy Demonstration.

Differential leukocyte composition determined using The White IRIS™ was compared to results obtained by visual interpretation of blood smears stained with Wright-stain as the reference method. Count accuracy, clinical sensitivity and precision were compared according to the NCCLS Approved Standard H20-A "Reference leukocyte differential count (proportional) and evaluation of instrumental methods," National Committee for Clinical Laboratory Standards, Villanova, PA, March 1992, hereinafter referred to as H20-A. Other suitable, well accepted statistical comparisons not prescribed in H2O-A were also performed to illustrate the effectiveness of The White IRIS even further. In addition, comparisons to proportional count and flagging results obtained with a Coulter STKS for the same group of specimens demonstrated the need for post primary analyzer review and the efficacy of The White IRIS in fulfilling this need as well as provided perspective with regards to current state-of-the-art hematology analyzers,

The following general conclusions can be made:

1. Inaccuracy, clinical sensitivity and imprecision studies according to H20-A have demonstrated substantial equivalence of leukocyte differential counts (proportional) derived from competent human interpretation of leukocyte images produced by The White IRIS to those from Wright-stained blood smears.
1. Additional statistical comparison (oneway ANOVA and paired t-test) of the results from the two instruments used in the study further demonstrated skilled competent observer inter-instrument as good or better than agreement between the two Wright-stain readers performing the predicate: method. Thus both agreement of the proposed new method with the established reference method and consistency within-run, instrument-to-instrument and over a few month period of intense use have been demonstrated in a way even more rigorous than specified by H2O-A.
1. Actual comparative performance measure in both review and primary procedural modes demonstrate how well The White IRIS can either complement or replace a 5part WBC differential capability on the Coulter STKS, the most popular such contemporary product in the market today.
1. Besides its demonstrated Wright-stain equivalency, and demonstrated superiority to the leading contemporary product in every leukocyte measure it makes, use of The White IRIS is also accompanied by significant safety and substantial labor saving benefits for the clinical laboratory.

9

Performance Characteristics on which Substantial Equivalence is Based

ווער

1 Accuracy

Differential leukocyte counts for 1,202 normal and abnormal patient specimens were obtained using both manually prepared and observed Wright stained smears (200 cell differential), read by two skilled technologists, and automated analysis on The White IRIS (2 instruments x 500 cell differential), reviewed by the same two skilled technologists.

Table 4 - Leukocyte Differential count correlation between methods. Neutrophils are the sum of polymorphonuclear neutrophils and bands, lymphocytes are the sum of normal lymphocytes and variant immature lymphocytes.

| Cell Type | Correlation | Slope | Intercept | Wright-Stain
Mean (%) | TWI Mean (%) |
|-----------------------|-------------|-------|-----------|--------------------------|--------------|
| Neutrophils | 0.98 | 0.96 | 4.16 | 56.13 | 57.90 |
| Lymphocytes | 0.98 | 0.93 | -0.97 | 31.06 | 27.85 |
| Monocytes | 0.91 | 1.03 | 1.19 | 7.69 | 9.12 |
| Eosinophils | 0.98 | 0.97 | 0.20 | 3.53 | 3.64 |
| Basophils | 0.87 | 0.78 | 0.18 | 0.70 | 0.72 |
| Segmented Neutrophils | 0.93 | 0.94 | 7.18 | 49.15 | 53.56 |
| Bands | 0.54 | 0.25 | 2.58 | 6.99 | 4.34 |
| Metamyelocytes | 0.84 | 0.64 | 0.08 | 0.40 | 0.33 |
| Myelocytes | 0.74 | 0.38 | 0.00 | 0.12 | 0.05 |
| Promyelocytes | 0.97 | 1.00 | 0.00 | 0.08 | 0.08 |
| Blasts | 0.96 | 1.13 | 0.03 | 0.25 | 0.32 |
| Normal Lymphocytes | 0.98 | 0.93 | -1.05 | 30.52 | 27.33 |
| Variant Lymphocytes | 0.41 | 0.31 | 0.35 | 0.55 | 0.52 |

10

2 Precision

Short term standard deviations calculated according to H20-A are tabulated for The White IRIS and for the Wright stain reference method in Table 5. Short term imprecision is based on the root square of the differences between replicates. For The White IRIS, each replicate is the average of two determinations (specimen volume permitting) or a single determination for each instrument. For the reference method, each replicate is a 200 cell differential by one or the other reader.

Table 5 - Imprecision of The White IRIS compared to that of the Wright-stain reference method represented by standard deviation (SD) calculated according to the method specified by H20-A.

| | The White IRIS
(1014 Specimens) | | Wright-stain
(1277 Specimens) | |
|-----------------------|------------------------------------|------|----------------------------------|------|
| Cell type | Mean (%) | SD | Mean (%) | SD |
| Neutrophils | 58.95 | 2.72 | 56.28 | 3.55 |
| Lymphocytes | 26.00 | 3.17 | 30.91 | 3.68 |
| Monocytes | 9.03 | 1.62 | 7.69 | 2.29 |
| Eosinophils | 3.65 | 0.83 | 3.54 | 1.31 |
| Basophils | 0.73 | 0.35 | 0.71 | 0.62 |
| Segmented Neutrophils | 54.64 | 4.25 | 49.47 | 4.72 |
| Bands | 4.33 | 2.94 | 6.81 | 3.68 |
| Metamyelocytes | 0.33 | 0.66 | 0.39 | 0.56 |
| Myelocytes | 0.05 | 0.17 | 0.12 | 0.27 |
| Promyelocytes | 0.04 | 0.17 | 0.08 | 1.33 |
| Blasts | 0.32 | 1.73 | 0.24 | 1.82 |
| Normal Lymphocytes | 26.38 | 3.19 | 30.38 | 3.67 |
| Variant Lymphocytes | 0.52 | 0.95 | 0.53 | 0.99 |

The following "within" run precision was established using 22 replicates of the same sample.

Table 6 - Precision of the Leukocyte Differential parameters is specified at 95% confidence limits.

| Leukocyte | Mean
(%) | 95% Confidence
Limits |
|-------------|-------------|--------------------------|
| Neutrophils | 54.96 | ± 5.0 |
| Lymphocytes | 33.46 | ± 5.0 |
| Monocytes | 7.11 | ± 2.5 |
| Eosinophils | 3.93 | ± 1.5 |
| Basophils | 0.51 | ± 1.0 |

11

3 Clinical Sensitivity

The following clinical sensitivity analysis is based on the evaluation of 1202 Leukocyte Differential Summaries
performed on The White IRIS performed on The White IRIS.

Table 7 - H20-A defined requirements for abnormal specimens to be included in the clinical sensitivity study.

H20-A requires at least 5 cases of each of these abnormal conditions	This Study
Characteristic Leukocyte
Differential Count Finding	Absolute Cell Count	Proportional Cell
Count	Number of
Specimens
Granulocytosis
and/or
Left Shift (Bands)	$\geq 9.0 \times 10^9/L$	> 80%	152
$\ $	$\geq 0.9 \times 10^9/L$	> 6%	197
Monocytosis	$\geq 0.8 \times 10^9/L$	> 10%	64
Eosinophilia	$\geq 0.5 \times 10^9/L$	> 7%	89
Lymphocytosis
and/or
Lymphocytes, Variant Forms	$\geq 3.5 \times 10^9/L$	> 50%	64
$\ $	$\geq 0.7 \times 10^9/L$		5
Granulocytopenia	$\leq 1.5 \times 10^9/L$	2%	66

Table 8 reflects reference ranges established from a group of 154 rormal (according to H20A criteria) specimens.

Table 8 - Reference Ranges (%) for Wright-Stain Smear and The White IRIS.

Leukocyte Type	Wright-Stain Smear		The White IRIS
	Lower Range	Upper Range	Lower Range	Upper Range
Segmented Neutrophils	31.25	71.68	34.48	72.74
Band Neutrophils	0.00	9.25	0.00	7.68
Lymphocytes	17.50	56.25	14.50	48.97
Variant Lymphocytes	0.00	1.25	0.00	1.17
Monocytes	3.25	11.00	4.60	12.27
Eosinophils	0.00	9.00	0.00	9.71
Basophils	0.00	2.00	0.00	1.54
Metamyelocytes	0.00	0.50	0.00	0.28
Myelocytes	0.00	0.25	0.00	0.05
Promyelocytes	0.00	0.00	0.00	0.00
Blasts	0.00	0.00	0.00	0.00

12

Using the reference ranges from Table 8, all specimens were classified as normal (all parameters within normal range) or abnormal (any parameter outside of normal range). The comparison after removing those cases for which parameters causing disagreement were within 95% confider.ce limits is shown in Table 9.

Table 9 - Crosstabulation of combined abnormal classifications after false positive and false negative cases for which differences that are within 95% confidence limits are removed. Values in parentheses ( ) are after false positive and false negative band decisions are removed.

| | | Results of The White IRIS
(Test Method) | | |
|-------------------------------------------------------------------------|----------------------------------------------------------------|-----------------------------------------------------------------|----------------------|-----------------|
| | | Positive
(Distributional &/or
Morphological
Abnormals) | Negative
(Normal) | Total |
| Results of
Wright-Stain/Light
Microscope
(Reference
Method) | Positive
(Distributional &/or
Morphological
Abnormal) | 716 | 36 (22) | 752 (738) |
| | Negative
(Normal) | 53 (48) | 292 | 345 (340) |
| | Total | 769 (764) | 328 (314) | 1097 (1078) |
| | Summary | | Agreement: | 91.89% (93.51%) |

False Positive:	15.36%	(14.12%)
False Negative:	4.79%	(2.98%)

13

A summary of discrepant cases is in Table 10. The 5% significance level of McNemar's statistic is 3.84. Thus for those cases that disagree outside the 95% confidence limits, other than excessive false negative bands and excessive false positive metamyelocytes, discrepancies are balanced.

ID :

| Statistical
Significance | Disagreements by cell types Number
of
Cases | Number of
Combined
Abnormal False
Negative | Number of
Combined
Abnormal False
Positive | McNemar's
Statistic |
|--------------------------------------------------|-------------- | All
Disagreements | TOTAL | Within 95%
Confidence
Limits | PMN | | Lymphocyte | | Lymphocyte and PMN | | Monocyte | | Monocyte and Lymphocyte | | Eosinophil | | Basophil | | Basophil and Lymphocyte | | Band neutrophil | | Band | | Variant lymphocyte | | Metamyelocyte | | Metamyelocyte | | Metamyelocyte | | Myelocyte | | Myelocyte and Lymphocyte | | Myelocyte | | Promyelocyte | | Blast | | Blast | | Megakaryocyte | | Megakaryocyte, Variant lymphocyte | 1 | 1 | | Plasma cell | | TOTAL | Outside
95%
Confidence
Limits | PMN | 2 | | Lymphocyte | | Lymphocyte and PMN | | Monocyte | | Monocyte and PMN | | Monocyte and Lymphocyte | | Eosinophil | | Basophil | | Band neutrophil | | Band neutrophil and PMN | | Band | | Variant lymphocyte | | Variant | | Variant | | Variant | | Metamyelocyte | | Blast | | TOTAL | Total
---------------------------------------|--------------------------------|-----------------------------------------------------|-----------------------------------------------------|------------------------|
| 194 | 78 | 116 | 7.44 |
| 10 | 2 | 8 | 3.60 |
| 11 | 5 | 6 | 0.09 |
| 5 | 2 | 3 | 0.20 |
| 27 | 10 | 17 | 1.81 |
| 1 | 0 | 1 | 1.00 |
| 5 | 3 | 2 | 0.20 |
| 7 | 1 | 6 | 3.57 |
| 1 | 0 | 1 | 1.00 |
| 1 | 0 | 1 | 1.00 |
neutrophil and Basophil | 1 | 0 | 1 | 1.00 |
| 10 | 6 | 4 | 0.40 |
| 7 | 3 | 4 | 0.14 |
and Monocyte | 1 | 1 | 0 | 1.00 |
and Variant lymphocyte | 1 | 0 | 1 | 1.00 |
| 6 | 2 | 4 | 0.67 |
| 1 | 1 | 0 | 1.00 |
and Metamyelocyte | 1 | 1 | 0 | 1.00 |
| 1 | 1 | 0 | 1.00 |
| 2 | 0 | 2 | 2.00 |
and Variant lymphocyte | 1 | 0 | 1 | 1.00 |
| 3 | 1 | 2 | 0.33 |
Lymphocyte and
| 0 | 1.00 |
| 1 | 1 | 0 | 1.00 |
| 105 | 42 | 63 | 4.20 |
| 1 | 1 | 0.00 |
| 5 | 2 | 3 | 0.20 |
| 6 | 1 | 5 | 2.67 |
| 11 | 3 | 8 | 2.27 |
| 1 | 0 | 1 | 1.00 |
| 1 | 0 | 1 | 1.00 |
| 1 | 0 | 1 | 1.00 |
| 3 | 0 | 3 | 3.00 |
| 19 | 14 | 5 | 4.26 |
| 2 | 2 | 0 | 2.00 |
neutrophil and Lymphocyte | 2 | 1 | 1 | 0.00 |
| 20 | 9 | 11 | 0.20 |
lymphocyte and PMN | 2 | 1 | 1 | 0.00 |
lymphocyte and Monocyte | 1 | 0 | 1 | 1.00 |
lymphocyte and Band neutrophil | 2 | 1 | 1 | 0.00 |
| 10 | 1 | 9 | 6.40 |
| 1 | 0 | 1 | 1.00 |
| 89 | 36 | 53 | 3.25 |

Table 10 - Analysis of combined abnormality classifications crosstabulation

14

The comparison of normal and abormal cases prior to removing false positive and false negative cases that are
t the comparison in the more of the 11 within 95% confidence limits is shown in Table 11.

Table 11 - Crosstabulation of combined abnormality classifications

| | | Results of The White IRIS
(Test Method) | | |
|--------------------------------------------------------------------------------|---------------------------------------------------------------------|--------------------------------------------------------------------|----------------------|-------|
| | | Positive
(Distributional
and/or
Morphological
Abnormal | Negative
(Normal) | Total |
| Results
of
Wright-stain/
Light
Microscope
(Reference
Method) | Positive
(Distributional
and/or
Morphological
Abnormal) | 716 | 78 | 794 |
| | Negative
(Normal) | 116 | 292 | 408 |
| | Total | 832 | 370 | 1202 |

Summary	Agreement:	82.95%
	False Positive:	28.43%
	False Negative:	9.82%

15

Table 11 is based on a 4 x 4 crosstabulation of the four mutually -xclusive outcomes for each sample processed:

1. Normal
  יו
1. Distributionally abnormal
  102 - 12 - 2 Read Printer 2
1. Morphologically abnormal
1. Both distributionally and morphologically abnormal.

Table 12 - Crossfabulation of specimen classifications by Wright-stain versus those of The White IRIS™

Wright-stain classification	Normal	Distributionally abnormal	Morphologically abnormal	Both distributionally and morphologically abnormal	Row Sum
Normal	292	62	40	14	408
Distributionally abnormal	30	230	8	73	341
Morphologically abnormal	38	14	32	11	95
Both distributionally and morphologically abnormal	10	122	15	211	358

Table 12 summarizes classifications for both methods. Overall agreement in this table is 63.6%. Based on Cohen's kappa' of 0.49 for this table one can reject the entries in the table are purely random and there is no agreement between methods.

ID :

Cohen, J. 1960. A coefficient of agreement for nominal scales. Educational and Psychological Measurement, 20: 37-46.

16

Hazard Analysis.

Laboratory instrument results are generally used by the physician as an adjunct to clinical observations made in the course of establishing a diagnosis and in monitoring the course of disease progress, when appropriate thereafter. Therefore, The White IRIS leukocyte differential analyzer is unlikely to present the patient with a direct hazard. Also, as long as the instrument operator follows the recommended operating procedures in the Operators Manual this risk is minimized.

It is expected that anyone using this instrument is a qualified laboratorian who will follow universal precautions and other "Standard Laboratory Practices" in regards to working with laboratory instruments, reagents, consumables, and patient blood specimens in a safe and precautious manner. Also, the laboratorian is expected to be trained as a skilled competent observer familiar with and experienced in the interpretative qualities of leukocyte images.

The hazard analysis below is intended to identify the potential hardware and software failures that might cause inadvertent erroneous test results and lists the system checks in the design to safeguard against adverse consequences.

| Potential Hazard | Potential Causes | Software/Hardware
Responses |
|-------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Bar code reading failure
could cause results to be
reported to the wrong
patient. | Bar Code Reader failure.
Unreadable bar code label.
No bar code label. | Software checksum
analysis with operator
alerts. No detectable bar
code or bar code error -
no sample processing or
missing code flagging. |
| Sample wheel positioning
failure could cause wrong
sample to be aspirated and
results reported to the
wrong patient ID. | Motor failure.
Encoder failure. | Optical sensor coupled
with software detection
and operator alerts. |
| Insufficient sample
aspirated for analysis could
cause erroneous results. | Insufficient sample.
Sample probe clog.
No vacuum or pressure. | Optical and ultrasonic
sensors coupled with
software detection and
operator alerts. |
| Failure of red blood cells to
settle out leaving too many
rbc's could cause
erroneous results. | No IRISettlant reagent
present.
IRISettlant reagent no
good.
Settling tubes non
functional. | Optical sensor with
software detection and
operator alerts. |
| Insufficient leukocyte-rich
plasma preparation could
cause erroneous results. | Insufficient sample.
No settling of RBCs: | Optical and ultrasonic
sensors coupled with
software detection and
operator alerts. |

	Table 13 - List of Hazards, their Causes, and System Responses,

Potential Hazard	Potential Causes	Software/Hardware
Responses
Non staining or improper
staining of white blood cells
could cause erroneous
results.	No IRISpectracolor
reagent present.
IRISpectracolor no good.
Specimen too old.	Optical and software
detection with operator
alerts.
Total or partial interruption
of flow of white cells
through the White IRIS
flowcell could cause
erroneous results.	Flowcell partial or total
clog.
No vacuum or pressure.
Hardware failure.	Optical and software
detection with operator
alerts.
Failure of the ViewStation
sorting algorithms could
cause erroneous results.	Power outage with bad
reboot.
Spike in line voltage.
Software lockup.	Reportable results require
the optical review, edit
and approval of
competent operator.
Previous patient sample not
properly washed from
system (carryover) could
cause erroneous results.	No IRIScrub reagent
present.
No vacuum or pressure.
Hardware failure.	Optical and ultrasonic
sensors with software
detection and operator
alerts.
Image data transfer from
Flow Microscope Module to
View-Station corrupted
during transmission could
cause erroneous results.	Power outage with bad
reboot.
Spike in line voltage.
Software lockup.	Software detection using
checksums to validate
data packets.
Reportable results require
the optical review, edit
and approval of
competent operator.
Optical System failure could
cause erroneous or no
results to be reported.	Light source inoperable.
Strobe inoperable.
Camera inoperable.	Optical and software
detection with operator
alerts.
Editing errors by competent
operator could cause
erroneous results to be
reported.	Wrong tag used to classify
cells.
Accidental touch stroke.	Edit confirmation
summary to be verified by
competent operator prior
to reporting results.
Contact of the operator with
the cap piercing unit during
operation could cause injury
to the operator.	Removal of needle cover
during operation.	Hardware detection with
software operator alerts
and instrument shutdown.
Contact with high voltage
inside the instrument could
cause electrical shock to
operator.	Removal of protective
covering isolating high
voltages.
Excessive leakage current.	Warning labels on system
and warnings in operating
instructions.
Grounding per code and
all metal parts bonded to
ground system.

17

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