(315 days)
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.
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.
Acceptance Criteria and Device Performance Study for The White IRIS
1. Table of Acceptance Criteria and Reported Device Performance
The provided documentation does not explicitly state formal acceptance criteria with numerical targets for each performance metric. However, the study aims to demonstrate substantial equivalence to the predicate method (Wright-stain/light microscope) in terms of accuracy, clinical sensitivity, and precision. The "acceptance criteria" are thus inferred from the comparisons made and the overall conclusion of "results equal to or better than the reference method."
| Performance Metric | Implied Acceptance Criterion (vs. Wright-Stain Reference) | The White IRIS Reported Performance |
|---|---|---|
| Accuracy | Correlation similar to or better than the reference; Slopes near 1, intercepts near 0 for leukocyte types. | - Correlations (r): Neutrophils (0.98), Lymphocytes (0.98), Monocytes (0.91), Eosinophils (0.98), Basophils (0.87), Segmented Neutrophils (0.93), Bands (0.54), Metamyelocytes (0.84), Myelocytes (0.74), Promyelocytes (0.97), Blasts (0.96), Normal Lymphocytes (0.98), Variant Lymphocytes (0.41). |
| - Overall Agreement (Abnormal Classification): 91.89% (93.51% after removing specific disagreement cases within 95% CI). (Table 9) - Agreement (Pre-removal of CI cases): 82.95% (Table 11) - Cohen's Kappa (4x4 Classification): 0.49 (rejects random agreement). (Table 12) | ||
| Precision | Standard deviations similar to or better than the reference method. | - SD compared to Wright-Stain (H20-A method): Generally lower or comparable SDs for most cell types (e.g., Neutrophils: 2.72 vs 3.55; Lymphocytes: 3.17 vs 3.68; Monocytes: 1.62 vs 2.29). - Within-run Precision (22 replicates): Neutrophils (± 5.0%), Lymphocytes (± 5.0%), Monocytes (± 2.5%), Eosinophils (± 1.5%), Basophils (± 1.0%) at 95% CI. (Table 6) |
| Clinical Sensitivity | Ability to correctly identify abnormal specimens (defined by H20-A criteria and reference ranges) with comparable or better performance than the reference method. | - The study evaluated 1202 specimens, including those required by H20-A for various abnormal conditions (e.g., Granulocytosis, Monocytosis, Eosinophilia, Lymphocytosis, Immature Cells). - False Negative Rate: 4.79% (2.98% after specific removals). (Table 9) - False Positive Rate: 15.36% (14.12% after specific removals). (Table 9) |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size:
- Accuracy: 1,202 normal and abnormal patient specimens (for correlation and overall agreement analysis).
- Precision (H20-A calculation): 1,014 specimens for The White IRIS; 1,277 specimens for Wright-stain.
- Precision (within-run): 22 replicates of the same sample.
- Clinical Sensitivity: 1,202 Leukocyte Differential Summaries (the same set as for accuracy).
- Data Provenance: Not explicitly stated regarding country of origin. The study is described as taking place in a clinical laboratory setting, comparing results to a standard reference method. It indicates a retrospective/cross-sectional design as it involves collecting specimens and analyzing them using both the new device and the predicate method for comparison.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- Number of Experts: Two skilled technologists.
- Qualifications: "Skilled technologists." The document also mentions "competent human observer... well skilled in both the use of the instrument and in the recognition of leukocyte classes." This implies trained medical laboratory professionals with expertise in manual leukocyte differential counting.
4. Adjudication Method for the Test Set
The primary reference method involves two skilled technologists reading manually prepared and observed Wright-stained smears. The analysis directly compares The White IRIS's results (reviewed by these same two technologists) against this "reference method."
While not explicitly stated as a formal "adjudication" in the sense of a third reader resolving discrepancies, the predicate method itself inherently relies on consensus or comparison between the two technologists' readings (implied when the "Wright-Stain Mean (%)" is presented). The study then compares the device's output, post human review, to this established reference.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- Was it done? Yes, in a limited sense. The study compares the performance of human readers (the two skilled technologists) when using The White IRIS (assisted interpretation) versus their performance using the traditional Wright-stain/light microscope method (unassisted interpretation).
- Effect Size (Improvement with AI vs. without AI assistance): The study reports on the "efficacy" of The White IRIS, highlighting that its use "provides results equal to or better than the reference method with less time expenditure and less biohazard exposure." However, it does not provide a quantifiable effect size specifically on how much human readers improve their accuracy or efficiency when using The White IRIS compared to their standalone performance. It mainly demonstrates equivalence or superiority of the combined system (IRIS + human review) to the manual method. For example, precision (SD) for most cell types is better with The White IRIS.
6. Standalone (Algorithm Only) Performance
- Was it done? No. The White IRIS explicitly requires a "skilled competent observer" to confirm or modify the classification of each cell. The device provides "presumptive" classifications, but human review is an integral part of its intended use. Therefore, a standalone algorithm-only performance assessment was not conducted, as it would not represent the intended clinical workflow.
7. Type of Ground Truth Used
- Expert Consensus / Reference Method: The ground truth for the test set was established by the Wright-stain/light microscope reference method, performed by two skilled technologists. This is a widely accepted, "Approved Standard" (NCCLS document H20-A) in hematology.
8. Sample Size for the Training Set
- The document does not specify a separate training set size. The reported studies (accuracy, precision, clinical sensitivity) are all described as evaluations of "The White IRIS" which implies the full, ready-for-use device. The technology involves "color image analysis" and classifies cells "presumptively," suggesting an underlying algorithm, but there's no mention of a distinct training phase or dataset with its own associated ground truth establishment.
9. How the Ground Truth for the Training Set Was Established
- As no separate training set is explicitly mentioned or analyzed in the provided text, information on how its ground truth was established is not available. The document focuses on the validation of the final device-with-human-in-the-loop system against the established predicate method.
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ID :
INTERNATIONAL REMOTE IMAGING SYSTEMS, INC.
9162 Eton Avenue Chatsworth, CA 91311 Phone 818-709-1244 818-700-9661 FAX
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.
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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:
-
- 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.
-
- 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.
-
- IRISpectracolor stain is not designed for discrimination of nuclear details in leukocytes.
-
- 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:
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ールした 고려
| Brief Discussion of Non-Clinical Factors supporting aDetermination of SubstantialEquivalence: | Involves a competent human observer to examinemicroscopic images as does the predicate methodand other similar predicate devices.See attached Substantial Equivalence comparisons. |
|---|---|
| Brief Discussion of ClinicalTests Supporting aDetermination of SubstantialEquivalence: | Conformance to National Committee for ClinicalLaboratory Standards Reference leukocyte differentialcount (proportional) and evaluation of instrumentalmethod: Approved Standard, NCCLS documentH20-A and other statistical comparisons to Wright-stain/light microscope reference method. |
| Conclusions Drawn fromClinical Tests: | Use of The White IRIS provides results equal to orbetter than the reference method with less timeexpenditure and less biohazard exposure. Seeattached Efficacy Demonstration. |
| Safety of Device: | See attached Hazard Analysis. |
:
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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) |
| SubstantialEquivalence | The White IRIS | Peripheral Blood Smear Stainedwith Wright Stain/LightMicroscope |
|---|---|---|
| Intended use is thesame, | Production of images of cellularcomponents of peripheral bloodpreparations to permit a skilled,competent observer tocharacterize these cells, enablingthe generation of a white blood celldifferential. | Production of images of cellularcomponents of peripheral bloodpreparations to permit a skilled,competent observer tocharacterize these cells, enablingthe generation of a white blood celldifferential. |
| Specimen analyzed isthe same. | Whole blood collected in bloodspecimen tube. | Whole blood collected in bloodspecimen tube. |
| Stain useddifferentially colorsdifferent cell types in asimilar way. | Leukocytes stained supravitally insuspension by 2-Methylpolymethine whichproduces unigue metachromasiasamong different types ofleukocytes. | Leukocytes stained after cellsdried and fixed on slide by Wright-stain (consisting of MethyleneBlue, Azures, and Eosin Y)produces the Romanowsky effect,differential coloration of cellcomponents. |
| Separation of WBCfrom RBC backgroundis similar. | Leukocytes separatedgravitationally from erythrocytes toallow mono-disperse presentationfor automatic randomizedselection. | Leukocytes separated byspreading in the feather edgeportion of blood smear to allowmanual search and selection fromamong monodispersed cells. |
| Mechanisms forpresenting individualWBC images tomicroscope objectiveare comparable. | Non-overlapping individual cells, inliquid suspension, in a flow cell areautomatically presented to andimaged by a microscope objective. | Non-overlapping individual cells,smeared and fixed on a glass slideare manually presented to andimaged by a microscope objective. |
| Optical means formagnifying images ofWBCs for observationand interpretation isthe same or similar. | A microscope images individualleukocytes on a camera sensorwhich produces a magnified videoimage for view and interpretation. | A microscope directly images andmagnifies individual leukocytes forview and interpretation through itsoculars. |
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Table 1 - continued (part 2 of 2).
| SubstantialEquivalence | The White IRIS | Peripheral Blood Smear Stainedwith Wright Stain/LightMicroscope |
|---|---|---|
| Viewing of images issimilar. | Individual cells are observed on avideo monitor in machine-orderedand counted groups of like sizeand color features. | Individual cells are observedthrough the oculars one-at-a-timewhile they are classified andcounted. |
| Overview scananalysis is similar andmore easilyaccomplished. | Scanning is accomplished at aglance of 500-cells organized ir amontage on a video monitor. | Scanning is accomplished bymoving the slide and manuallycharacterizing the kinds of cellsobserved. |
| Features used todistinguish among thevarious WBC types arethe same or similar. | Cytoplasm of different leukocytetypes stained characteristically. | Cytoplasm of different leukocytetypes stained characteristically. |
| While nucleus is not stained,nuclear shape may often bediscerned. | Nuclear stain and shape used todistinguish among differentleukocyte types. | |
| Size of nucleus (relative to cellsize) and cell size. | Size of nucleus (relative to cellsize) and cell size. | |
| Image interpretationrequirements are thesame. | Differentiation of cells requires askilled competent observer. | Differentiation of cells requires askilled competent observer. |
| Result format is thesame and quality isbetter. | The differential proportional countis based on 500-cells. | The differential proportional countis usually based on only 100-cells. |
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| Substantial | The White IRIS/Flow Microscope | Conventional Slide Microscope |
|---|---|---|
| Equivalence | ||
| Intended use is thesame. | To enable a skilled, competentobserver to examine, characterizeand differentiate WBCcompositions. | To enable a skilled, competentobserver to examine, characterizeand differentiate WBCcompositions. |
| Means for presentingspecimen to device isthe same principle. | Flow microscopy of leukocytesmonodispersed in suspension.(Used in conjunction with videocamera, and monitor). | Slide microscopy of leukocytesmonodispersed in dried, stainedperipheral blood smear. (In someinstances, cells may besuspended on the slide in a wetmount). |
| Microscopic imageinterpretationrequirements aresimilar. | Differentiation of cells requires askilled competent observer. | Differentiation of cells requires askilled competent observer. |
| Results rely oncounting individualcells and are based onthe same arithmeticand quality is better. | The differential proportional countis based on observing 500 cells. | The differential proportional countis usually based on observing only100 cells. |
Table 2 - Similarities and Differences between The White IRIS Flow Microscope and the Conventional Light Microscope.
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| Table 3 - Similarities and Differences between The White IRIS and the Generic Flow | |
|---|---|
| Microscope and The Yellow IRIS (part 1 of 2). |
| SubstantialEquivalence | The White IRIS for WBCDifferentiation | Flow Microscope/The YellowIRIS for UA and Body FluidBlood Cell Examination andCounting |
|---|---|---|
| Intended use isparallel. | Production of images of cellularcomponents of peripheral bloodpreparations to permit a skilled,competent observer tocharacterize and count these cells,enabling the generation of a whiteblood cell differential. | Production of images of formedelements in urine including bloodand other cells, and blood cells inother body fluids, to permit askilled, competent observer tocharacterize and count thesecomponents to compose a whitecell differential. |
| Stain used allowsmicroscopic objects tobe identified bydifferential coloration ina similar way. | Leukocytes stained with2-Methylpolymethine while insuspension. | Formed elements stained withIRIStain, containing primarilyCrystal Violet while in suspension. |
| Mechanisms forpresenting individualcell and other formedelement images tomicroscope objectiveare comparable. | Individual cells, in liquidsuspension, in a flow cell areautomatically selected and imagedby a microscope objective. | Individual cells and other formedelements, in liquid suspension, in aflow cell are automatically selectedand imaged by a microscopeobjective. |
| Presentation of imagesfor viewing are thesame. | Individual cells are presented or avideo monitor in machine-orderedand counted groups of like sizeand color features. | Individual cells and other formedelements are presented on a videomonitor in machine-ordered andcounted groups of like size andcolor features. |
| Features used todistinguish among thevarious leukocytetypes are the same orsimilar. | Cytoplasm of different leukocytetypes stained characteristically.While nucleus is not stained,nuclear shape may often bediscerned.Size of nucleus (relative to cellsize) and cell size | Cytoplasm of different cellsstained characteristically.Nuclear stain and shape used todistinguish among different celltypes.Size of nucleus (relative to cellsize) and cell size |
| SubstantialEquivalence | The White IRIS for WBCDifferentiation | Flow Microscope/The YellowIRIS for UA and Body FluidBlood Cell Examination andCounting |
| Presentation of imagesto skilled, competentobserver is the same | Leukocytes in flow cell are viewedthrough a microscope by a videocamera. Images are "captured"and electronically presented to askilled, competent observer forinterpretation on a video monitor | Analytes in flow cell are viewedthrough a microscope by a videocamera. Images are "captured"and electronically presented to askilled, competent observer forinterpretation on a video monitor. |
| Image montageorganization is similar. | Cells are sorted into ranks ofcomparable size and color. | Cells and other formed elementsare sorted into ranks ofcomparable size. |
| Results are observedand expressed in thesame way. | Scanning is accomplished at aglance of 500-cells organized in amontage on a video monitor. Thedifferential proportional count isbased on competent observeracknowledged and assignedclassification of 500 cell images. | Scanning is accomplished byobserving a sequences ofmontages on a video monitor.Counts are based on competentobserver assigned classification ofcell images. |
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Table 3 - continued (part 2 of 2).
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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:
-
- 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.
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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-StainMean (%) | 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 |
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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% ConfidenceLimits |
|---|---|---|
| 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 |
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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 LeukocyteDifferential Count Finding | Absolute Cell Count | Proportional CellCount | Number ofSpecimens |
| Granulocytosisand/orLeft 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 |
| Lymphocytosisand/orLymphocytes, Variant Forms | $\geq 3.5 \times 10^9/L$ | > 50% | 64 |
| $\ $ | $\geq 0.7 \times 10^9/L$ | 5 | |
| Granulocytopenia | $\leq 1.5 \times 10^9/L$ | < 10% | 11 |
| Lymphopenia | $\leq 1.0 \times 10^9/L$ | < 7% | 70 |
| Immature Cells, including Blasts | $\geq 0.1 \times 10^9/L$ | > 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 |
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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 &/orMorphologicalAbnormals) | Negative(Normal) | Total | ||
| Results ofWright-Stain/LightMicroscope(ReferenceMethod) | Positive(Distributional &/orMorphologicalAbnormal) | 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%) |
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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 :
| StatisticalSignificance | Disagreements by cell types | TotalNumberofCases | Number ofCombinedAbnormal FalseNegative | Number ofCombinedAbnormal FalsePositive | McNemar'sStatistic |
|---|---|---|---|---|---|
| AllDisagreements | TOTAL | 194 | 78 | 116 | 7.44 |
| Within 95%ConfidenceLimits | PMN | 10 | 2 | 8 | 3.60 |
| Lymphocyte | 11 | 5 | 6 | 0.09 | |
| Lymphocyte and PMN | 5 | 2 | 3 | 0.20 | |
| Monocyte | 27 | 10 | 17 | 1.81 | |
| Monocyte and Lymphocyte | 1 | 0 | 1 | 1.00 | |
| Eosinophil | 5 | 3 | 2 | 0.20 | |
| Basophil | 7 | 1 | 6 | 3.57 | |
| Basophil and Lymphocyte | 1 | 0 | 1 | 1.00 | |
| Band neutrophil | 1 | 0 | 1 | 1.00 | |
| Band neutrophil and Basophil | 1 | 0 | 1 | 1.00 | |
| Variant lymphocyte | 10 | 6 | 4 | 0.40 | |
| Metamyelocyte | 7 | 3 | 4 | 0.14 | |
| Metamyelocyte and Monocyte | 1 | 1 | 0 | 1.00 | |
| Metamyelocyte and Variant lymphocyte | 1 | 0 | 1 | 1.00 | |
| Myelocyte | 6 | 2 | 4 | 0.67 | |
| Myelocyte and Lymphocyte | 1 | 1 | 0 | 1.00 | |
| Myelocyte and Metamyelocyte | 1 | 1 | 0 | 1.00 | |
| Promyelocyte | 1 | 1 | 0 | 1.00 | |
| Blast | 2 | 0 | 2 | 2.00 | |
| Blast and Variant lymphocyte | 1 | 0 | 1 | 1.00 | |
| Megakaryocyte | 3 | 1 | 2 | 0.33 | |
| Megakaryocyte, Lymphocyte andVariant lymphocyte | 1 | 1 | 0 | 1.00 | |
| Plasma cell | 1 | 1 | 0 | 1.00 | |
| TOTAL | 105 | 42 | 63 | 4.20 | |
| Outside95%ConfidenceLimits | PMN | 2 | 1 | 1 | 0.00 |
| Lymphocyte | 5 | 2 | 3 | 0.20 | |
| Lymphocyte and PMN | 6 | 1 | 5 | 2.67 | |
| Monocyte | 11 | 3 | 8 | 2.27 | |
| Monocyte and PMN | 1 | 0 | 1 | 1.00 | |
| Monocyte and Lymphocyte | 1 | 0 | 1 | 1.00 | |
| Eosinophil | 1 | 0 | 1 | 1.00 | |
| Basophil | 3 | 0 | 3 | 3.00 | |
| Band neutrophil | 19 | 14 | 5 | 4.26 | |
| Band neutrophil and PMN | 2 | 2 | 0 | 2.00 | |
| Band neutrophil and Lymphocyte | 2 | 1 | 1 | 0.00 | |
| Variant lymphocyte | 20 | 9 | 11 | 0.20 | |
| Variant lymphocyte and PMN | 2 | 1 | 1 | 0.00 | |
| Variant lymphocyte and Monocyte | 1 | 0 | 1 | 1.00 | |
| Variant lymphocyte and Band neutrophil | 2 | 1 | 1 | 0.00 | |
| Metamyelocyte | 10 | 1 | 9 | 6.40 | |
| Blast | 1 | 0 | 1 | 1.00 | |
| TOTAL | 89 | 36 | 53 | 3.25 |
Table 10 - Analysis of combined abnormality classifications crosstabulation
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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(Distributionaland/orMorphologicalAbnormal | Negative(Normal) | Total | ||
| ResultsofWright-stain/LightMicroscope(ReferenceMethod) | Positive(Distributionaland/orMorphologicalAbnormal) | 716 | 78 | 794 |
| Negative(Normal) | 116 | 292 | 408 | |
| Total | 832 | 370 | 1202 |
| Summary | Agreement: | 82.95% |
|---|---|---|
| False Positive: | 28.43% | |
| False Negative: | 9.82% |
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Table 11 is based on a 4 x 4 crosstabulation of the four mutually -xclusive outcomes for each sample processed:
-
- Normal
יו
- Normal
-
- Distributionally abnormal
102 - 12 - 2 Read Printer 2
- Distributionally abnormal
-
- Morphologically abnormal
-
- 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.
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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/HardwareResponses |
|---|---|---|
| Bar code reading failurecould cause results to bereported to the wrongpatient. | Bar Code Reader failure.Unreadable bar code label.No bar code label. | Software checksumanalysis with operatoralerts. No detectable barcode or bar code error -no sample processing ormissing code flagging. |
| Sample wheel positioningfailure could cause wrongsample to be aspirated andresults reported to thewrong patient ID. | Motor failure.Encoder failure. | Optical sensor coupledwith software detectionand operator alerts. |
| Insufficient sampleaspirated for analysis couldcause erroneous results. | Insufficient sample.Sample probe clog.No vacuum or pressure. | Optical and ultrasonicsensors coupled withsoftware detection andoperator alerts. |
| Failure of red blood cells tosettle out leaving too manyrbc's could causeerroneous results. | No IRISettlant reagentpresent.IRISettlant reagent nogood.Settling tubes nonfunctional. | Optical sensor withsoftware detection andoperator alerts. |
| Insufficient leukocyte-richplasma preparation couldcause erroneous results. | Insufficient sample.No settling of RBCs: | Optical and ultrasonicsensors coupled withsoftware detection andoperator alerts. |
| Table 13 - List of Hazards, their Causes, and System Responses, | |||
|---|---|---|---|
| Potential Hazard | Potential Causes | Software/HardwareResponses | |
| Non staining or improperstaining of white blood cellscould cause erroneousresults. | No IRISpectracolorreagent present.IRISpectracolor no good.Specimen too old. | Optical and softwaredetection with operatoralerts. | |
| Total or partial interruptionof flow of white cellsthrough the White IRISflowcell could causeerroneous results. | Flowcell partial or totalclog.No vacuum or pressure.Hardware failure. | Optical and softwaredetection with operatoralerts. | |
| Failure of the ViewStationsorting algorithms couldcause erroneous results. | Power outage with badreboot.Spike in line voltage.Software lockup. | Reportable results requirethe optical review, editand approval ofcompetent operator. | |
| Previous patient sample notproperly washed fromsystem (carryover) couldcause erroneous results. | No IRIScrub reagentpresent.No vacuum or pressure.Hardware failure. | Optical and ultrasonicsensors with softwaredetection and operatoralerts. | |
| Image data transfer fromFlow Microscope Module toView-Station corruptedduring transmission couldcause erroneous results. | Power outage with badreboot.Spike in line voltage.Software lockup. | Software detection usingchecksums to validatedata packets.Reportable results requirethe optical review, editand approval ofcompetent operator. | |
| Optical System failure couldcause erroneous or noresults to be reported. | Light source inoperable.Strobe inoperable.Camera inoperable. | Optical and softwaredetection with operatoralerts. | |
| Editing errors by competentoperator could causeerroneous results to bereported. | Wrong tag used to classifycells.Accidental touch stroke. | Edit confirmationsummary to be verified bycompetent operator priorto reporting results. | |
| Contact of the operator withthe cap piercing unit duringoperation could cause injuryto the operator. | Removal of needle coverduring operation. | Hardware detection withsoftware operator alertsand instrument shutdown. | |
| Contact with high voltageinside the instrument couldcause electrical shock tooperator. | Removal of protectivecovering isolating highvoltages.Excessive leakage current. | Warning labels on systemand warnings in operatinginstructions.Grounding per code andall metal parts bonded toground system. |
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.
§ 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.”