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Autonomous early detection of eye disease in childhood photographs

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Science Advances  02 Oct 2019:
Vol. 5, no. 10, eaax6363
DOI: 10.1126/sciadv.aax6363
  • Fig. 1 Examples of pathologic and physiologic leukocoria detected in childhood photographs by the prototype CRADLE application.

    (A) Pathologic leukocoria is caused by the reflection of light off abnormal ocular surfaces including aggregated γ-crystalline (cataract), cholesterol (Coats’ disease), tumor surfaces (retinoblastoma), or the abnormal reflection of light off the optic disc (refractive error, anisometropic amblyopia, or strabismus). (B to F) Examples of pathologic leukocoria in photographs of test children from this study who have been diagnosed with (B) hyperopia, (C) retinoblastoma, (D) Coats’ disease, (E) anisometropic amblyopia, and (F) cataract. (G) Child without an eye disorder exhibiting normal red reflex (right eye) and physiologic leukocoria (left eye) caused by reflection of light off the optic disc during off-axis photography (27). Insets designate leukocoric pupil positively detected by the prototype CRADLE application operating on iPhone X. Photo credit: With permission from the subjects’ legal guardian.

  • Fig. 2 Training the CRADLE prototype application to detect pathologic leukocoria in photographs of children with eye disease.

    (A) Representative arrays of leukocoric (top) and nonleukocoric (bottom) pupils used to train CRADLE to detect leukocoria. (B) Example of pathologic leukocoria detected by CRADLE in test child with retinoblastoma. (C) CRADLE detection of pathologic leukocoria caused by cataract (bottom right) and retinoblastoma (all other panels). Red box indicates positive leukocoria detection; green box indicates negative leukocoria detection. The insets in the upper right corner of each photograph shows a magnified view of the leukocoric pupil detected by CRADLE. Photo credit: With permission from the subjects’ legal guardian.

  • Fig. 3 Longitudinal frequency and detection of pathologic leukocoria in childhood photographs of 20 test children with an eye disorder.

    Plots 1 to 20 depict leukocoria occurrence among 23,248 photographs of 20 children from before to after diagnosis. Orange bars represent the total number of leukocoric photographs collected on a specific day; blue represents the fraction of those photographs detected by CRADLE. Blue dashed line denotes first detection of pathologic leukocoria by CRADLE; red dashed line denotes age of clinical diagnosis. Crop of first leukocoric pupil detected by CRADLE is shown (leukocoria was not detected by CRADLE for child 13). Rb, retinoblastoma; Cts, Coats’ disease; Cat, cataract; Ab, amblyopia; Hp hyperopia. L (left), R (right), and B (bilateral) indicate which eye was affected by each disorder (child 19 exhibited hyperopia in left eye and amblyopia in right eye). The duplicate analysis of these photographic libraries by CRADLE operating on iPhone 7 and Google Pixel 2XL smartphones can be found in figs. S7 and S8. Photo credit: With permission from the subjects’ legal guardian.

  • Fig. 4

    Probability of CRADLE prototype to (A) accurately or (B) falsely detect a single photograph with leukocoria as a function of number of photographs analyzed (based on ITP and IFP rates from analysis by CRADLE of 23,248 photographs of 20 children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia). (C and D) Comparison of average hue and value (top) and saturation and value (bottom) of cropped photographs of leukocoric pupils of children with retinoblastoma that were (C) detected and (D) undetected by CRADLE. *Ab is identical to Rb in ITP probability plot. IFP rate = 0 due to small sample size.

  • Table 1 Sensitivity, specificity, and accuracy of the prototype CRADLE application (iPhone X) at detecting pathologic leukocoria in childhood photographs.

    AgeSensitivity (TPR)Specificity (SPC)Accuracy (ACC)No. of
    diagnosed
    No./total no.*% (95% CI)No./total no.*% (95% CI)No./total no.*% (95% CI)
    ≤1 month3/1717.6 (0.0–35.8)10/1662.5 (38.8–86.2)13/3339.4 (22.7–56.1)3/20
    ≤2 months7/1741.2 (17.8–64.6)6/1637.5 (13.8–61.2)13/3339.4 (22.7–56.1)4/20
    ≤3 months10/1855.6 (32.6–78.5)7/1838.9 (16.4–61.4)17/3647.2 (30.9–63.5)6/20
    ≤6 months15/2075.0 (56.0–94.0)5/2025.0 (6.0–44.0)20/4050.0 (34.5–65.5)9/20
    ≤1 year18/2090.0 (76.9–100.0)4/2020.0 (2.5–37.5)22/4055.0 (39.6–70.4)14/20
    ≤1.5 years18/2090.0 (76.9–100.0)4/2020.0 (2.5–37.5)22/4055.0 (39.6–70.4)15/20
    ≤2 years18/2090.0 (76.9–100.0)4/2020.0 (2.5–37.5)22/4055.0 (39.6–70.4)20/20

    *Total number refers to the total number of children whose faces and open eye(s) were photographed in each age interval. The natural occurrence of physiological leukocoria in control children lowers specificity over time. Sensitivity is low in the first few months of life because certain disorders, such as unilateral retinoblastoma, Coats’ disease, and refractive error, are typically not present at birth, whereas bilateral retinoblastoma can be present at birth or develop in the first few months of life. Number of children diagnosed in each respective age period.

    • Table 2 Incidence and detection rate of leukocoria in photographs collected by parents of 20 test children and 20 healthy control children (iPhone X).

      N/A, not applicable.

      Unilateral retinoblastoma
      (n = 8)
      Bilateral retinoblastoma
      (n = 7)
      Coats’ disease, cataract,
      amblyopia, hyperopia
      (n = 5)
      Healthy control
      (n = 20)*
      Average age at diagnosis
      (days)
      4021141277N/A
      Average age of detection by
      CRADLE prototype (days)
      11775276N/A
      No. of photographs collected90657129705429,734
      No. of leukocoric photographs
      collected
      444927304144
      No. of leukocoric photographs
      detected
      by CRADLE
      1382897281
      No. of leukocoric photographs
      collected before diagnosis
      261293232N/A
      No. of leukocoric photographs
      detected by CRADLE before
      diagnosis
      748756N/A
      ITP rate31.08%31.18%23.68%56.25%
      IFP rate0.75%0.61%0.33%0.79%

      *Data listed for 20 control children without an eye disorder. Eight of 20 control children did not exhibit physiologic leukocoria during the time period of photography. Table S8 lists personalized values for each control child.

      †Sum of all facial photographs (with open eyes) collected from each patient from each respective category.

      ‡Rates of intrinsic true positive (TP) and FP leukocoria detection refer to the average true or false detection of leukocoria by CRADLE per photograph (see table S7 for personalized values for each test child).

      Supplementary Materials

      • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/10/eaax6363/DC1

        Supplementary Materials and Methods

        Supplementary Text

        Fig. S1. Free CRADLE/White Eye Detector application for iOS or Android.

        Fig. S2. Examples of pathologic leukocoria detection by CRADLE in photographs with low pupil resolution.

        Fig. S3. Comparison of photography angle and detection of pathologic leukocoria by CRADLE.

        Fig. S4. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the iPhone X smartphone.

        Fig. S5. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the iPhone 7 smartphone.

        Fig. S6. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the Google Pixel 2XL smartphone.

        Fig. S7. Longitudinal frequency and detection of pathologic leukocoria in childhood photographs of 20 test children with eye disease using the iPhone 7 smartphone.

        Fig. S8. Longitudinal frequency and detection of pathologic leukocoria in childhood photographs of 20 test children with eye disease using the Google Pixel 2XL smartphone.

        Fig. S9. Effect of image resolution on classification of leukocoric eye by CRADLE using the iPhone X smartphone.

        Fig. S10. Average HSV coordinates of leukocoric pupils from test and control children.

        Table S1. Personalized detection rates of pathologic leukocoria by CRADLE (iPhone 7) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.

        Table S2. Personalized detection rates of pathologic leukocoria by CRADLE (Google Pixel 2XL) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.

        Table S3. Personalized detection rates of physiologic leukocoria by CRADLE (iPhone 7) among photographic libraries of 20 control children.

        Table S4. Personalized detection rates of physiologic leukocoria by CRADLE (Google Pixel 2XL) among photographic libraries of 20 control children.

        Table S5. Sensitivity, specificity, and accuracy of CRADLE (iPhone 7) for detecting pathologic leukocoria in childhood photographs.

        Table S6. Sensitivity, specificity, and accuracy of CRADLE (Google Pixel 2XL) for detecting pathologic leukocoria in childhood photographs.

        Table S7. Personalized detection rates of pathologic leukocoria by CRADLE (iPhone X) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.

        Table S8. Personalized detection rates of physiologic leukocoria by CRADLE (iPhone X) among photographic libraries of 20 control children.

        Table S9. Example of a data sheet used to obtain intrinsic detection rates from test and control children.

        Table S10. Linear ranking matrix used to assign a single outcome to a photograph containing two pupils (based on the occurrence of the highest rank of order: ITP > IFN > IFP > ITN).

        Table S11. Camera make and model used to capture photographs of test and control children (extracted from metadata).

        References (5355)

      • Supplementary Materials

        This PDF file includes:

        • Supplementary Materials and Methods
        • Supplementary Text
        • Fig. S1. Free CRADLE/White Eye Detector application for iOS or Android.
        • Fig. S2. Examples of pathologic leukocoria detection by CRADLE in photographs with low pupil resolution.
        • Fig. S3. Comparison of photography angle and detection of pathologic leukocoria by CRADLE.
        • Fig. S4. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the iPhone X smartphone.
        • Fig. S5. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the iPhone 7 smartphone.
        • Fig. S6. Longitudinal frequency and detection of physiologic leukocoria among 29,734 photographs of 20 control children using the Google Pixel 2XL smartphone.
        • Fig. S7. Longitudinal frequency and detection of pathologic leukocoria in childhood photographs of 20 test children with eye disease using the iPhone 7 smartphone.
        • Fig. S8. Longitudinal frequency and detection of pathologic leukocoria in childhood photographs of 20 test children with eye disease using the Google Pixel 2XL smartphone.
        • Fig. S9. Effect of image resolution on classification of leukocoric eye by CRADLE using the iPhone X smartphone.
        • Fig. S10. Average HSV coordinates of leukocoric pupils from test and control children.
        • Table S1. Personalized detection rates of pathologic leukocoria by CRADLE (iPhone 7) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.
        • Table S2. Personalized detection rates of pathologic leukocoria by CRADLE (Google Pixel 2XL) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.
        • Table S3. Personalized detection rates of physiologic leukocoria by CRADLE (iPhone 7) among photographic libraries of 20 control children.
        • Table S4. Personalized detection rates of physiologic leukocoria by CRADLE (Google Pixel 2XL) among photographic libraries of 20 control children.
        • Table S5. Sensitivity, specificity, and accuracy of CRADLE (iPhone 7) for detecting pathologic leukocoria in childhood photographs.
        • Table S6. Sensitivity, specificity, and accuracy of CRADLE (Google Pixel 2XL) for detecting pathologic leukocoria in childhood photographs.
        • Table S7. Personalized detection rates of pathologic leukocoria by CRADLE (iPhone X) among 23,248 photographs of 20 test children with retinoblastoma, Coats’ disease, cataract, anisometropic amblyopia, and hyperopia.
        • Table S8. Personalized detection rates of physiologic leukocoria by CRADLE (iPhone X) among photographic libraries of 20 control children.
        • Table S9. Example of a data sheet used to obtain intrinsic detection rates from test and control children.
        • Table S10. Linear ranking matrix used to assign a single outcome to a photograph containing two pupils (based on the occurrence of the highest rank of order: ITP > IFN > IFP > ITN).
        • Table S11. Camera make and model used to capture photographs of test and control children (extracted from metadata).
        • References (5355)

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