1. Accuracy of transcutaneous bilirubin measurement NEMC Evidence Report Rebecca Flynn O’Brien, MD Division of General Pediatrics and Adolescent Medicine The Floating Hospital for Children Tufts-New England Medical Center

2. Terms TcB = Transcutaneous bilirubin TSB = Total serum bilirubin HPLC = High Performance Liquid Chromatography

3. Description of included studies 47 qualifying studies in 50 publications evaluated test performance and/or correlation of TcB to TSB –Minolta Airshields bilirubinometer (41 studies; 6,779 subjects) –BiliCheck (3 studies; 809 subjects) –Ingram Icterometer (4 studies; 245 subjects) –Colormate III (1 study; 900 subjects )

4. Minolta AirShields Bilirubinometer * Minolta Airshields Jaundice Meter TM (2002) Handheld, fiberoptic techniques to illuminate skin and subcutaneous tissue Spectrophotometric analysis of intensity of yellow color Requires development of correlation curves at each institution relating TcB index and TSB Daily calibration of instrument *Manufactured by Minolta/Hill-Rom Air-Shield, Hatbro, PA

5. Accuracy of Minolta AirShields Studied over 20 years, diverse populations 22 of 41 studies reported test performance, sensitivity, and specificity of TcB Threshold TcB index to predict threshold TSB Measurement sites: forehead, mid-sternum or mixed

6. Test Performance (Sensitivity/Specificity) Minolta AirShields Bilirubinometer Studies varied as to TSB threshold levels used Limits ability to combine data across studies (Evidence Report Table 3.21, p 76) META-ANALYSIS 3 studies reported test performance of TcB index to predict TSB > 11 (10-11.7) 11 studies reported test performance of TcB index to predict TSB > 13 (12.5-13) 3 studies reported test performance of TcB index to predict TSB > 15 (14.5-15.2)

7. Pooled Sensitivity and Specificity of Minolta AirShields predicting TSB > 11mg/dl 3 studies, 502 paired TcB and TSB measures at forehead Random Effects Model pooled estimates: Study, Yearn Threshold TcB index Sens (95% CI)Spec (95% CI) Knudsen, 199213890.75 (0.55-0.890.65 (0.56-0.74) Knudsen, 199020710.20.72 (0.61-0.80)0.81 (0.73-0.88) Maisels, 1982157200.91(0.70-0.98)0.90 (0.83-0.94) Overall5020.76 (0.64-0.85)0.80 (0.63-0.91)

8. Pooled sensitivity and specificity of Minolta AirShields predicting TSB>13 11 studies, 1560 paired TcB and TSB measures Cutoff TcB index ranged from 13-24 SROC curve shows heterogeneity across studies that is due to more than just a threshold effect Random Effects Model pooled estimates –Sensitivity 0.85 (0.77-0.91) –Specificity 0.77 (0.66-0.85)

9. SROC curve Minolta AirShields as Screening Tool for TSB>13

10. Pooled Sensitivity and Specificity Minolta AirShields predicting TSB>15 3 studies, 299 paired TcB and TSB forehead measures All 3 studies had sensitivity of 100% (SROC curve not appropriate, no threshold effect) Studyn Threshold TcB index Sens. (95% CI)Spec. (95% CI) Dai, 199640171.00 (0.63-1.00)0.66 (0.47-0.81) Sheridan-,198257201.00 (0.40-1.00)0.75 (0.61-0.86) Fok, 1986202221.00 (0.79-1.00)0.66 (0.58-0.72 Overall2990.95 (0.77-0.99)0.67 (0.61-0.73)

11. Meta-analysis of correlation coefficients for Minolta Airshields 38 of 41 studies linear regression analysis of Pearson’s correlation coefficient (r) TcB versus TSB r values ranged from 0.52 to 0.96 Pooled r = 0.84 (95% CI 0.81-0.87) Evidence Report Fig S3, p241

12. Limitations of meta-analysis of correlation coefficients Correlation coefficient does not provide information as to clinical utility of diagnostic test Correlation coefficient (r) is highly dependent on distribution of serum bilirubin Correlation measures ignore bias Measures relative rather than absolute agreement

13. Factors affecting test accuracy of Minolta AirShields Bilirubinometer Study designs varied as to study population All infants versus jaundiced infants Racial background Measurement site Age at measurement Type of assay for TSB reference “gold” standard Subgroup analysis was done in some studies

14. Factors affecting test accuracy of Minolta Airshield Bilirubinometer Higher correlation of TcB with TSB Sternum or forehead vs other sites Term vs. Near term White vs. Black No phototherapy vs. phototherapy

15. Measurement Sites-Minolta Airshields meta-analysis of correlation coefficients Body site (#studies) nPooled r 95% CI Forehead (12)1,9360.870.82-0.90 Sternum (11)1,8150.900.86-0.92 Abdomen (3)4770.850.73-0.92 Upper back (6)6120.840.77-0.90 Lower back (3)4770.820.59-0.92 Sole (3)4770.670.40-0.84 Palm (2)1410.610.27-0.82

16. Gestational age or birthweight Minolta AirShields Bilirubinometer 5 studies reported separate correlation coefficients Term (GA>37 wk or BW > 2500g) Near term infants (GA 34-37 wk or BW < 2500 g) No significant differences, trend lower in near term nPooled r 95% CI Term4250.810.75-0.86 Near Term3080.740.64-0.82

17. Race or skin color Minolta AirShields Bilirubinometer 6 studies compared correlation coefficients across race or skin color at forehead 3 studies at sternum site 2 studies in US found significant differences in White vs Black infants Other racial groups studied included Malay, Chinese, Indian No Hispanic subgroups were analyzed

18. Race or skin color at forehead meta-analysis Minolta AirShields Bilirubinometer Race (#studies)NPooled r 95% CI Black (3)2580.590.42-0.71 Chinese (3)3920.810.47-0.94 Indian (2)1500.750.49-0.88 Malay (3)3100.850.82-0.88 White (3)5640.750.48-0.89 Overall16740.760.68-0.83

19. Phototherapy Minolta Airshields 6 studies reported on effect of phototherapy All studies had lower correlation coefficients if had received phototherapy, significant in 2 studies Meta-analysis of correlation coefficient –No PhotoRx (n=870) r = 0.85 (0.79-0.89) –PhotoRx (n=213) r = 0.78 (0.72-0.83)

20. Ingram Icterometer Transparent Plexiglas with 5 painted transverse strips of precise and graded hue Used since 1925 Press Plexiglas against infant’s nose until skin blanches and color compared with yellow stripes and jaundice score applied Advantage is low cost

21. Test accuracy of Ingram Icterometer 4 studies reported correlation coefficient r of TcB to TSB Turkey (n=96) r=0.78 US Black (n=55)r=0.96 India (n=11)r=0.97 India (n=77)r=0.97 US White (n=106) r=0.63 Pooled correlation coefficient r=0.92 (95% CI 0.72-0.98)

22. Test Perfomance (Sensitivity/Specificity) Ingram Icterometer 3 of 4 studies reported test performance 2 studies reported TSB threshold > 12.9 mg/dl 1 study reported TSB threshold > 10 mg/dl StudyCountrynSens. (%) Spec. (%) Threshold Ict Threshold TSB Bilgen,1998Turkey9610048312.9 Schumacher,1985US1068274312.9 Gupta, 1991India779771310 Preterm115086310

23. Bilicheck TM* Handheld device uses in vivo multiwavelength spectral reflectance technique Allows for individual optical densities (ODs) attributed to bilirubin, Hg, melanin Theoretically improves TcB measurement by accounting for skin thickness, blood content and flow, maturity and pigmentation (Bhutani, Gourley, Adler et al, 2000) Fiberoptic probe on forehead with light source triggered after appropriate contact *SpectRX Inc., Norcross, GA

24. Accuracy of BilicheckTM Study, Year CountryRace (n)Reference Standard Bhutani, 2000 USMixed race (490) HPLC Lodha, 2000 IndiaIndian (109) Lab TSB* Rubaltelli, 2001 EuropeMixed Race (210) HPLC Twin beam Microbilimeter (Ginveri Technologie Biomediche )

25. Test Performance Bilicheck TM StudyrSens. (%) Spec. (%) Threshold TcB Threshold TSB Bhutani0.9110088> 75 th %ile> 95 th %ile Lodha0.8369 47 20 89 99 100 13 15 18 13 15 18 Rulbatelli0.87- 0.89 97-66 92-52 90-50 64-89 71-95 87-99 10-13 12-15 14-17 13 15 17

26. Accuracy of Bilicheck TM Bhutani, Gourley, Adler et al., 2000 n=1788 samples in 490 healthy term/near term infants predischarge 59% White; 29% Black; 3% Hispanic, 4% Asian 11 devices Correlation of TcB with HPLC TSB r=0.91

27. Accuracy of Bilicheck TM Bhutani VK, Gourley GR et al. Pediatrics 2000;106(2)

28. Error distribution: paired HPLC TSB and TcB Bhutani VK, Gourley GR et al. Pediatrics 2000; 106(2)

29. Accuracy of Bilicheck Rulbatelli, Gourley, Loskamp 2001 Multicenter, 6 European hospitals, n=35 each site Newborn infants undergoing TSB as part of care Multiple users TcB and multiple lab TSB methods compared to “gold standard” HPLC Single independent lab for HPLC TSB r=0.89 forehead and r=0.88 sternum TcB/HPLC Lab TSB/HPLC r=0.93

30. Accuracy of Bilicheck compared to Lab TSB HPLC TSB-BilicheckLab TSB-BilicheckHPLC TSB-Lab TSB Rulbatelli, Gourley, Loskam et al. Pediatrics 2001;107:1264-1271

31. Accuracy of Bilicheck-Error Plot HPLC TSB - Bilicheck Lab TSB -Bilicheck Lab TSB - HPLC TSB Rulbatelli, Gourley, Loskam et al. Pediatrics 2001;107:1264-1271

32. TcB or Lab TSB compared with HPLC TSB HPLC > 13 HPLC > 15HPLC > 17 Rulbatelli, Gourley, Loskam et al. Pediatrics 2001;107:1264-1271

33. Accuracy of Bilicheck Lodha R, Deorari AK, Jatan V et al. 2000 109 jaundiced term Indian infants (TSB>8) TSB by “twin beam” microbilimeter Correlation coefficient r=0.8 overall Subgroup (n= 46, TSB>13) r=0.64

34. Direct comparison accuracy Minolta Airshields vs Bilicheck Robertson, Kazmierczak, Vos, 2002 Compared the Jaundice Meter JM 102 (Minolta/Hill-ROM Air-Shields) to SpectRx Bilicheck TM n=101 jaundiced term infants not on phototherapy TcB by both methods compared to lab TSB Bilicheck performed superiorly r=0.937 Jaundice Meter r=0.704 Skin color was significant for Jaundice Meter

35. Bilicheck vs Minolta Airshields (JM Meter) Robertson 2002

36. Colormate III * Hand held colorimeter with Xenon flash tube and light sensors connected to portable computer Measures band of wavelengths from 400- 700 nm with filters to assess reflectance of specific wavelengths Data processed by computer to assess luminosity (lightness), redness and yellowness Baseline measure prior to jaundiced, measure 3 of 4 sites * Chromatics Color Sciences International, Inc., New York, NY

37. Accuracy of Colormate III N=1600 measurements in 900 infants 2441 infants enrolled at birth, 2 sites Term and Preterm TcB within 30 h birth and every 6-8 h 900 infants had TSB 72 B, 110 W, 615 H, 103 A Mean BW 3135 g –53 < 2000g –19 < 1500g Tayaba R et al, Pediatrics 1998; 102 (3)

38. Visual Inspection vs Chromatics III TcB N=1470 measures in 851 infants N=1600 measures in 900 infants

39. Chromatics III Phototherapy N=284 measures in 61 patients Tayaba et al, 1998

40. Conclusions/Limitations TCB measurements by all 3 devices have a linear correlation to TSB Correlation coefficient does not provide information as to clinical utility of diagnostic test, however many of the studies reported only correlation of TcB with TSB Correlation coefficient (r) is highly dependent on distribution of serum bilirubin All of the devices perform less well as screening tests at higher levels of bilirubin

41. Conclusions/Limitations Minolta Airshields bilirubinometer –Performs best at sternum or forehead site –Performs less well in Black vs White infants –As a screening test, it does not perform consistently across studies as evidenced by SROC Ingram icterometer –Small number of studies –Lacks objectivity of other methods as depends on observer visualization

42. Conclusions/Limitations Newer Bilicheck TM device that theoretically correct effects of melanin and hemoglobin appears to be an improvement over older devices Future research should confirm these findings in larger sample sizes of diverse populations and include effects of phototherapy