Accuracy of transcutaneous bilirubin measurement

NEMC Evidence Report

Rebecca Flynn O’Brien, MDDivision of General Pediatrics and Adolescent Medicine

The Floating Hospital for Children

Tufts-New England Medical Center

Terms• TcB = Transcutaneous bilirubin

• TSB = Total serum bilirubin

• HPLC = High Performance Liquid Chromatography

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 )

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

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

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)

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, Year n Threshold TcB index

Sens (95% CI) Spec (95% CI)

Knudsen, 1992 138 9 0.75 (0.55-0.89 0.65 (0.56-0.74)

Knudsen, 1990 207 10.2 0.72 (0.61-0.80) 0.81 (0.73-0.88)

Maisels, 1982 157 20 0.91(0.70-0.98) 0.90 (0.83-0.94)

Overall 502 0.76 (0.64-0.85) 0.80 (0.63-0.91)

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)

SROC curve Minolta AirShields asScreening Tool for TSB>13

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)

Study n Threshold

TcB indexSens. (95% CI) Spec. (95% CI)

Dai, 1996 40 17 1.00 (0.63-1.00) 0.66 (0.47-0.81)

Sheridan-,1982 57 20 1.00 (0.40-1.00) 0.75 (0.61-0.86)

Fok, 1986 202 22 1.00 (0.79-1.00) 0.66 (0.58-0.72

Overall 299 0.95 (0.77-0.99) 0.67 (0.61-0.73)

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

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

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

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

Measurement Sites-Minolta Airshieldsmeta-analysis of correlation coefficients

Body site (#studies)

n Pooled

r

95% CI

Forehead (12) 1,936 0.87 0.82-0.90

Sternum (11) 1,815 0.90 0.86-0.92

Abdomen (3) 477 0.85 0.73-0.92

Upper back (6) 612 0.84 0.77-0.90

Lower back (3) 477 0.82 0.59-0.92

Sole (3) 477 0.67 0.40-0.84

Palm (2) 141 0.61 0.27-0.82

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

n Pooled

r

95% CI

Term 425 0.81 0.75-0.86

Near Term 308 0.74 0.64-0.82

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

Race or skin color at forehead meta-analysis Minolta AirShields Bilirubinometer

Race (#studies) N Pooled

r

95% CI

Black (3) 258 0.59 0.42-0.71

Chinese (3) 392 0.81 0.47-0.94

Indian (2) 150 0.75 0.49-0.88

Malay (3) 310 0.85 0.82-0.88

White (3) 564 0.75 0.48-0.89

Overall 1674 0.76 0.68-0.83

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)

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

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)

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

Study Country n Sens. (%)

Spec. (%)

Threshold Ict

Threshold TSB

Bilgen,1998 Turkey 96 100 48 3 12.9

Schumacher,1985 US 106 82 74 3 12.9

Gupta, 1991 India 77 97 71 3 10

Preterm 11 50 86 3 10

BilicheckTM*

• 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

Accuracy of BilicheckTMStudy, Year

Country Race (n) Reference Standard

Bhutani, 2000

US Mixed race (490)

HPLC

Lodha, 2000

India Indian (109)

Lab TSB*

Rubaltelli, 2001

Europe Mixed Race (210)

HPLC

Twin beam Microbilimeter (Ginveri Technologie Biomediche)

Test Performance BilicheckTM

Study r Sens. (%)

Spec. (%)

Threshold TcB

Threshold TSB

Bhutani 0.91 100 88 > 75th %ile > 95th %ile

Lodha 0.83 69

47

20

89

99

100

13

15

18

13

15

18

Rulbatelli 0.87-0.89

97-66

92-52

90-50

64-89

71-95

87-99

10-13

12-15

14-17

13

15

17

Accuracy of BilicheckTM

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

Accuracy of BilicheckTM

Bhutani VK, Gourley GR et al. Pediatrics 2000;106(2)

Error distribution: paired HPLC TSB and TcB

Bhutani VK, Gourley GR et al. Pediatrics 2000; 106(2)

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

Accuracy of Bilicheck compared to Lab TSB

HPLC TSB-Bilicheck Lab TSB-Bilicheck HPLC TSB-Lab TSB

Rulbatelli, Gourley, Loskam et al. Pediatrics 2001;107:1264-1271

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

TcB or Lab TSB compared with HPLC TSB

HPLC > 13 HPLC > 15 HPLC > 17

Rulbatelli, Gourley, Loskam et al. Pediatrics 2001;107:1264-1271

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

Direct comparison accuracyMinolta Airshields vs Bilicheck• Robertson, Kazmierczak, Vos, 2002• Compared the Jaundice Meter JM 102

(Minolta/Hill-ROM Air-Shields) to SpectRx BilicheckTM

• 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

Bilicheck vs Minolta Airshields (JM Meter)

Robertson 2002

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

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)

Visual Inspection vs Chromatics III TcB

N=1470 measures in 851 infants N=1600 measures in 900 infants

Chromatics III PhototherapyN=284 measures in 61 patients

Tayaba et al, 1998

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

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

Conclusions/Limitations

• Newer BilicheckTM 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