Comparing the accuracy of NEORUBIN NEO-2020 jaundice meter, Dräger JM103 jaundice meter and conventional blood testing for estimating total serum bilirubin in infants with jaundice in Malaysia

doi:10.21203/rs.3.rs-2111253/v1

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Research Article

Comparing the accuracy of NEORUBIN NEO-2020 jaundice meter, Dräger JM103 jaundice meter and conventional blood testing for estimating total serum bilirubin in infants with jaundice in Malaysia

https://doi.org/10.21203/rs.3.rs-2111253/v1

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Objective: To assess the accuracy of NEORUBIN® NEO-2020, a transcutaneous bilirubinometer in the clinical evaluation of bilirubin levels, versus a competitor device (Dräger JM103) and conventional blood testing (gold standard comparator) in infants diagnosed with jaundice in Malaysia.

Study design: Infants who were brought to a public primary care clinic for follow-up due to suspected jaundice were screened using Dräger JM103 to assess the level of total serum bilirubin (TsB). Newborn infants who were at least 1 day old and born after 35–44 weeks of gestation/pregnancy with a TsB between 6–13.4 mg/dL/day (103–229 μmol/L/day) at screening were included in the study. Bilirubin levels of the infants were measured using NEO-2020, Dräger JM103, and conventional blood testing and the readings compared to validate NEO-2020’s accuracy, robustness, and reliability in clinical settings against the competitor device and conventional blood testing.

Results: Compared to Dräger JM103, NEO-2020 showed a sensitivity of 99.4% (95% CI 96.9, 100), specificity of 0% (as all subjects in the study had jaundice symptoms), positive predictive value of 96.7% (95% CI 96.9, 96.7), and negative predictive value of 0%. The NEO-2020 had a 96.2% (95% CI 92.3, 98.5) accuracy rate in clinically evaluating bilirubin levels.

Conclusion(s): Serum bilirubin levels recorded by the non-invasive NEO-2020 bilirubinometer were comparable to the readings from Dräger JM103 and conventional blood testing. Further tweaking and tests may improve the accuracy of NEO-2020.

Administration

Cutaneous

Bilirubinometry

Hyperbilirubinemia

Jaundice

Neonatal

Neonatal Screening

Sensitivity and Specificity

Transcutaneous bilirubinometry

Prevention of neonatal hyperbilirubinemia requires rapid diagnosis and management. Diagnosis of this condition depends on the estimation of bilirubin levels in the blood. The current gold standard of estimating bilirubin levels is conventional laboratory blood analysis for total serum bilirubin (TsB) levels [1]. However, this method comes with major discomfort and pain for the infants as blood sampling is often done by heel prick. This invasive approach also has potential long-term consequences as many infants are small in size and may have underlying blood-related conditions reducing the amount of blood in them. Neonatal hyperbilirubinemia can also be diagnosed through visual estimation, but this is not reliable to assess the actual condition of the patient [2]. Therefore, non-invasive methods such as transcutaneous bilirubinometry that is both painless and accurate can be beneficial.

Transcutaneous bilirubinometry provides a non-invasive indication of serum bilirubin levels through the assessment of yellow coloration of the skin. Transcutaneous bilirubinometer was developed in the early 80s [3, 4], and has gone through many changes improving the accuracy and reliability of the device. There is extensive evidence on transcutaneous bilirubin measurements as a reliable screening tool to assess TsB [5–8].

The current study aimed to assess the accuracy of NEORUBIN® NEO-2020, a transcutaneous bilirubinometer for clinical evaluation of bilirubin levels versus a competitor device (Dräger JM103) and conventional blood testing. There have been no previous studies on NEO-2020’s safety and efficacy.

Study design

In this prospective study, NEO-2020 (the test device) was compared to Dräger JM103 (competitor device) and conventional blood testing (gold standard comparator). Both NEO-2020 and Dräger JM103 are a non-invasive approach for measuring TsB (or transcutaneous bilirubin (TcB)) while conventional blood testing involved capillary blood sampling or heel prick. The study was conducted in a single center (Klinik Kesihatan Pandaraman, Klang), which is a public primary care clinic.

Bilirubin levels of the infants were measured using NEO-2020, Dräger JM103, and conventional blood testing and the readings compared to validate NEO-2020’s accuracy, robustness, and reliability in clinical settings against the competitor device and gold standard comparator.

Study population

Newborn infants who were at least 1 day old and born after 35–44 weeks of gestation/pregnancy with a TsB between 6–13.4 mg/dL/day (103–229 µmol/L/day) at screening were included in the study. Infants with TsB of greater than 13.4 mg/dL/day (229 µmol/L/day) at screening, hydrops fetalis, major congenital malformations, diseases or skin conditions that investigators considered would preclude or interfere with the use of the NEO-2020 were excluded from the study.

Sampling and measurements

Infants who were brought to the clinic for follow-up due to suspected jaundice were screened using the comparator device to assess the level of TsB. If the level fell in the range required for study entry, the parents/legal guardian of the infant were informed of the study. Eligible infants were only enrolled into the study after written informed consent was obtained from the parents/guardian.

As infants have limited blood volume, blood sample for the study was taken when the enrolled subject was already scheduled for blood collection during a regular clinic visit. No blood collection was scheduled specifically for study purposes.

To prevent discomfort, readings from the test device and comparator device were taken first and recorded before blood sample collection. Readings for both devices were taken from the forehead of the infant and by the same staff. Readings from the devices were taken within 5 minutes before the scheduled heel prick to avoid variation. Each set of readings were taken at a unique time and considered as a complete sample. Subjects could provide multiple set of samples as TsB and TcB levels of the same subject may vary at different periods. If there was a lag time of more than 15 minutes between the readings and blood sample collection, the sample was discarded and another set of readings obtained and recorded. This was to prevent change in bilirubin levels between TcB and TsB measurements. The readings from the devices were measured in mg/dL.

Each sample consisted of three readings from NEO-2020 and one reading from the Dräger JM103 and one blood sample within 2–5 seconds to account for any random differences. After three readings were taken using the NEO-2020 device, one final result (based on the device’s proprietary algorithm prediction on bilirubin level) was produced by the NEO-2020 printer.

Statistical analysis

The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy with 95% CI were generated comparing NEO-2020 with Dräger JM103 and conventional blood testing. The accuracy of serum bilirubin values measured were described in mean, standard deviation, and median.

Of the 183 infants included in the study, half were males (54.6%) and majority were Malays (74.3%), the dominant ethnic group in Malaysia (Table 1). Mean body weight was 2.96 kg (SD 0.39). Almost all patients had normal body temperature. Most of the infants were breast fed (98%) with 68% being exclusively breast fed (Table 1).

Table 1

Health and socio-demographic characteristics of study participants
TOTAL	183
Gender, N (%) Male Female	100 (54.6) 83 (45.4)
Race, N (%) Malay Chinese Indian Others^‡	136 (74.3) 25 (13.7) 7 (3.8) 15 (8.2)
Mean body weight, kg	2.96 (0.39)
Mean body temperature, ^OC (SD)	36.6 (0.37)
Body temperature range, N (%) Normal Abnormal	182 (99.5) 1 (0.5)
Infant feeding status, N (%) Exclusively breastfed Formula milk Breastfed & formula milk	125 (68.3) 4 (2.2) 54 (29.5)
SD, standard deviation
^‡Bajau, Bidayuh, Bugis, Iban, Kadazan, Murut, Rungus, Suluk and non-Malaysians from Indonesia, Myanmar, Pakistan, and Vietnam

Mean serum bilirubin levels for all infants were comparable with 10.8 mg/dL (SD 2.2) for NEO-2020 versus 9.9 mg/dL (SD 2.2) for Dräger JM103 and 11.1 mg/dL (SD 2.7) for conventional blood testing (Table 2). The rate of positive test results were similar (99.4% for NEO-2020; 96.7% for Dräger JM103 and 96.7% for conventional blood test) (Table 2).

Table 2

Total serum bilirubin levels of study participants measured using NEO-2020, Dräger JM103, and conventional blood testing (n = 183)
TSB concentration	NEO-2020	Dräger JM103	Blood TSB concentration
TSB levels in mg/dL Minimum Maximum Mean Standard deviation	5.1 17.4 10.8 2.2	4.1 15.2 9.9 2.2	4.0 20.6 11.1 2.7
Positive results, N (%)	182 (99.4)	177 (96.7)	177 (96.7)
TSB, total serum bilirubin
*The inclusion criteria of the study was serum bilirubin < 13.5 mg/dL. Some infants had jaundice symptoms at screening (which explained the higher serum bilirubin) but was confirmed negative based on TSB levels.

Compared to conventional blood testing, NEO-2020 showed a sensitivity of 99.4% and PPV of 97.0% (Table 3). As all subjects in the study had jaundice symptoms, the specificity and NPV of the device were 0% (Table 3). The NEO-2020 had an estimated accuracy of 96.2% (95% CI 92.3, 98.5), similar to that of the Dräger JM103 device (94.0% [95% CI 90.2, 97.4]) (Table 3).

Table 3

Sensitivity, specificity, positive predictive values, and negative predictive values for TSB concentration for NEO-2020 and Dräger JM103 versus blood TSB concentration (n = 183)
	Blood TSB concentration (Gold standard)
	Positive	Negative	Total
NEO-2020 TSB concentration
Positive	176	6	182
Negative	1	0	1
Total	177	6
Sensitivity (95% CI)	99.4% (96.9, 100.0)
Specificity (95% CI)	0% (0.0, 45.9)
PPV (95% CI)	96.7% (96.6, 96.7)
NPV (95% CI)	0% (NA)
Accuracy (95% CI)	96.2% (92.3, 98.5)
Dräger JM103 TSB concentration
Positive	172	5	177
Negative	5	1	6
Total	177	6
Sensitivity (95% CI)	97.2% (93.5, 99.1)
Specificity (95% CI)	16.7% (0.42, 64.1)
PPV (95% CI)	97.2% (96.0, 98.0)
NPV (95% CI)	16.7% (2.7, 59.3)
Accuracy (95% CI)	94.0% (90.2, 97.4)
NPV, negative predictive value; PPV, positive predictive value; TSB, total serum bilirubin

Compared to Dräger JM103, NEO-2020 showed a sensitivity of 99.4% and PPV of 96.7% (Table 4). As indicated earlier, the specificity and NPV were 0% (Table 4). The accuracy rate for NEO-2020 versus Dräger JM103 was 96.2% (95% CI 92.3, 98.5),

Table 4

Sensitivity, specificity, positive predictive values, and negative predictive values for TSB concentration for NEO-2020 versus Dräger JM103 (n = 183)
	Dräger JM103 TSB concentration
	Positive	Negative	Total
NEO-2020 TSB concentration
Positive	176	6	182
Negative	1*	0	1
Total	177	6
Sensitivity (95% CI)	99.4% (96.9, 100.0)
Specificity (95% CI)	0% (0.0, 45.9)
PPV (95% CI)	96.7% (96.6, 96.7)
NPV (95% CI)	0% (NA)
Accuracy (95% CI)	96.2% (92.3, 98.5)
NPV, negative predictive value; PPV, positive predictive value; TSB, total serum bilirubin
*Infant had jaundice symptoms at screening but was confirmed negative based on TSB levels.

Of the 183 patients in the study, 24 were Chinese or Vietnamese who usually have lighter color skin. The average accuracy of NEORUBIN® was 80%. The average accuracies of NEORUBIN® were 82% in infants with medium skin colors (Malay, Bajau, Bidayuh, Bugis, Iban, Kadazan, Murut, Suluk, Indonesian, Myanmarese) and 80% in darker skin infants (Indian and Pakistani).

One mild severe serious adverse event (high serum bilirubin level despite phototherapy) was reported. It was suspected to be Erb-Duchenne Palsy and concluded as not related to the NEO-2020 device. The affected infant was hospitalized but subsequently recovered.

This prospective study showed that the accuracy of NEORUBIN® NEO-2020 for the clinical evaluation of bilirubin levels in infants was comparable to a competitor transcutaneous bilirubinometer (Dräger JM103) and conventional blood testing. The NEO-2020 had sensitivity of 99.4% and PPV of 96.7% versus Dräger JM103 and sensitivity of 99.4% and PPV of 97.0% versus conventional blood testing. The high accuracy of the device in measuring bilirubin levels in infants with jaundice symptoms were regardless of gestational or postnatal age, sex, Asian ethnicity, and feeding behavior. These results were also in line with other high-performing transcutaneous bilirubinometers as demonstrated in other studies [9, 10].

The key strengths of this study were its prospective study design and being the first study to assess NEO-2020’s efficacy and safety. And despite being a single site study, the 183 participants were of different ethnicities, with a good representation of the ethnic groups in Malaysia and included ethnicities from Indonesia, Myanmar, Pakistan and Vietnam. Another advantage is the use of the same staff to take the measurements from both devices and a single measurement site (forehead), which prevented any user-induced variations in the readings.

There are concerns that skin color may affect the accuracy of a non-invasive jaundice meter (TcB) in predicting bilirubin levels [9–13]. One study involving the jaundice meter JM 103 showed that the TcB was underestimating the TSB for infants with light or medium skin color while overestimating the TSB for the darker skin infants [13]. In our study, however, NEORUBIN® demonstrated high and consistent accuracy rates (in the range of 80%) in estimating bilirubin level in infant’s skin despite different skin colors (average accuracy of 82%). Therefore, NEORUBIN® is a reliable tool to assess transcutaneous bilirubin regardless of skin color and ideal for use in multiethnic populations.

The study had several limitations. As all infants in this study had serum bilirubin < 13.5 mg/dL, the results are only applicable to similar infants who appear well and are not severely jaundiced. The accuracy of NEO-2020 was not explored in infants with higher serum bilirubin levels, which is necessary for the proper management of infants who require intensive phototherapy or are potential candidates for total exchange transfusion.

In conclusion, serum bilirubin levels of up 13.5 mg/dL can be detected with the non-invasive NEO-2020 bilirubinometer with sensitivity of 99.4%, PPV of 96.7% and accuracy of 96.2% over the forehead in infants with jaundice symptoms. These results were comparable to the readings from another non-invasive bilirubinometer (Dräger JM103) as well as conventional blood testing. In addition, the consistent and high accuracy rates in different skin colors make NEO-2020 bilirubinometer suitable for use in multiethnic populations. Further improvements to the device’s algorithm and testing

may lead to better results.

and acronyms

NPV

Negative predictive value

PPV

Positive predictive value

TcB

Transcutaneous bilirubin

TsB

Total serum bilirubin

Conflict of interest

Abdul Rahman B and Muhammad Khairil Z were employees of Recove Group Sdn Bhd which sponsored the study and invented the technology. Ruziaton H, Noor Harzana H, and Faridah AB received remunerations from Recove Group Sdn Bhd through the Clinical Research Malaysia.

Funding

The study was sponsored by the Malaysian Technology Development Corporation Sdn Bhd through the Commercialization, Research and Development Fund.

Author Contributions

Ruziaton H (principal investigator), Noor Harzana H (sub-investigator), and Faridah AB (sub-investigator) carried out the study. Abdul Rahman B and Muhammad Khairil Z were involved in developing the technology for NEORUBIN®. Ruziaton H took the lead in writing the manuscript. All authors provided critical feedback as well as read and approved the final manuscript.

Acknowledgments

The authors thank the Director General Ministry Of Health Malaysia, Selangor State Health Director, and Klang Health District Officer for their approval for the study to be conducted in Klinik Kesihatan Pandamaran. The authors also thank the Ministry of Science, Technology and Innovation Malaysia as well as the Malaysian Technology Development Corporation Sdn Bhd for financial support under the Commercialization, Research and Development Fund.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki and in agreement with the International Conference on Harmonization guidelines on Good Clinical Practice. Approval was granted by the Ministry of Health’s Medical Research Ethics Committee (23 October 2018/NMRR-18-1806-42638) and the Medical Device Authority for the investigational use medical device (16 November: MDA/IU/2018/142, 19 June 2019 MDA/IU/2019/074 & 21 Jan 2020 MDA/IU/2020/011).

Informed consent

Written informed consent was obtained from the parents or legal guardians of the infants included in the study.

Data statement

The readings from the devices and total serum bilirubin results for the study participants are available on a restricted cloud-based database on request from the authors.

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Competing interest reported. Funding: Research grants Funder: Malaysian Technology Development Corporation Sdn Bhd Research Grant Name: Commercialization, Research and Development Fund

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Comparing the accuracy of NEORUBIN NEO-2020 jaundice meter, Dräger JM103 jaundice meter and conventional blood testing for estimating total serum bilirubin in infants with jaundice in Malaysia

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Abstract

Introduction

Materials And Methods

Study design

Study population

Sampling and measurements

Statistical analysis

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

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