Hong Kong Med J 2018 Jun;24(3):226–37 | Epub 4 Jun 2018
DOI: 10.12809/hkmj176939
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong
Chloe M Mak, MD, FHKAM (Pathology)1; Eric CY Law, PhD, FHKAM (Pathology)2,3; Hencher HC Lee, MA, FRCPA1; WK Siu, PhD, FHKAM (Pathology)1; KM Chow, FRCOG, FHKAM (Obstetrics and Gynaecology)4; Sidney KC Au Yeung, FRCOG, FHKAM (Obstetrics and Gynaecology)5; Hextan YS Ngan, FRCOG, FHKAM (Obstetrics and Gynaecology)6; Niko KC Tse, FHKCPaed, FHKAM (Paediatrics)7; NS Kwong, FHKCPaed, FHKAM (Paediatrics)8; Godfrey CF Chan, FHKCPaed, FHKAM (Paediatrics)9; KW Lee, FRCOG, FHKAM (Obstetrics and Gynaecology)4; WP Chan, MB, ChB, FHKAM (Obstetrics and Gynaecology)4; SF Wong, FRCOG, FHKAM (Obstetrics and Gynaecology)5; Mary HY Tang, FRCOG, FHKAM (Obstetrics and Gynaecology)6; Anita SY Kan, MRCOG, FHKAM (Obstetrics and Gynaecology)6; Amelia PW Hui, FRCOG, FHKAM (Obstetrics and Gynaecology)6; PL So, FRCOG, FHKAM (Obstetrics and Gynaecology)5; CC Shek, FHKCPaed, FHKAM (Paediatrics)7; Robert SY Lee, FHKCPaed, FHKAM (Paediatrics)7; KY Wong, FHKCPaed, FHKAM (Paediatrics)9; Eric KC Yau, FHKCPaed, FHKAM (Paediatrics)7; KH Poon, MRCP(UK), FHKCPaed8; Sylvia Siu, MB, ChB, FHKAM (Paediatrics)8; Grace WK Poon, FHKCPaed, FHKAM (Paediatrics)9; Anne MK Kwok, FHKCPaed, FHKAM (Paediatrics)9; Judy WY Ng, BAppSc(Nurs), MSSc (Counselling)4; Vera CS Yim, FHKAN (HKCMW), MSC5; Grace GY Ma, BSN, MHSM (Health Services Management)6; CH Chu, MS10; TY Tong, MSc1; YK Chong, FHKCPath, FHKAM (Pathology)1; Sammy PL Chen, FRCPA, FHKAM (Pathology)1; CK Ching, FRCPA, FHKAM (Pathology)1; Angel OK Chan, MD, FHKAM (Pathology)3; Sidney Tam, FRCP, FHKAM (Pathology)4; Ruth LK Lau, MB, ChB, FHKAM (Pathology)11; WF Ng, MB, ChB, FHKAM (Pathology)11; KC Lee, MB, ChB, FHKAM (Pathology)1; Albert YW Chan, MD, FHKAM (Pathology)1; CW Lam, PhD, FHKAM (Pathology)2
1 Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Kwai Chung, Hong Kong
2 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
3 Division of Clinical Biochemistry, Queen Mary Hospital, Pokfulam, Hong Kong
4 Department of Obstetrics and Gynaecology, Princess Margaret Hospital, Kwai Chung, Hong Kong
5 Department of Obstetrics and Gynaecology, Tuen Mun Hospital, Tuen Mun, Hong Kong
6 Department of Obstetrics and Gynaecology, Queen Mary Hospital, Pokfulam, Hong Kong
7 Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Kwai Chung, Hong Kong
8 Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong
9 Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Pokfulam, Hong Kong
10 Department of Pathology, United Christian Hospital, Kwun Tong, Hong Kong
11 Department of Pathology, Yan Chai Hospital, Tsuen Wan, Hong Kong
Corresponding author: Dr CW Lam (ching-wanlam@pathology.hku.hk)
 Full paper in PDF
Introduction: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners’ report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM.
Methods: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling.
Results: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years.
Conclusion: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.
New knowledge added by this study
  • The feasibility of the OPathPaed service model was evaluated in 2440 neonates. The main focus was on parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall, and counselling.
  • Of 210 health care professionals who responded to a survey, 73.6% were unaware of newborn screening for inborn errors of metabolism (IEM), 87.6% urged for more education, and 91.3% supported implementing expanded newborn screening for IEM immediately or within 3 years.
Implications for clinical practice or policy
  • The OPathPaed service model for implementing expanded newborn screening for IEM is feasible for local public hospital settings.
  • Health care professionals support implementation of newborn screening for IEM. In addition, there is a substantial need of more education.
The expansion of newborn screening (NBS) for various genetic disorders with a focus on inborn errors of metabolism (IEM) has become a mandatory part of health care policy worldwide. Multiplex testing by tandem mass spectrometry has extended the scope of NBS far beyond the traditional ‘one test for one disease’ paradigm, requiring only a tiny blood sample, obtained by a simple heel prick.1 2 As a result, many inherited diseases are now screened for to allow early diagnosis and intervention and thereby prevent permanent damage or potential deaths.
Inborn errors of metabolism are a group of rare metabolic diseases with heterogeneous clinical presentations and genetic aetiologies. They are individually rare but collectively common. In 2011, Lee et al3 reported a 5-year retrospective review on the laboratory diagnosis of amino acid disorders, organic acidurias, and fatty acid beta-oxidation defects in three regional hospitals. The overall local incidence of classical IEM was 1 in 4122 live births.3 No phenylketonuria was identified through the screening of 18 000 newborns in the early 1970s.4 Hyperphenylalaninaemia was the second most common amino acid disorder reported by Lee et al,3 with an incidence of 1 in 29 542 live births. Another study by Hui et al5 reported the overall incidence of common IEM as 1 in 5400. According to the Hong Kong Paediatric Metabolic Registry, there were two cohorts, the first one with 20 years from 1982 to 2002 with 89 IEM patients and the second one with 14 years from 1996 to 2010 with 120 IEM patients. The estimated incidence of IEM was 1 in 7580 (unpublished data); however, as that was a voluntary case-finding study from several hospitals, the incidence was likely to be an underestimate. These figures are similar to those reported worldwide, such as 1 in 5800 in mainland China,6 1 in 5882 in Taiwan,7 and 1 in 4000 in America.8
In 2000, a mandatory NBS programme for hyperphenylalaninaemia, congenital hypothyroidism, and congenital deafness was implemented in mainland China.9 In 2006, the American College of Medical Genetics recommended 29 metabolic diseases (IEM) for which screening should be mandated.10 Since then, the scope of this recommendation has been expanding (Recommended Uniform Screening Panel, the Secretary of the Department of Health and Human Services11).12 In Hong Kong, population screening for congenital hypothyroidism and glucose-6-phosphate dehydrogenase (G6PD) deficiency using umbilical cord blood has been mandatory since March 1984 under the Neonatal Screening Unit of the Clinical Genetic Service, Department of Health. This programme has resulted in a significant reduction in related morbidities and mortalities.
In 2008, a coroner inquest was called to investigate the sudden death of a 14-year-old boy with a postmortem genetic diagnosis of glutaric acidaemia type II.13 The Coroners’ Report demanded that “The Department of Health, the Hospital Authority, the Faculty of Medicine of various universities and others concerned should carry out a feasibility study to see whether universal check may be carried out on all newborn babies for congenital metabolism defect.”14
To be effective, an expanded NBS programme needs to be coupled with improved general awareness of IEM and NBS. Educational support and training are required for frontline clinicians engaged in the diagnosis and care of patients with IEM.15 Several studies have shown that health care professionals do not have satisfactory awareness and knowledge of IEM.15 16 17 18 Therefore, a better understanding of the awareness of IEM among health care professionals in Hong Kong is needed.
We have conducted the first feasibility pilot study on the expanded NBS service model in a hospital setting in Hong Kong and the first survey on the knowledge and opinions on NBS for IEM among health care professionals in Hong Kong.
This prospective pilot study was conducted in phases from 1 October 2012 to 31 August 2014, involving three public hospitals and The University of Hong Kong (HKU), with over 40 collaborators from departments of pathology, paediatrics, and obstetrics. Phases 1 and 2 involved a single-site study conducted at Princess Margaret Hospital from 1 October 2012 to 31 October 2013 and then at Tuen Mun Hospital from 1 November 2013 to 31 March 2014. Phase 3 was university (HKU)-based and the recruitment was open to the public from 3 March 2014 to 31 August 2014. Phase 4 was a two-site study at the Tuen Mun Hospital and Queen Mary Hospital from 4 April 2014. Phase 5 was carried out at all three hospitals from 2 July 2014 until 31 August 2014. The OPathPaed model for expanded NBS was used for evaluation.19 The OPathPaed model includes 10 steps: parental education, consent, sampling, sample dispatch, dried blood spot (DBS) preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis (Fig 1).

Figure 1. OPathPaed service model for delivery of expanded NBS for IEM in Hong Kong
Pilot study to investigate the feasibility of the 10-step OPathPaed model
Step 1: Parental education
Educational talks were delivered by chemical pathologists during antenatal visits. With the help of the Save Babies Through Screening Foundation, we added Chinese subtitles to the video titled “Newborn Screening Saves Babies One Foot at a Time”. The video is available online (https://www.youtube.com/watch?v=dxFit_a601w). DVDs and a locally designed pamphlet with an email address and telephone number for enquiries were distributed to expectant mothers (Fig 2). In order to raise public awareness, several interviews with the media were arranged and reports were published in several newspapers20 21 22 and radio and television programmes.23 24

Figure 2. Chinese version of pilot study pamphlet on newborn screening for inborn errors of metabolism
Step 2: Obtaining consent
A consent form was designed for NBS for IEM (data not shown). Educational videos and pamphlets were used to inform the parents. Written informed consent was collected during a postnatal talk after the education session. The talk was conducted in group presentation for the mothers by chemical pathologists.
Step 3: Sampling
Paediatricians or pathologists organised training for phlebotomists on the heel prick technique, in compliance with the Clinical and Laboratory Standard Institute guidelines.25 An instruction sheet with photographs of valid and invalid DBS samples was provided as guidance for the phlebotomists (Fig 3). Samples were collected from neonates aged between 24 hours and 28 days.

Figure 3. Instruction guide with examples of valid and invalid dried blood spot samples
Step 4: Dried blood spot dispatching
Drying racks and special boxes designed for specimen transport before complete drying were delivered to the testing sites. Complete drying of blood spots was ensured for valid sample integrity. The blood spot cards were dried perpendicular to each other above and below the rack position to avoid contact contamination between blood spots of different patients.
Step 5: Dried blood spot preparation and testing
Two commercial DBS assay kits: (1) MassChrom Amino Acids and Acylcarnitines from Dried Blood/Non-derivatised (Chromsystems Instruments & Chemicals GmBH, Gräfelfing, Germany); and (2) NeoBase Non-derivatized MSMS kit (with succinylacetone assay; PerkinElmer, Waltham [MA], US) were validated for use in the study. In addition to a manual puncher and an autopuncher for DBS preparation, a fully automated online extraction system (DBS-MS 500; CAMAG, Muttenz, Switzerland) was also evaluated. The precision and local reference intervals of the commercial assay kits are listed in Table 1. Our laboratory has participated in the Newborn Screening Quality Assurance Programme organised by the US Centers for Disease Control and Prevention (CDC) since 2011. The disease panel included in the study is shown in Table 2.8 10 11

Table 1. Precision performance and local reference intervals for full-term babies for two commercial assay kits (NeoBase, MassChrom)

Table 2. Disease panel included in the study11
Step 6: Reporting
Chemical pathologists were responsible for reporting of positive results to the paediatricians. The CDC cut-off for clinical decision (https://wwwn.cdc.gov/NSQAP/Restricted/CDCCutOffs.aspx) and the Region 4 Stork Collaborative Project (https://www.clir-r4s.org/) data interpretation tools were applied during interpretation of the results.
Step 7: Recall and counselling
Newborn Screening ACT Sheets and Confirmatory Algorithms by the American College of Medical Genetics (https://www.ncbi.nlm.nih.gov/books/NBK55827/) were followed for patient recall. All abnormal results were examined by chemical pathologists. These chemical pathologists were also responsible for contacting the parents for post-test counselling and for arranging subsequent hospital referrals for care by paediatricians.
Step 8: Confirmation test
Confirmation of diagnosis was provided by regional laboratories through measurements of functional metabolites (mainly plasma amino acid levels, plasma acylcarnitine levels, and urine organic acid levels) and genetic diagnosis by DNA sequencing wherever appropriate.
Step 9: Treatment and monitoring
Admission logistics and treatment protocols for neonatal units with on-call rosters were established by hospital paediatricians. The same regional laboratories mentioned in Step 8 continued to provide biochemical diagnostic services.
Step 10: Cost-benefit analysis
A cost-benefit analysis has been conducted and published previously.26 Hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency was used as an example to evaluate the costs and benefits of implementing an expanded NBS programme in Hong Kong. Assuming an annual birth rate of 50 000 and hyperphenylalaninaemia incidence of 1 in 29 542 live births, the annual medical costs and adjusted loss of workforce would be HK$20 773 207. The implementation and operational costs of an expanded NBS programme are expected to be HK$10 473 848 annually. Thus, implementing the expanded NBS programme is expected to result in an annual saving of HK$9 632 750.26
Survey of health care professionals’ knowledge and opinions of newborn screening for inborn errors of metabolism
A questionnaire was distributed by convenience sampling to 430 health care professionals who worked in hospitals and were not involved in the pilot study. These self-administered questionnaires were distributed to local health care professionals including medical doctors, nurses, and other allied health care professionals either in person with returning envelopes or via email to department heads for further distribution. The self-administered questionnaire in English was modified from a previously published questionnaire that was tested among parents.27 The self-administered questionnaire included 13 questions that covered the local practice of the existing NBS programme, as well as knowledge and opinions of an expanded NBS programme. No personal identifiers were included in the questionnaire and questions were mostly in a closed-ended format. Data analyses were performed using Excel 2000 (Microsoft Corp. Redmond [WA], US) and GraphPad QuickCalcs (http://graphpad.com/quickcalcs/ConfInterval1.cfm). Percentages for each question were calculated as the number of replies divided by the total number of respondents for that question. The questions and corresponding responses are shown in Table 3.

Table 3. Survey questions on knowledge and opinions of newborn screening for inborn errors of metabolism and responses from health care professionals in Hong Kong (n=210)
Pilot study recruitment
By 31 August 2014, 2440 neonates had been recruited. The DBSs were collected from neonates aged 24 to 48 hours (n=2064, 84.6%), 3 to 5 days (n=331, 13.6%), 5 to 7 days (n=9, 0.4%), and 7 to 28 days (n=36, 1.5%). The participation rate was 86.6% on the days when blood samples were collected. There were no recorded DBS sampling or dispatch failures. The method validation and results of the DBS amino acids and acylcarnitine assays have been published elsewhere28; further details are available from the corresponding author on request. Overall, no true-positive cases were found in this pilot study, likely because of the limited sample size. Six (0.25%) false-positive cases were detected in 2440 neonates; of these, two had mild elevations in long-chain acylcarnitine levels, two had high tyrosine levels, one had a high citrulline level, and one had a low free carnitine level. Subsequent laboratory findings were all normal. No false-negative cases were reported from the IEM clinics of the involved hospitals within 2 years after project completion. However, patients who emigrated or received treatment at private institutions could not be followed up.
Health care professionals’ knowledge and opinions of newborn screening for inborn errors of metabolism
A total of 430 questionnaires were distributed and 210 (48.8%) completed responses were received. Results are shown in Table 3. Of the respondents, 50.0% were nurses and 32.9% were doctors. The doctors worked mainly in departments of paediatrics (47.8%), pathology (21.7%), and obstetrics (17.4%). Most (89.6%) respondents were aware of the existing NBS programme for hypothyroidism and G6PD deficiency; however, 47.5% did not know about IEM and 73.6% had not heard of expanded NBS for IEM. Most (87.6%) respondents agreed that more education on IEM and NBS is needed.
This is the first prospective pilot study on NBS for IEM in Hong Kong, and it has successfully evaluated the feasibility of the OPathPaed model. This study is also the first to investigate the knowledge and opinions on NBS for IEM of local health care professionals.
To implement an expanded NBS programme for IEM successfully in Hong Kong, there are several important points that need to be addressed. First, awareness and knowledge of NBS for IEM among the general public and among health care professionals should be improved.27 Second, comprehensive data on the local disease spectrum and incidence should be made available; such data were not available until recently.3 5 Third, free flow of information and sharing of experiences among colleagues working in the acute care and public health sectors should be facilitated. Fourth, more emphasis should be given to regular updates on NBS health care policy, confirmatory investigation service support, and treatment protocols. Last, the use of umbilical cord blood samples in the existing programme is unsuitable for an expanded NBS programme for IEM because of unacceptably high false-negative rates.29 The metabolites associated with many amino acid disorders, organic acid disorders, and fatty acid oxidation disorders are not elevated in cord blood. In 2013, the hospital-based OPathPaed model was published for the implementation of an expanded NBS programme suitable for a local setting.19 The present study further confirms the feasibility of the OPathPaed model for use on a larger scale. The OPathPaed model integrates expert input from obstetricians, pathologists, and paediatricians. Because babies born in Hong Kong are normally delivered in hospitals, the OPathPaed model approach should be able to achieve full coverage.
The success of an expanded NBS programme for IEM would depend not only on the diagnostics but also on how well patients diagnosed with IEM could be managed. It is difficult to accumulate experience and the many metabolic diseases can easily cause confusion. In addition, sophisticated management requires individualised drug formulations, which may not be easily accessible or may involve off-label prescriptions. Overseas studies have identified significant knowledge gaps among clinicians involved in the follow-up care of newborns with IEM identified by NBS.15 16 17 18 Some were poorly prepared to follow up the initial diagnosis, provide appropriate counselling, or make appropriate clinical referrals.17 In our study, 73.6% of 210 health care professionals (who were not involved in the pilot study) were unaware of the expanded NBS programme, and 47.5% of respondents did not know what IEM were. The majority of respondents (87.6%) agreed that better education was needed and 91.3% supported expanding NBS for IEM immediately or within 3 years. According to a parental survey among 172 parents regarding NBS for IEM,27 over 89% had never heard of NBS for IEM or metabolic disorders. Although some IEM may be incurable, 97% of parents supported an expanded NBS programme and 82.8% of parents supported implementation of this expansion immediately or within 3 years.27
The present study also provides the first local evaluation of the fully automated DBS-MS 500 system. The DBS is directly eluted into the extraction chamber, with an online extraction system connecting with the tandem mass spectrometer. There is no need for DBS card punching. Together with the integrated optical card recognition and barcode reading module, this automation minimises the risk of sample misidentification during manual processing. The precision and accuracy demonstrated are comparable to those of conventional procedures. However, because the DBS-MS 500 system requires application of an internal standard solution before extraction, the financial cost per extraction would be higher than that for conventional methods. In addition, special DBS cards are required for the extraction chamber. Third-party DBS cards of a specific quality may not easily fit into the system. The throughput of up to 500 DBS cards per run is more than adequate for local needs, as there are about 50 000 live births annually in Hong Kong.
The limitations of the pilot study include small and non-representative sample size, a relatively short study period that may have been inadequate for follow-up to confirm true negatives, and the convenience sampling and low response rate of the health care professional survey.
The present pilot study investigated the feasibility of an expanded NBS for IEM in Hong Kong, and surveyed health care professionals for their knowledge and opinions on NBS for IEM. We successfully evaluated the OPathPaed model on a larger scale than has been attempted previously and demonstrated that health care professionals have a favourable opinion of implementing an expanded NBS programme in Hong Kong. It is timely that, as this pilot study was completed, the needs of parents and health care workers were addressed in the Hong Kong Special Administrative Region Chief Executive’s Policy Address of 2015, when a government-led initiative was announced to study the feasibility of NBS for IEM in the public health care system on a large scale.
Author contributions
All authors have made substantial contributions to the concept or design of this study; acquisition of data; analysis or interpretation of data; drafting of the article; and critical revision for important intellectual content.
We acknowledge all collaborators, doctors, nurses, medical technologists, phlebotomists, information technologists, and parents for their efforts and support. We thank the Save Babies Through Screening Foundation for allowing us to use their video for educational purpose. We thank CAMAG Germany for providing technical support during the evaluation of the DBS-MS 500. The CAMAG had no role in the study design, data collection, analysis, reporting, or manuscript preparation.
This work was funded by the SK Yee Medical Foundation. The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.
All authors have no conflicts of interest to disclose. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.
Ethical approval
Local ethical approval was obtained from each of the regional hospitals involved in this study.
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