1. IntroductionInherited metabolic diseases (IMD) are a group of genetic disorders arising from the inherent deficiency of a certain enzyme or cofactor that impairs normal metabolism. Accumulation of excessive toxic substances or deficiency of essential metabolites in the body may damage vital organs, posing a significant risk of morbidity and mortality to patients. A small proportion of IMD can be diagnosed and treated early with diet therapy or pharmacotherapy and may benefit significantly from disease monitoring. As initial symptoms for treatable conditions, e.g., vomiting and characteristic odours [1], are often non-specific and non-exclusive, IMD conditions are likely to be under-detected before symptomatic manifestation. Delayed detection and diagnosis can result in poor health prognosis, severe medical conditions, physical or mental developmental problems, and even death, posing a heavy toll on individuals and the health care system.Most developed countries have placed great emphasis on extensive IMD screening programmes for treatable conditions to prevent significant developmental delay or severe morbidity and mortality in individuals with treatable IMD conditions. The advancement of tandem mass spectrometry (MS/MS) has led to the rapid development of expanded newborn IMD screening programmes [2], which can efficiently identify infants at increased risk for the conditions in question, enabling specific diagnostic testing and early treatment if warranted to allow for the best possible outcome. The heel-prick blood test (herein blood test) is the most frequently deployed method, examining the subject’s blood sample collected on a filter paper card. The number of disorders screened varies by country, depending on funding, regulations, techniques used, and disease prevalence in the population [3]. Although there are no universal criteria for conditions to be included in the screenings, there is consensus around Wilson and Jungner’s classic screening criteria [4,5] that the screened diseases should have (i) a well-defined natural history, (ii) a high disease prevalence in the general population, (iii) increased mortality and morbidity rates when left untreated, and (iv) effective medical treatment and management plans, such that the results of the screening are meaningful and conducive to improving the health of affected individuals. In the context of newborn screening, disease prevalence is not one of the criteria. Screening a rare disease in the absence of an accepted treatment may be appropriate when it will provide a net benefit to the child or the family [6].Parental use of the internet to seek health information related to screening is frequently observed during pregnancy [7] and newborn screening processes [8,9,10]. Araia and Potter [11] assessed the content quality of online North American websites on newborn screening programmes and reported an imbalanced emphasis on benefits rather than potential harms. The majority of materials mentioned the purpose and benefits of screening, descriptions of the screening process, and the conditions to be tested. Few sources included information on the possibility of receiving a false-positive or false-negative result, the need for diagnostic follow-up, or the storage or disposal policy of the collected blood spot sample. Although parents often go online and seek information, it is uncertain how they process the online information that determines their health behaviour, such as test uptake or refusal. Given that the internet is one of the most popular sources for medical information among parents, the accuracy and comprehensiveness of the advertised IMD tests play an essential role in parents’ decision-making, their understanding of the test results, and, eventually, the health of the next generation.In Hong Kong, IMD are common among recognised rare diseases with an incidence rate of 1 in 1376 [12]. In response to public health concerns, in 2015, government-subsidised hospitals instituted a territory-wide newborn metabolic diseases screening programme. Participation in the programme is completely voluntary. Testing, counselling, and follow-up services are centralised at Hong Kong Children’s Hospital. Prior to the launch of the universal screening programme, only newborn cord blood test screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency and congenital hypothyroidism was offered to all newborns free of charge at birth. IMD screening was available only as a pay-per-service test performed in the private healthcare sector. Patients diagnosed with IMD require care from a multidisciplinary team with medical, nursing, and dietetic specialities. Alternatively, IMD screening using blood tests can be done in private clinics and hospitals. The IMD screening using urine tests can be purchased, primarily via the internet, as a self-expensed test. Urine tests were widely used in the early years of the public health programme to screen for certain conditions such as phenylketonuria, by detecting phenyl ketones in the urine. However, they were later replaced by blood tests for higher sensitivity [13,14].

The study objectives are to (1) map the local adoption of IMD screening using blood and urine tests in local public and private sectors, including public hospitals, private hospitals, a university-affiliated private clinic, and commercial laboratories; and (2) evaluate the comprehensiveness of the corresponding published resources.

4. DiscussionThis study found that expanded newborn metabolic screening has been disseminated across various healthcare sectors at parents’ disposal with or without professional healthcare assistance. Echoing a North American study [11], our findings showed that most sources were inclined to focus on the benefits and were less likely to highlight the risks or test limitations. For instance, the urine test providers rarely mentioned false-positive or false-negative results or the necessity of a follow-up diagnosis. Other unaddressed essential information included the risk of pain and incidental findings, which, though uncommon, demand attention. As opposed to the claim of having virtually perfect accuracy, screening tests always carry the risk of false results. In a local 18-month prospective study, two mothers were incidentally picked up with IMD of carnitine uptake deficiency (CUD) and classic phenylketonuria [12]. False-negative cases were also reported [20,21]. The complexity of genetic information from IMD screening accentuates the pivotal role of healthcare professionals in pre-test and post-test counselling to explain the meanings of different results. We observed some variabilities and incorrect descriptions in introducing the urine tests, both within and across the resources. A few highlighted the simplicity of the urine test and potentially overstated the invasiveness of the blood test. Urine tests also claimed to screen for four times as many conditions as blood tests (150+ and 25+ conditions; see Appendix A and Appendix B). The majority of the screenable conditions are outside of the core panel recommended by the American College of Medical Genetics [22]. Some conditions advertised in the urine test may have been recommended to be identified using the more sensitive dried blood spot card over urine (e.g., phenylketonuria) [13]. Some conditions detected may turn out to be benign, with symptoms often ameliorating and disappearing naturally during follow-up (e.g., Short-Chain Acyl-CoA Dehydrogenase Deficiency) [23]. Some commercial labs claim that urine can be used to perform protein or glucose screening and screen for rare non-childhood conditions such as Meigs syndrome and gestational diabetes mellitus.Of additional concern, our findings reported that sources incorrectly described the urine test as diagnostic in nature for some diseases that are more sensitive to a blood test (e.g., pyridoxine-5′-phosphate oxidase (PNPO) Deficiency). It is vital to note that the heel prick blood test using MS/MS is proven to be a more efficient and cost-effective technique [24]. The blood test is the standardised method adopted by most, if not all, national screening programmes, including in Hong Kong. The urine test is a diagnostic test for a limited scope of IMD only and not a replacement for conventional blood tests. Most urine-based IMD screenings remained in the research phase, and some were reported to be not sensitive enough for screening [25]. More evidence must be accumulated before these tests are marketed commercially. The healthcare community came to a consensus that blood-based IMD by MS/MS is a good screening test and may require further diagnostic tests. Local tertiary hospital protocols and guidelines listed specific two-tiered approaches and strategic steps to best eliminate inaccurate reporting of results. Appropriate follow-up and professional referral mechanisms should be made available. Further tests as confirmation should always be considered when the first-line tests indicate an increased risk of an IMD. On the opposite end, some commercial laboratory genetic tests that claim to be all-in-one screening and diagnostic tools can thus create a misconception in parents and delay their seeking medical advice.Hong Kong Chinese parents always want the best care to reassure them about their child’s health. About three-fifths of pregnancies were delivered in the public sector [26], implying that two-fifths of newborn mothers delivered in the private sectors, not benefitting from free-of-charge IMD screening. The latter group are more likely under the influence of commercial resources to take the IMD test. These urine test services are advertised predominantly on the internet and available online at parents’ own choice and expense without medical guidance. The popular notion of “the more you know about the child, the better” is commonly reported among parents for better planning regarding the child’s development [27]. Without a comprehensive understanding of what conditions are necessary to be screened, parents may be under the impression that a greater number of screenable conditions would be the best option. Zayts and Luo [28] studied the language used by commercial laboratories in Hong Kong. They found that online materials tend to use sentimental terms or make inflated claims about the value of genetic tests to pursue a marketing agenda. In concordance with the results of Zayts and Luo, we found that some advertisements described IMD as “silent killers” and emphasised the advantage of getting “reassurance” in controlling the child’s developmental health and well-being. The use of storytelling and linguistic foregrounding is prevalent and potentially biased in promoting health, making targeted advertisement audiences relatable to these shared parental responsibilities, emotions, and narratives. It is unsurprising that the public may have been misled easily and overestimated the utility of the commercial laboratory test. Making an informed choice under the influence of biased information and in the absence of health care providers is also questionable, especially considering the Hong Kong Chinese population has attained a low genomic literacy [29]. Genetic counsellors’ views towards any commercial laboratory tests were nuanced. They asserted that these commercial tests should be provided responsibly with appropriate access to information, an informed consent process, and professional advice [30]. To better protect the parents, or broadly, the public interest, the Steering Committee on Genomic Medicine issued strategic plans for developing genomic medicine. One of the scopes is to recommend pre-testing consultation with qualified healthcare professionals [31]. In Hong Kong, the development of genetic counselling as a licensing profession is lagging behind compared with other developed regions and countries [32]. Recognising the limited capacities in clinical genetics and bioinformatics, the Steering Committee recommended that academic institutes offer relevant internationally certified programmes to meet the burgeoning service demand [31]. Another indicative action is promoting the proper use of genetic and genomic tests. Implementing additional regulatory measures on commercial tests from a top-down approach is crucial yet complex, varying by country. For example, France and Germany ban commercial genetic tests and mandate the involvement of healthcare professionals in any genetic examination [33]. Like many regions and countries, Hong Kong does not provide legislation governing commercial laboratory tests. These tests are recognised as goods under the law unless false trade descriptions and inaccurate, misleading or incomplete information regarding the goods provided are evident. Without timely regulation and oversight, the incorrect descriptions might create a public misconception about utilising these commercial laboratory tests to inform health decisions.