State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

OBJECTIVES: To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. METHODS: This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULTS: During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). CONCLUSIONS: Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Mild-moderate congenital hearing loss: secular trends in outcomes across four systems of detection.

BACKGROUND: Universal newborn hearing screening (UNHS) targets moderate or greater hearing loss. However, UNHS also frequently detects children with mild loss that results in many receiving early treatment. The benefits of this approach are not yet established. We aimed to (i) compare language and psychosocial outcomes between four hearing loss detection systems for children aged 5-8 years with congenital mild-moderate hearing loss; (ii) determine whether age of detection predicts outcomes; and (iii) compare outcomes between children identified via well-established UNHS and the general population. METHODS: Linear regression adjusted for potential confounding factors was used throughout. Via a quasi-experimental design, language and psychosocial outcomes were compared across four population-based Australian systems of hearing loss detection: opportunistic detection, born 1991-1993, n = 50; universal risk factor referral, born 2003-2005, n = 34; newly established UNHS, born 2003-2005, n = 41; and well-established UNHS, born 2007-2010, n = 21. In pooled analyses, we examined whether age of detection predicted outcomes. Outcomes were similarly compared between the current well-established UNHS system and typically developing children in the Early Language in Victoria Study, born 2003, n = 1217. RESULTS: Age at diagnosis and hearing aid fitting fell steadily across the four systems. For moderate losses, mean expressive language (P for trend .05) and receptive vocabulary (P for trend .06) improved across the four systems, but benefit was not obvious for mild losses. In pooled analyses, diagnosis before age six months predicted better language outcomes for moderate losses. Children with mild-moderate losses exposed to well-established UNHS continue to experience expressive language scores well below children in the general population (adjusted mean difference -8.9 points, 95% CI -14.7 to -3.1). CONCLUSIONS: Treatment arising from UNHS appears to be clearly benefitting children with moderate hearing losses. However, rigorous trials are needed to quantify benefits, versus costs and potential harms, of early aiding of children with mild losses.

Enhancing the ethical conduct of genetic research: investigating views of parents on including their healthy children in a study on mild hearing loss.

Clinical genetic research is often regarded as more ethically problematic than other forms of research, and in some countries is subject to specific regulation, requiring researchers to follow specialised guidelines. In this paper, an approach to enhancing the ethical conduct of genetic research is proposed, which is believed to be more effective than simply attempting to follow general guidelines. The potential concerns, likely areas of misunderstanding and negative reactions of the participant group are systematically investigated before starting a study on genetics. This would constitute, in effect, an ethical pilot study, similar to a feasibility pilot study to test equipment, procedures and logistics. The findings of the ethical pilot study would be used to help in designing ethically important aspects of research protocol, such as recruitment procedures, written and other information for potential participants, informed consent processes and reporting of results including ambiguous or uncertain results.

The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children.

BACKGROUND: There is a lack of information on prevalence, cause and consequences of slight/mild bilateral sensorineural hearing loss (SNHL) in children. We report the first systematic genetic analysis of the GJB2 gene in a population-derived sample of children with slight/mild bilateral SNHL. METHODS: Hearing tests were conducted in 6240 Australian elementary school children in Grades 1 and 5. 55 children (0.88%) were found to have a slight/mild sensorineural hearing loss. 48 children with slight/mild sensorineural hearing loss and a matched group of 90 children with normal hearing participated in a genetic study investigating mutations in the GJB2 gene, coding for connexin 26, and the presence of the del(GJB6-D13S1830) and del(GJB6-D13S1854) deletions in the GJB6 gene, coding for connexin 30. RESULTS: Four of 48 children with slight/mild sensorineural hearing loss were homozygous for the GJB2 V37I change. The four children with homozygous V37I mutations were all of Asian background and analysis of SNPs in or near the GJB2 gene suggests that the V37I mutation arose from a single mutational event in the Asian population. DISCUSSION: Based on the prevalence of carriers of this change we conclude that V37I can be a causative mutation that is often associated with slight/mild sensorineural hearing loss. No other children in the slight/mild hearing loss group had a hearing loss related to a GJB2 mutation. One child with normal hearing was homozygous for the R127H change and we conclude that this change does not cause hearing loss. Two children of Asian background were carriers of the V37I mutation. Our data indicate that slight/mild sensorineural hearing loss due to the GJB2 V37I mutation is common in people of Asian background.

Hearing impairment: a population study of age at diagnosis, severity, and language outcomes at 7-8 years.

BACKGROUND: Better language outcomes are reported for preschool children with hearing impairment (HI) diagnosed very early, irrespective of severity. However, population studies of older children are required to substantiate longer term benefits of early detection. AIMS: To study impact of age of diagnosis and severity of HI in a population cohort of 7-8 year old children. METHODS: Eighty eight 7-8 year old children born in Victoria, who were (a) fitted with hearing aids for congenital HI by 4.5 years and (b) did not have intellectual or major physical disability were studied. Main outcome measures were Clinical Evaluation of Language Fundamentals (CELF) and Peabody Picture Vocabulary Test (PPVT). Predictors were pure tone average (0.5, 1, 2 kHz) in better ear at diagnosis and age at diagnosis. Marginal (adjusted) means were estimated with general linear models. RESULTS: Response rate was 67% (n = 89; 53 boys). Mean age at diagnosis was 21.6 months (SD 14.4); 21% had mild, 34% moderate, 21% severe, and 24% profound HI; mean non-verbal IQ was 104.6 (SD 16.7). Mean total CELF score was 76.7 (SD 21.4) and mean PPVT score 78.1 (SD 18.1). Age of diagnosis, adjusted for severity and IQ, did not contribute to language scores. In contrast, adjusted mean CELF and PPVT language scores fell sequentially with increasing severity of HI. CONCLUSIONS: More severe HI, but not later diagnosis, was strongly related to poorer language outcomes at 7-8 years. Further systematic study is needed to understand why children with hearing impairment have good or poor outcomes.

Qualitative analysis of parents' experience with early detection of hearing loss.

AIMS: To determine key themes from parents' comments on paths to diagnosis and intervention for their children with hearing loss, following introduction of at-risk neonatal hearing screening and modification of distraction test screening for infants not at-risk. METHODS: Parents of children born in 1993 in Victoria, Australia, who were eligible for screening via the Victorian Infant Hearing Screening Program and who were subsequently diagnosed with a permanent congenital hearing loss and fitted with hearing aids prior to the year 2000 were asked to complete a semi-structured questionnaire shortly after aid fitting. Two researchers independently analysed parent comments using the constant comparative method. RESULTS: Parents of 82 children (61%) replied to the questionnaire. Themes analysis revealed a generally positive response to neonatal ABR screening, with a mixed response to the distraction test; powerful emotions experienced by parents at diagnosis including denial and shock; frustration arising from delays in diagnosis, and communication difficulties with providers. Special difficulties testing children with other medical and developmental problems, confusion about tympanostomy tube insertion, and difficulty with wearing hearing aids were also reported. Some children had experienced problems in the school setting. Experience of post-diagnostic services was generally positive. CONCLUSIONS: Parents need greater support both during the testing of screen failures and at the time of diagnosis. Providers need more training in how to communicate findings to parents, particularly at times when parents are experiencing strong emotions. Parents need more strategies to enable hearing aid wearing in very young children. Some children with additional medical, developmental, and behavioural problems need specialised approaches to testing.

Slight and mild hearing loss in primary school children.

Although slight/mild sensorineural hearing loss affects about 3% of the school-aged population, with many more children having such impairments at single frequencies or in only one ear, little is known about its impacts on language, learning, and quality of life. This annotation explores what is known about prevalence and impact of this condition and argues for large-scale research to better address these issues.

Six month impact of false positives in an Australian infant hearing screening programme.

AIMS: To assess short and longer term parent reported impacts of false positive referrals in the Victorian Infant Hearing Screening Program (VIHSP). METHODS: Mailed retrospective case-control survey of infants consecutively referred to VIHSP between December 1998 and April 1999 for whom audiology did not confirm permanent hearing loss, comprising 137 infants screened with a neonatal risk factor questionnaire and 148 older infants screened with two consecutive behavioural (distraction) tests. The two control groups comprised non-referred screened infants matched by domicile, age, and gender. Main outcome measures were parent reported emotions experienced before and after child's audiology test, parent estimated impact of hearing loss, the Child Vulnerability Scale, audiology assessment satisfaction questionnaire, and questions relating to their child's hearing and language development. RESULTS: Final sample: at risk cases (AR) 108 (79% response), at risk controls 64 (51%); distraction test cases (DT) 103 (70%), distraction test controls 53 (41%). Parents across all groups believed that hearing loss would have major effects on a child's language (91-96%), schooling (81-91%), and employment opportunities (67-75%). Before audiology, 71% (AR) and 72% (DT) of case parents were anxious/worried, falling to 4% and 15% afterwards. After the test 82% (AR) and 79% (DT) reported relief, but 19% and 18% continued to feel worried. Ongoing concerns about hearing, language, development, and general health were comparable for AR cases compared to controls, and for DT cases compared to controls. CONCLUSIONS: Hearing screening tests are generally well received. Parents are realistic about the impact of childhood hearing loss and report a range of negative emotions when a false positive hearing screen requires referral. Although most are reassured by a normal test, a substantial number report continuing concern.

Six year effectiveness of a population based two tier infant hearing screening programme.

AIMS: To determine whether a two tier universal infant hearing screening programme (population based risk factor ascertainment and universal distraction testing) lowered median age of diagnosis of bilateral congenital hearing impairment (CHI) >40 dB HL in Victoria, Australia. METHODS: Comparison of whole population birth cohorts pre and post introduction of the Victorian Infant Hearing Screening Program (VIHSP). All babies surviving the neonatal period born in Victoria in 1989 (pre-VIHSP) and 1993 (post-VIHSP) were studied. (1) Pre-1992: distraction test at 7-9 months. (2) Post-1992: infants with risk factors for CHI referred for auditory brain stem evoked response (ABR) assessment; all others screened by modified distraction test at 7-9 months. RESULTS: Of the 1989 cohort (n = 63 454), 1.65/1000 were fitted with hearing aids for CHI by end 1995, compared with 2.09/1000 of the 1993 cohort (n = 64 116) by end 1999. Of these, 79 cases from the 1989 cohort (1.24/1000) and 72 cases from the 1993 cohort (1.12/1000) had CHI >40 dB HL. Median age at diagnosis of CHI >40 dB HL for the 1989 birth cohort was 20.3 months, and for the 1993 cohort was 14.2 months. Median age at diagnosis fell significantly for severe CHI but not for moderate or profound CHI. Significantly more babies with CHI >40 dB HL were diagnosed by 6 months of age in 1993 than in 1989 (21.7% v 6.3%). Compared to the six years pre-VIHSP, numbers aided by six months were consistently higher in the six years post-VIHSP (1.05 per 100 000 births versus 13.4 per 100 000 births per year). CONCLUSIONS: VIHSP resulted in very early diagnosis for more infants and lowered median age of diagnosis of severe CHI. However, overall results were disappointing.

Clinical markers of serious illness in young infants: a multicentre follow-up study.

OBJECTIVE: To perform a multicentre follow-up study to determine if previously identified markers of serious illness in early infancy were robust and statistically reliable. METHODS: Infants aged 1 week to 26 weeks presenting to the Emergency Departments of the Royal Children's Hospital and two Melbourne metropolitan hospitals were seen over a 12-month period. Eleven clinical markers as well as their temperature were documented by nursing staff and resident medical officers. Serious illness was defined if infants had a positive body fluid bacterial culture, a positive chest X-ray or if significant treatment was required in hospital. The predictive values, sensitivity and specificity for the individual and the best combination of clinical markers were determined. RESULTS: Assessments (3806) were performed with 312 infants being assessed as seriously ill (8.2%). The combination of either drowsiness on history or examination, pallor on history or examination, breathing difficulty (chest wall recession), temperature above 38 degrees C and a lump being present, identified 82.5% of all babies deemed subsequently to be seriously ill. The positive predictive value of an infant who was febrile, drowsy and pale on examination was 70.7% (previous study 74%). CONCLUSIONS: This study confirmed the high individual predictive value of arousal variables, pallor, and chest wall recession, especially when associated with fever, reaffirming their utility in the recognition of serious illness in infants under 6 months of age.

Late diagnosis of congenital sensorineural hearing impairment: why are detection methods failing?

This study was designed to look in detail at the paths to diagnosis for a group of 197 children with congenital sensorineural hearing impairment (SNHI), who were diagnosed between 1989 and 1991 in the state of Victoria, Australia. Despite the existence of universal infant screening at 7-9 months by distraction test or questionnaire, the median age at diagnosis for the study group was 18.0 months, with median age at aid fitting of 20.8 months, and median age at commencement of specialised intervention programmes of 22.3 months. Parent questionnaires completed for 143 (73%) of these children showed that 49% had known risk factors for hearing loss yet only 20% of them had been referred for audiological assessment before the 7-9 month screen. Only 63% of those eligible for the 7-9 month screen had received it. Of those children who were screened by distraction test 46% passed as did 57% of those screened by questionnaire. Twenty four parents (17%) described how they had initially 'denied' their own observations of their infants' abnormal hearing behaviour. When concerns were raised with professionals, 10% of parents were falsely reassured without audiological assessment. Detection methods are failing through a combination of poor screen test efficacy, incomplete population coverage, and parental and professional denial.