Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing.

BACKGROUND: Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. AIM: To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. METHODS: Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. RESULTS: The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309-66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. CONCLUSION: Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.

First trimester screening cut-offs for noninvasive prenatal testing as a contingent screen: Balancing detection and screen-positive rates for trisomy 21.

OBJECTIVE: To provide data on how screen-positive and detection rates of first trimester prenatal screening for fetal Down syndrome vary with changes in the risk cut-off and maternal age to inform contingency criteria for publicly funded noninvasive prenatal testing. MATERIALS AND METHODS: First trimester screening and diagnostic data were collected for all women attending for first trimester fetal aneuploidy screening in Western Australia between 2005 and 2009. Prenatal screening and diagnostic data were linked to pregnancy outcomes, including data from the Midwives' Notification System and the Western Australian Registry of Developmental Anomalies. The prevalence of Down syndrome and performance of screening by risk cut-off and/or for women >35 years were analysed. RESULTS: The current screening risk cut-off of 1:300 has screen-positive and detection rates of 3.5% and 82%. The screen-positive rate increases by 0.7-0.8% for each 100 point change in risk, up to 19.2% at 1:2500 (96% detection rate). Including all women >35 years as screen positive would increase the screen-positive rate and detection rates to 30.2% and 97.2%. CONCLUSION: Variation in screening risk cut-off and the use of maternal age to assess eligibility for noninvasive testing could significantly impact the demand for, and cost of, the test. A contingent first trimester screening approach for risk assessment is superior to the use of a combination of screening and maternal age alone. These data will inform decisions regarding the criteria used to determine eligibility for publicly funded noninvasive prenatal testing.

Folate status in Aboriginal people before and after mandatory fortification of flour for bread-making in Australia.

BACKGROUND: Mandatory fortification of wheat flour for bread-making was introduced in Australia in September 2009, to assist in the prevention of neural tube defects (NTD). NTD are twice as common in Aboriginal compared with non-Aboriginal infants, and folate levels are lower in the Aboriginal population. AIMS: This study was undertaken to compare folate status and NTD in the Aboriginal population before and after fortification. METHODS: Postfortification, 95 Aboriginal men and nonpregnant women aged 16-44 years in metropolitan and regional Western Australia (WA) completed a rapid dietary assessment tool and had blood taken to measure red cell folate. Measures were compared with prefortification values obtained in an earlier study using the same methods. Data on NTD in Aboriginal infants were obtained from the WA Register of Developmental Anomalies. RESULTS: No participant was folate deficient. The mean red cell folate increased after fortification to 443 ng/mL for males and 567 ng/mL for females. The mean difference between red cell folate after fortification compared with before was 129 ng/mL for males (95% CI 81-177); t = 5.4; P < 0.0001) and 186 ng/mL for females (95% CI 139-233); t = 7.9; P < 0.0001). Most participants ate fortified shop-bought bread at least weekly, resulting in an estimated additional folate intake per day of 178 (males) and 145 (females) dietary folate equivalents. NTD prevalence fell by 68% following fortification (prevalence ratio 0.32 (CI 0.15-0.69)). CONCLUSIONS: The population health intervention of mandatory fortification of wheat flour for bread-making has had the desired effect of increasing folate status and reducing NTD in the Australian Aboriginal population.

Screening for Down syndrome in the second trimester of pregnancy.

Antenatal screening for fetal anomalies has provided women and their partners with information to make reproductive choices based on the risk of serious chromosomal or structural defects since the 1990s. Alternative tests include first-trimester screening (combined ultrasound and maternal serum markers), second-trimester maternal serum markers and noninvasive cell-free DNA testing. The recent recommendations by the Royal Australian and New Zealand College of Obstetrics and Gynaecology and the Human Genetics Society of Australasia against second-trimester triple testing are based on unsound performance criteria, raise several contestable issues around access and equity and challenge the principles of governments providing affordable options.

Impact of prenatal screening and diagnostic testing on trends in Down syndrome births and terminations in Western Australia 1980 to 2013.

OBJECTIVE: To assess how prenatal screening and diagnostic testing have impacted the diagnosis, termination and birth prevalence of Down syndrome in Western Australia (1980-2013). METHOD: We analysed trends in termination rates and birth prevalence of Down syndrome using aggregated data (1980-2013). We modelled the expected live-birth rate and prevalence of Down syndrome and compared different eras of screening and diagnosis with respect to the impact on live-birth rate and prevalence of Down syndrome. RESULTS: Between 1980 and 2013, the rate of Down syndrome pregnancies increased, corresponding to a greater proportion of babies born to older women. Following the introduction of screening in 1994, the rate of live-born infants with Down syndrome reduced significantly (p = 0.001). The rate of terminations of pregnancy for Down syndrome remained stable over this period. In the absence of termination, the Down syndrome live-birth rate would have risen from 1.1 per 1000 to 2.17 per 1000 between 1980 and 2013. CONCLUSION: Prenatal testing in Western Australia has reduced the birth prevalence of Down syndrome despite an increased rate of Down syndrome pregnancies. Most women for whom a prenatal diagnosis of fetal Down syndrome is made, chose to terminate the pregnancy (93%), and this proportion has not changed over the study period.

The potential impact of NIPT as a second-tier screen on the outcomes of high-risk pregnancies with rare chromosomal abnormalities.

AIM: To describe the potential impact of using noninvasive prenatal testing (NIPT) as a second-tier test, on the diagnosis and outcomes of pregnancies identified as high risk through first trimester screening (FTS) in a cohort of real pregnancies. MATERIALS AND METHODS: Western Australian FTS and diagnostic data (2007-2009) were linked to pregnancy outcomes. Karyotype results from invasive prenatal testing in high-risk women were analysed. The outcomes of abnormal results that would not be detected by NIPT, assuming a panel of trisomy 21/18/13 and sex chromosome aneuploidies, and the likelihood of diagnosis in a screening model using NIPT as a second-tier test are described. RESULTS: Abnormal karyotype results were reported in 224 of 1488 (15%) women with high-risk pregnancies having invasive diagnostic testing. NIPT potentially would have identified 85%. The 33 abnormalities unidentifiable by NIPT were triploidies (n = 7, 21%), balanced (n = 8, 24%) and unbalanced rearrangements (n = 10, 30%) and level III mosaicisms (n = 8, 24%). For conditions not identifiable by NIPT, fetal sonographic appearance was likely to have led to invasive testing for 10 of 17 (59%) pathogenic abnormalities. If a policy was adopted recommending invasive testing for FTS risk >1:50 and/or ultrasound detected abnormality, the residual risk of an unidentified pathogenic chromosomal abnormality in those without a diagnosis would have been 0.33% (95% CI 0.01-0.65%). CONCLUSIONS: A screening model with NIPT as a second-tier for high-risk pregnancies would be unlikely to have changed the outcome for the majority of pregnancies. Optimising the diagnosis of rare pathogenic abnormalities requires clear indicators for invasive testing over NIPT.

The increase in cancer prevalence and hospital burden in Western Australia, 1992-2011.

PURPOSE: To describe cancer prevalence and hospital service utilization by prevalent cancer patients in Western Australia from 1992 to 2011. METHODS: This study was a population-based cohort study using the Western Australia (WA) Cancer Registry (1982 to 2011) as the source of incident cancer cases. These data were linked to mortality (1982 to 2011) and hospital morbidity (1998 to 2011) records via the WA Data Linkage System to ascertain complete and limited-duration prevalence and cancer-related hospitalizations over time. Prevalence rates were calculated using estimated residential population data from the Australian Bureau of Statistics. RESULTS: In 2011, one in every 27 people living in WA had been diagnosed with cancer at some time in their lifetime, and one in 68 had been diagnosed within the previous five years. Between 1992 and 2011, complete cancer prevalence in Western Australia increased by a magnitude of 2.5-fold. Forty-five and 44% of the increase in complete cancer prevalence in males and females between 1992 and 2011 can be attributed to prostate and breast cancer, respectively. The absolute number of cancer-related bed days increased 81 and 74% in males and females, respectively, diagnosed within one year, between 1998 and 2011. CONCLUSIONS: The prevalence of cancer and the burden it places on hospitals continues to rise, demanding ongoing efforts to prevent cancer through modifiable risk factors and better, more efficient use of health resources. Steps should to be taken to understand and address overdiagnosis and overtreatment.

Blueprint for a deliberative public forum on biobanking policy: were theoretical principles achievable in practice?

BACKGROUND: Public deliberation is recommended for obtaining citizen input to policy development when policies involve contested ethical dimensions, diverse perspectives on how to trade-off competing public interests and low public awareness of these perspectives. Several norms have been proposed for the design of deliberative methods. Evidence is scarce regarding whether such norms are achievable in practice. PURPOSE: This paper refers to principles of deliberative democracy theory to describe a deliberative public forum on biobanking. Practical challenges and contextual facilitators of achieving deliberative ideals are discussed, along with factors that influenced use of the forum output in policy development. METHOD: The forum ran for 4 days over two weekends in Perth, Western Australia. Key methodological features were socio-demographic stratification to randomly recruit a mini-public of citizens for discursive representation, provision of information inclusive of diverse perspectives and framed for difference, provision of a fair way for reasoning and collective decision making and adoption of processes to achieve publicity, accountability and independence from undue institutional influence. RESULTS: Most design principles were achieved in practice, with the fundamental exception of representativeness. Factors influencing these outcomes, and the use of deliberated outputs to develop policy, included institutional characteristics, the design involvement of deliberative experts and quality of the outputs when compared to other consultation methods. CONCLUSIONS: Public deliberations can achieve design ideals and influence (ethics-based) public health policy. The representation of 'hard to reach' citizens and their views needs further consideration, particularly as this relates to the procedural legitimacy of ethical analyses and the just inclusion of deliberative citizen advice within the broader policy-making process.

Prenatal screening for Down syndrome in Australia: costs and benefits of current and novel screening strategies.

OBJECTIVE: To analyse the cost-effectiveness and performance of noninvasive prenatal testing (NIPT) for high-risk pregnancies following first-trimester screening compared with current practice. METHODS: A decision tree analysis was used to compare the costs and benefits of current practice of first-trimester screening with a testing pathway incorporating NIPT. We applied the model to 32 478 singleton pregnancies screened between January 2005 and December 2006, adding Medicare rebate data as a measure of public health system costs. The analyses reflect the actual uptake of screening and diagnostic testing and pregnancy outcomes in this cohort. RESULTS: The introduction of NIPT would reduce the number of invasive diagnostic procedures and procedure-related fetal losses in high-risk women by 88%. If NIPT was adopted by all women identified as high risk by first-trimester combined screening, up to 7 additional Down syndrome fetuses could be confirmed. The cost per trisomy 21 case confirmed, including NIPT was 9.7% higher ($56,360) than the current prenatal testing strategy ($51,372) at a total cost of $3.91 million compared with $3.57 million over 2 years. CONCLUSION: Based on the uptake of screening and diagnostic testing in a retrospective cohort of first-trimester screening in Western Australia, the implementation of NIPT would reduce the number of invasive diagnostic tests and the number of procedure-related fetal losses and increase the cost by 9.7% over two years. Policy planning and guidelines are urgently required to manage the funding and demand for NIPT services in Australia.

Baseline investigations of folate status in Aboriginal and non-Aboriginal West Australians prior to the introduction of mandatory fortification.

OBJECTIVE: In September 2009, Australia implemented mandatory folic acid fortification of wheat flour for bread-making to reduce the incidence of neural tube defects. Our study aimed to establish baseline folate status data in Aboriginal and non-Aboriginal Western Australians. METHODS: Patients who presented at a health service or collection centre for blood tests were invited to participate. One hundred and ninety-one Aboriginals and 159 non-Aboriginals were recruited between April 2008 and September 2009. Participants completed a five-minute questionnaire and had blood taken for red blood cell (RBC) folate and serum vitamin B12. Data were analysed using SPSS (version 17.0.2, SPSS Inc., Chicago, IL, USA). RESULTS: Ten per cent (95% confidence intervals (CI): 5, 19) of the Aboriginal women participants and 26% (95% CI: 16, 40) of men had RBC folate concentrations below 250 ng/mL, the cut-off associated with folate deficiency. None of the non-Aboriginal women (95% CI: 0, 4) and 4% of the non-Aboriginal men (95% CI: 2, 12) had RBC folate concentrations below 250 ng/mL. All participants were vitamin B12 replete. None of the 96 Aboriginal and 8% of non-Aboriginal women aged 16-44 reported consumption of supplements with a daily intake of >400 µg folic acid during the previous week. CONCLUSIONS AND IMPLICATIONS: This study established a baseline of RBC folate, folate consumption and supplement use in Aboriginal and non-Aboriginal groups. We identified 10% of Aboriginal women and none of non-Aboriginal women participants with low folate concentrations. The higher prevalence of folate deficiency in Aboriginal participants suggests they are more likely to benefit from a universal program of folate fortification.

Socio-demographic disparities in the uptake of prenatal screening and diagnosis in Western Australia.

INTRODUCTION: Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state-wide programme. METHODS: Prenatal screening data (2005-2006) were collected from accredited ultrasound and pathology laboratories in Western Australia. Screening data were linked to diagnostic and pregnancy outcome data. Performance characteristics of screening and uptake by socio-demographic characteristics were analysed. RESULTS: Complete screening data were collected for 35,142 of the estimated 38,081 women screened during 2005 and 2006. There were 59,999 births related to this screening period. The lowest uptake of screening was among women who were Aboriginal (14.9%), living in remote areas (38.0%), under the age of 25 (40.2%), in the lowest quintile of the SEIFA index (41.6%) and with three or more children (48.4%). Logistic regression analysis showed all socio-demographic factors to be strongly associated with screening behaviour, with adjustment for ethnicity, socio-economic status, age, parity and area of residence. DISCUSSION: Our results have important implications for the delivery of prenatal screening services in Western Australia. While the screening programme meets international and national performance standards, the disparities in screening uptake suggest inequity in access to services, particularly for Aboriginal, remote and socio-economically disadvantaged women.

Factors driving CT utilisation in tertiary hospitals: a decomposition analysis using linked administrative data in Western Australia.

OBJECTIVES: While CT scanning plays a significant role in healthcare, its increasing use has raised concerns about inappropriate use. This study investigated factors driving the changing use of CT among people admitted to tertiary hospitals in Western Australia (WA). DESIGN AND SETTING: A repeated cross-sectional study of CT use in WA in 2003-2005 and 2013-2015 using linked administrative heath data at the individual patient level. PARTICIPANTS: A total of 2 375 787 tertiary hospital admissions of people aged 18 years or older. MAIN OUTCOME MEASURE: Rate of CT scanning per 1000 hospital admissions. METHODS: A multivariable decomposition model was used to quantify the contribution of changes in patient characteristics and changes in the probability of having a CT over the study period. RESULTS: The rate of CT scanning increased by 112 CT scans per 1000 admissions over the study period. Changes in the distribution of the observed patient characteristics were accounted for 62.7% of the growth in CT use. However, among unplanned admissions, changes in the distribution of patient characteristics only explained 17% of the growth in CT use, the remainder being explained by changes in the probability of having a CT scan. While the relative probability of having a CT scan generally increased over time across most observed characteristics, it reduced in young adults (-2.8%), people living in the rural/remote areas (-0.8%) and people transferred from secondary hospitals (-0.8%). CONCLUSIONS: Our study highlights potential improvements in practice towards reducing medical radiation exposure in certain high risk population. Since changes in the relative probability of having a CT scan (representing changes in scope) rather than changes in the distribution of the patient characteristics (representing changes in need) explained a major proportion of the growth in CT use, this warrants more in-depth investigations in clinical practices to better inform health policies promoting appropriate use of diagnostic imaging tests.

Increasing use of CT requested by emergency department physicians in tertiary hospitals in Western Australia 2003-2015: an analysis of linked administrative data.

OBJECTIVE: This study aimed to examine trends in number of CT scans requested by tertiary emergency department (ED) physicians in Western Australia (WA) from 2003 to 2015 across broad demographic and presentation characteristics, anatomical areas and presented symptoms. DESIGN: An observational cross-sectional study over study period from 2003 to 2015. SETTING: Linked administrative health service data at individual level from WA. PARTICIPANTS: A total of 1 666 884 tertiary hospital ED presentations of people aged 18 years or older were included in this study MAIN OUTCOME MEASURE: Number of CT scans requested by tertiary ED physicians in an ED presentation. METHODS: Poisson regression models were used to assess variation and trends in number of CT scans requested by ED physicians across demographic characteristics, clinical presentation characteristics and anatomical areas. RESULTS: Over the entire study duration, 71 per 1000 ED episodes had a CT requested by tertiary ED physicians. Between 2003 and 2015, the rate of CT scanning almost doubled from 58 to 105 per 1000 ED presentations. After adjusted for all observed characteristics, the rate of CT scans showed a downward trend from 2009 to 2011 and subsequent increase. Males, older individuals, those attending ED as a result of pain, those with neurological symptoms or injury or with higher priority triage code were the most likely to have CT requested by tertiary ED physicians. CONCLUSIONS: Noticeable changes in the number of CTs requested by tertiary ED physicians corresponded to the time frame of major health reforms happening within WA and nationally.

Informing policy for the Australian context - Costs, outcomes and cost savings of prenatal carrier screening for cystic fibrosis.

AIMS: To examine the costs, outcomes and cost savings of three models of prenatal cystic fibrosis (CF) carrier screening compared to no screening from a public health sector perspective. METHODS: A decision tree was generated to estimate costs and outcomes for each screening model for a hypothetical cohort of 38 000 pregnancies. Sensitivity analysis assessed the impact of model parameter variation. RESULTS: Under baseline assumptions, the initial annual cost to provide a prenatal CF carrier-screening programme is Au$5.32 million, Au$3.35 million and $2.93 million for one-step, two-step simultaneous and two-step sequential screening respectively. Annual costs are significantly lower for an established programme. No screening model provides a net saving over a lifetime horizon; however, the results were sensitive to variation in lifetime cost of care, screening test costs and number of pregnancies per carrier couple. CONCLUSIONS: Under some scenarios, prenatal CF carrier screening is cost saving to the health system; however, this is not conclusive and depends on several factors. Cost remains a potential barrier due to the substantial level of funding required in the short term. Feasibility and psychosocial, ethical and legal implications of screening need to be considered. Additionally, consultation is required with the Australian community on the acceptability and/or desire for prenatal CF carrier screening.

How have advances in CT dosimetry software impacted estimates of CT radiation dose and cancer incidence? A comparison of CT dosimetry software: Implications for past and future research.

OBJECTIVE: Organ radiation dose from a CT scan, calculated by CT dosimetry software, can be combined with cancer risk data to estimate cancer incidence resulting from CT exposure. We aim to determine to what extent the use of improved anatomical representation of the adult human body "phantom" in CT dosimetry software impacts estimates of radiation dose and cancer incidence, to inform comparison of past and future research. METHODS: We collected 20 adult cases for each of three CT protocols (abdomen/pelvis, chest and head) from each of five public hospitals (random sample) (January-April inclusive 2010) and three private clinics (self-report). Organ equivalent and effective dose were calculated using both ImPACT (mathematical phantom) and NCICT (voxelised phantom) software. Bland-Altman plots demonstrate agreement and Passing-Bablok regression reports systematic, proportional or random differences between results. We modelled the estimated lifetime attributable risk of cancer from a single exposure for each protocol, using age-sex specific risk-coefficients from the Biologic Effects of Ionizing Radiation VII report. RESULTS: For the majority of organs used in epidemiological studies of cancer incidence, the NCICT software (voxelised) provided higher dose estimates. Across the lifespan NCICT resulted in cancer estimates 2.9%-6.6% and 14.8%-16.3% higher in males and females (abdomen/pelvis) and 7.6%-19.7% and 12.9%-26.5% higher in males and females respectively (chest protocol). For the head protocol overall cancer estimates were lower for NCICT, but with greatest disparity, >30% at times. CONCLUSION: When the results of previous studies estimating CT dose and cancer incidence are compared to more recent, or future, studies the dosimetry software must be considered. Any change in radiation dose or cancer risk may be attributable to the software and phantom used, rather than-or in addition to-changes in scanning practice. Studies using dosimetry software to estimate radiation dose should describe software comprehensively to facilitate comparison with past and future research.

Newborn bloodspot screening policy framework for Australia.

BACKGROUND: The aim of newborn bloodspot screening (NBS) is to identify rare genetic and non-genetic conditions in children soon after birth in order to commence therapies that prevent the development of progressive, serious, and irreversible disabilities. Universal NBS programmes have been implemented in most countries, with minor adaptations to target conditions most relevant to the local healthcare environment. AIMS: In this article, we describe the initiatives of international and Australian governments to develop policies to address the expansion of NBS in their healthcare systems. METHODS: We have reviewed published public policies and literature to formulate recommendations based on clinical, social, legal, and ethical principles to inform a national governance and policy framework for Australia. RESULTS: Australian policy makers have been slow to develop a coordinated plan. While the experience from other governments can guide our national policy, there are specific areas that require further consideration by Australian health experts. Key reforms involve the separation of policy and operational activities, multidisciplinary decision-making and oversight by the Australian Health Ministers' Advisory Council for policy direction. CONCLUSION: A formal national policy framework will guide the coordination of NBS services that can adapt to the needs of Australian children and families.

The Western Australian family connections genealogical project: detection of familial occurrences of single gene and chromosomal disorders.

AIM: To investigate using a Western Australian (WA) genealogical database for the identification of single gene and chromosome disorders among families. METHOD: Hospital admissions for single gene and chromosome disorders recorded during 2000-2006 were identified from the WA Hospital Morbidity Data System. The proportion of these conditions occurring in family groups was then identified using genealogical links created through the WA Family Connections Genealogical Project. RESULTS: There were 216 family clusters among 11,303 people who were recorded as having a genetic or chromosomal disorder on their hospital admission record. The most common single gene conditions found to occur in multiple family members included blood clotting disorders such as Factor VIII deficiency and Von Willebrand's disease, followed by cystic fibrosis, myotonic dystrophies, neurofibromatosis, tuberous sclerosis, and osteogenesis imperfecta. DISCUSSION: Single gene disorders most commonly occurring in multiple family members have been identified using the WA Family Connections Genealogical Project. These disorders reflect the most common single gene disorders requiring hospital admission, but which are not fatal before reproductive age and do not result in a loss of fertility. They are also restricted to disorders with earlier onset, as the WA Family Connections Genealogical Project currently covers 2-3 of the most recent generations. This study demonstrates the utility of record linkage genealogies to identify kindred with genetic disorders, offering a rich resource of information for focused genetic epidemiological research.