Estimating the impact of bias in causal epidemiological studies: the case of health outcomes following assisted reproduction.

Researchers interested in causal questions must deal with two sources of error: random error (random deviation from the true mean value of a distribution), and bias (systematic deviance from the true mean value due to extraneous factors). For some causal questions, randomization is not feasible, and observational studies are necessary. Bias poses a substantial threat to the validity of observational research and can have important consequences for health policy developed from the findings. The current piece describes bias and its sources, outlines proposed methods to estimate its impacts in an observational study, and demonstrates how these methods may be used to inform debate on the causal relationship between medically assisted reproduction (MAR) and health outcomes, using cancer as an example. In doing so, we aim to enlighten researchers who work with observational data, especially regarding the health effects of MAR and infertility, on the pitfalls of bias, and how to address them. We hope that, in combination with the provided example, we can convince readers that estimating the impact of bias in causal epidemiologic research is not only important but necessary to inform the development of robust health policy and clinical practice recommendations.

Economic Evaluation of Newborn Screening for Severe Combined Immunodeficiency.

Evidence on the cost-effectiveness of newborn screening (NBS) for severe combined immunodeficiency (SCID) in the Australian policy context is lacking. In this study, a pilot population-based screening program in Australia was used to model the cost-effectiveness of NBS for SCID from the government perspective. Markov cohort simulations were nested within a decision analytic model to compare the costs and quality-adjusted life-years (QALYs) over a time horizon of 5 and 60 years for two strategies: (1) NBS for SCID and treat with early hematopoietic stem cell transplantation (HSCT); (2) no NBS for SCID and treat with late HSCT. Incremental costs were compared to incremental QALYs to calculate the incremental cost-effectiveness ratios (ICER). Sensitivity analyses were performed to assess the model uncertainty and identify key parameters impacting on the ICER. In the long-term over 60 years, universal NBS for SCID would gain 10 QALYs at a cost of US $0.3 million, resulting in an ICER of US$33,600/QALY. Probabilistic sensitivity analysis showed that more than half of the simulated ICERs were considered cost-effective against the common willingness-to-pay threshold of A$50,000/QALY (US$35,000/QALY). In the Australian context, screening for SCID should be introduced into the current NBS program from both clinical and economic perspectives.

Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency.

Spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) are rare, inherited genetic disorders with severe mortality and morbidity. The benefits of early diagnosis and initiation of treatment are now increasingly recognized, with the most benefits in patients treated prior to symptom onset. The aim of the economic evaluation was to investigate the costs and outcomes associated with the introduction of universal newborn screening (NBS) for SCID and SMA, by generating measures of cost-effectiveness and budget impact. A stepwise approach to the cost-effectiveness analyses by decision analytical models nested with Markov simulations for SMA and SCID were conducted from the government perspective. Over a 60-year time horizon, screening every newborn in the population and treating diagnosed SCID by early hematopoietic stem cell transplantation and SMA by gene therapy, would result in 95 QALYs gained per 100,000 newborns, and result in cost savings of USD 8.6 million. Sensitivity analysis indicates 97% of simulated results are considered cost-effective against commonly used willingness-to-pay thresholds. The introduction of combined NBS for SCID and SMA is good value for money from the long-term clinical and economic perspectives, representing a cost saving to governments in the long-term, as well as improving and saving lives.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

STUDY QUESTION: In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER: In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY: There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION: This is a novel population-based birth cohort study of 898 084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks' gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included a total of 898 084 births (606 488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009-2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent's age, parity, socio-economic status, maternal country of birth, remoteness of mother's dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother's age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81-0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74-0.77]). LIMITATIONS, REASONS FOR CAUTION: The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS: With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women's and Children's Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The clinical performance and cost-effectiveness of two psychosocial assessment models in maternity care: The Perinatal Integrated Psychosocial Assessment study.

PROBLEM: Although perinatal universal depression and psychosocial assessment is recommended in Australia, its clinical performance and cost-effectiveness remain uncertain. AIM: To compare the performance and cost-effectiveness of two models of psychosocial assessment: Usual-Care and Perinatal Integrated Psychosocial Assessment (PIPA). METHODS: Women attending their first antenatal visit were prospectively recruited to this cohort study. Endorsement of significant depressive symptoms or psychosocial risk generated an 'at-risk' flag identifying those needing referral to the Triage Committee. Based on its detailed algorithm, a higher threshold of risk was required to trigger the 'at-risk' flag for PIPA than for Usual-Care. Each model's performance was evaluated using the midwife's agreement with the 'at-risk' flag as the reference standard. Cost-effectiveness was limited to the identification of True Positive and False Positive cases. Staffing costs associated with administering each screening model were quantified using a bottom-up time-in-motion approach. FINDINGS: Both models performed well at identifying 'at-risk' women (sensitivity: Usual-Care 0.82 versus PIPA 0.78). However, the PIPA model was more effective at eliminating False Positives and correctly identifying 'at-risk' women (Positive Predictive Value: PIPA 0.69 versus Usual Care 0.41). PIPA was associated with small incremental savings for both True Positives detected and False Positives averted. DISCUSSION: Overall PIPA performed better than Usual-Care as a psychosocial screening model and was a cost-saving and relatively effective approach for detecting True Positives and averting False Positives. These initial findings warrant evaluation of longer-term costs and outcomes of women identified by the models as 'at-risk' and 'not at-risk' of perinatal psychosocial morbidity.

Impact of influenza on hospitalization rates in children with a range of chronic lung diseases.

BACKGROUND: Data on burden of severe influenza in children with a range of chronic lung diseases (CLDs) remain limited. METHOD: We performed a cohort study to estimate burden of influenza-associated hospitalization in children with CLDs using population-based linked data. The cohort comprised all children in New South Wales, Australia, born between 2001 and 2010 and was divided into five groups, children with: (a) severe asthma; (b) bronchopulmonary dysplasia (BPD); (c) cystic fibrosis (CF); (d) other congenital/chronic lung conditions; and (e) children without CLDs. Incidence rates and rate ratios for influenza-associated hospitalization were calculated for 2001-2011. Average cost/episode of hospitalization was estimated using public hospital cost weights. RESULTS: Our cohort comprised 888 157 children; 11 058 (1.2%) had one of the CLDs. The adjusted incidence/1000 child-years of influenza-associated hospitalization in children with CLDs was 3.9 (95% CI: 2.6-5.2) and 0.7 (95% CI: 0.5-0.9) for children without. The rate ratio was 5.4 in children with CLDs compared to children without. The adjusted incidence/1000 child-years (95% CI) in children with severe asthma was 1.1 (0.6-1.6), with BPD was 6.0 (3.7-8.3), with CF was 7.4 (2.6-12.1), and with other congenital/chronic lung conditions was 6.9 (4.9-8.9). The cost/episode (95% CI) of influenza-associated hospitalization was AUD 19 704 (95% CI: 11 715-27 693) for children with CLDs compared to 4557 (95% CI: 4129-4984) for children without. DISCUSSION: This large population-based study suggests a significant healthcare burden associated with influenza in children with a range of CLDs.

Mental health consultations in the perinatal period: a cost-analysis of Medicare services provided to women during a period of intense mental health reform in Australia.

Objective To quantify total provider fees, benefits paid by the Australian Government and out-of-pocket patients' costs of mental health Medicare Benefits Schedule (MBS) consultations provided to women in the perinatal period (pregnancy to end of the first postnatal year). Method A retrospective study of MBS utilisation and costs (in 2011-12 A$) for women giving birth between 2006 and 2010 by state, provider-type, and geographic remoteness was undertaken. Results The cost of mental health consultations during the perinatal period was A$17.5million for women giving birth in 2007, rising to A$29million in 2010. Almost 9% of women giving birth in 2007 had a mental health consultation compared with more than 14% in 2010. An increase in women accessing consultations, along with an increase in the average number of consultations received, were the main drivers of the increased cost, with costs per service remaining stable. There was a shift to non-specialist care and bulk billing rates increased from 44% to 52% over the study period. In 2010, the average total cost (provider fees) per woman accessing mental health consultations during the perinatal period was A$689, and the average cost per service was A$133. Compared with women residing in regional and remote areas, women residing in major cities where more likely to access consultations, and these were more likely to be with a psychiatrist rather than an allied health professional or general practitioner. Conclusion Increased access to mental health consultations has coincided with the introduction of recent mental health initiatives, however disparities exist based on geographic location. This detailed cost analysis identifies inequities of access to perinatal mental health services in regional and remote areas and provides important data for economic and policy analysis of future mental health initiatives. What is known about the topic? The mental healthcare landscape in Australia has changed significantly over the last decade, with the introduction of numerous policies aimed at prevention, screening and improving access to treatment. Several of these policies have been aimed at perinatal depression, which affects 15% of women giving birth. What does this paper add? This is the first population-based, cost analysis of mental health consultations during the perinatal period (pregnancy to end of the first postnatal year) in Australia. Almost 9% of women giving birth in 2007 had a mental health consultation funded though the MBS, compared with more than 14% in 2010. Over the same period there was a shift from psychiatric consultations to allied health and primary care consultations. In 2010, the total cost (provider fee) of these consultations was A$29million, equating to an average cost per woman of A$689 and A$133 per service. Despite the changing policy environment, significant disparities exist in access to care according to geographic remoteness. What are the implications for practitioners? Recent policy initiatives have resulted in increasing access to mental health consultations for women around the time of childbirth. However, policies are needed that target women outside of major cities. Furthermore, evidence is needed on whether the increase in access has resulted in improved mental health outcomes for women at this vulnerable time. The cost data provided by this study are unique and will inform future mental health policy development and health economic evaluations.

The role, yield and cost of paediatric faecal elastase-1 testing.

OBJECTIVE: Faecal elastase-1 (FE1) is a sensitive marker for exocrine pancreatic enzyme insufficiency. Pancreatic insufficiency (EPI) leads to maldigestion and subsequent poor weight gain. Thus, FE1 is performed as work-up for children with failure to thrive (FTT). However, EPI in the paediatric population outside of cystic fibrosis (CF) is rare. This study aimed to identify the indications for FE1 testing and their diagnostic yield in children. The secondary aim was to evaluate the cost per case of EPI detected for the various indications. DESIGN: All FE1 tests performed on children (0-18 years) at a tertiary paediatric hospital in Sydney, Australia between 2010 and 2013 (inclusive) were identified. A retrospective chart audit was performed to identify the indication for testing FE1. The diagnostic yield based on FE1 cut-offs <200 and < 100 µg/g were assessed. RESULTS: The most common indication for testing FE1 was "FTT only" (71/216, 32.9%), however, in this cohort of patients, FE1 was least likely to be positive with only 2 out of the 71 (2.8%) patients returning a positive result. In comparison, CF was the second most common indication for testing (60/216, 27.8%), but nearly half (48.8%) of tests returned a positive result in this cohort. The cost per case detected (FE1 <200 µg/g) reflected the test yield with an average cost per positive test of $262.50 (AUD2015) for FTT with short-gut syndrome and $420.00 (AUD2015) for CF-related indications. CONCLUSION: Our study shows that for patients with isolated failure to thrive, FE1 testing is low yield and costly.

The National Perinatal Depression Initiative: An evaluation of access to general practitioners, psychologists and psychiatrists through the Medicare Benefits Schedule.

OBJECTIVE: To evaluate the impact of the National Perinatal Depression Initiative on access to Medicare services for women at risk of perinatal mental illness. METHOD: Retrospective cohort study using difference-in-difference analytical methods to quantify the impact of the National Perinatal Depression Initiative policies on Medicare Benefits Schedule mental health usage by Australian women giving birth between 2006 and 2010. A random sample of women of reproductive age enrolled in Medicare who had not given birth where used as controls. The main outcome measures were the proportions of women giving birth each month who accessed a Medicare Benefits Schedule mental health items during the perinatal period (pregnancy through to the end of the first postnatal year) before and after the introduction of the National Perinatal Depression Initiative. RESULTS: The proportion of women giving birth who accessed at least one mental health item during the perinatal period increased from 88 to 141 per 1000 between 2007 and 2010. The difference-in-difference analysis showed that while there was an overall increase in Medicare Benefits Schedule mental health item access as a result of the National Perinatal Depression Initiative, this did not reach statistical significance. However, the National Perinatal Depression Initiative was found to significantly increase access in subpopulations of women, particularly those aged under 25 and over 34 years living in major cities. CONCLUSION: In the 2 years following its introduction, the National Perinatal Depression Initiative was found to have increased access to Medicare funded mental health services in particular groups of women. However, an overall increase across all groups did not reach statistical significance. Further studies are needed to assess the impact of the National Perinatal Depression Initiative on women during childbearing years, including access to tertiary care, the cost-effectiveness of the initiative, and mental health outcomes. It is recommended that new mental health policy initiatives incorporate a planned strategic approach to evaluation, which includes sufficient follow-up to assess the impact of public health strategies.