Effectiveness of sensory modulation for people with schizophrenia: A multisite quantitative prospective cohort study.

INTRODUCTION: Current research evidence suggests that people with schizophrenia have sensory processing difficulties. Sensory modulation has growing evidence for use in this population. This study aimed to evaluate the extent to which health, social, cognitive, and occupational functioning outcomes were impacted by sensory modulation interventions for people with schizophrenia. METHODS: A prospective observational cohort study using a waitlist control design was used in two large hospital and health services in Queensland, Australia. The study recruited patients who used sensory modulation (n = 30) across the two hospitals and those who did not use sensory modulation interventions as a control (n = 11). Results were analysed using a series of planned comparisons including independent and paired t-tests, and mixed ANOVA was used whenever statistically indicated. The analysed measures were pre- and post-intervention scores. RESULTS: This study found no statically significant differences between the control and intervention groups at both pre- and post-intervention. However, analysis of results from within the intervention group showed statistically significant improvements between pre- and post-test scores on distress, occupational functioning, and health and social functioning but not on sensory processing and global cognitive processing. Further analysis of results from this study, compared with those from an earlier study on the general population showed significant differences in Low Registration and Sensation Avoiding, as measured by the Adult/Adolescent Sensory Profile, between participants with schizophrenia and those without schizophrenia. CONCLUSION: This study provides evidence to suggest that sensory modulation interventions can be complementary to standard care when utilised appropriately in clinical settings. Findings also suggest that the sensory profile of people with schizophrenia is different to that of the general population and this may have clinical implications. Further longitudinal research is needed with larger and randomised samples, using more targeted measures to better explore effectiveness of sensory modulation interventions.

Exact confidence limits after a group sequential single arm binary trial.

Group sequential single arm designs are common in phase II trials as well as attribute testing and acceptance sampling. After the trial is completed, especially if the recommendation is to proceed to further testing, there is interest in full inference on treatment efficacy. For a binary response, there is the potential to construct exact upper and lower confidence limits, the first published method for which is Jennison and Turnbull (1983). We place their method within the modern theory of exact confidence limits and provide a new general result that ensures that the exact limits are consistent with the test result, an issue that has been largely ignored in the literature. Amongst methods based on the minimal sufficient statistic, we propose two exact methods that out-perform Jennison and Turnbull's method across 10 selected designs. One of these we prefer and recommend for practical and theoretical reasons. We also investigate a method based on inverting Fisher's combination test, as well as a pure tie-breaking variant of it. For the range of designs considered, neither of these methods result in large enough improvements in efficiency to justify violation of the sufficiency principle. For any nonadaptive sequential design, an R-package is provided to select a method and compute the inference from a given realization.

Tests for noninferiority trials with binomial endpoints: A guide to modern and quasi-exact methods for biomedical researchers.

Applied statisticians and pharmaceutical researchers are frequently involved in the design and analysis of clinical trials where at least one of the outcomes is binary. Treatments are judged by the probability of a positive binary response. A typical example is the noninferiority trial, where it is tested whether a new experimental treatment is practically not inferior to an active comparator with a prespecified margin δ. Except for the special case of δ = 0, no exact conditional test is available although approximate conditional methods (also called second-order methods) can be applied. However, in some situations, the approximation can be poor and the logical argument for approximate conditioning is not compelling. The alternative is to consider an unconditional approach. Standard methods like the pooled z-test are already unconditional although approximate. In this article, we review and illustrate unconditional methods with a heavy emphasis on modern methods that can deliver exact, or near exact, results. For noninferiority trials based on either rate difference or rate ratio, our recommendation is to use the so-called E-procedure, based on either the score or likelihood ratio statistic. This test is effectively exact, computationally efficient, and respects monotonicity constraints in practice. We support our assertions with a numerical study, and we illustrate the concepts developed in theory with a clinical example in pulmonary oncology; R code to conduct all these analyses is available from the authors.

MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue.

BACKGROUND: Major histocompatibility complex (MHC) class I chain-related protein A (MICA) and MHC class I chain-related protein B (MICB) are polymorphic proteins that are induced upon stress, damage or transformation of cells which act as a 'kill me' signal through the natural-killer group 2, member D receptor expressed on cytotoxic lymphocytes. MICA/B are not thought to be constitutively expressed by healthy normal cells but expression has been reported for most tumour types. However, it is not clear how much of this protein is expressed on the cell surface. METHODS: Using a novel, well-characterised antibody and both standard and confocal microscopy, we systematically profiled MICA/B expression in multiple human tumour and normal tissue. RESULTS: High expression of MICA/B was detected in the majority of tumour tissues from multiple indications. Importantly, MICA/B proteins were predominantly localised intracellularly with only occasional evidence of cell membrane localisation. MICA/B expression was also demonstrated in most normal tissue epithelia and predominantly localised intracellularly. Crucially, we did not observe qualitative differences in cell surface expression between tumour and MICA/B expressing normal epithelia. CONCLUSIONS: This demonstrates for the first time that MICA/B is more broadly expressed in normal tissue and that expression is mainly intracellular with only a small fraction appearing on the cell surface of some epithelia and tumour cells.

Accurate p-values for adaptive designs with binary endpoints.

Adaptive designs encompass all trials allowing various types of design modifications over the course of the trial. A key requirement for confirmatory adaptive designs to be accepted by regulators is the strong control of the family-wise error rate. This can be achieved by combining the p-values for each arm and stage to account for adaptations (including but not limited to treatment selection), sample size adaptation and multiple stages. While the theory for this is novel and well-established, in practice, these methods can perform poorly, especially for unbalanced designs and for small to moderate sample sizes. The problem is that standard stagewise tests have inflated type I error rate, especially but not only when the baseline success rate is close to the boundary and this is carried over to the adaptive tests, seriously inflating the family-wise error rate. We propose to fix this problem by feeding the adaptive test with second-order accurate p-values, in particular bootstrap p-values. Secondly, an adjusted version of the Simes procedure for testing intersection hypotheses that reduces the built-in conservatism is suggested. Numerical work and simulations show that unlike their standard counterparts the new approach preserves the overall error rate, at or below the nominal level across the board, irrespective of the baseline rate, stagewise sample sizes or allocation ratio. Copyright © 2017 John Wiley & Sons, Ltd.

Implementing evidence-based practices in supported employment on the Gold Coast for people with severe mental illness.

AIM: The aim of this project was to evaluate program outcomes following the implementation of an evidence-based approach to supported employment on the Gold Coast, Queensland, Australia. METHOD: A prospective observational design was used to evaluate employment outcomes and fidelity to the evidence-based principles and practices of a specialised form of supported employment. The cohort was defined as all those (n = 114) that entered the program at each of three sites within a 21-month period. Each participant was followed up for a minimum of six months. All three sites implemented the employment program by establishing a partnership between a non-government organisation and the Gold Coast community mental health service. RESULTS: The primary outcome variable was the proportion commencing competitive employment during the follow-up period from among those that commenced receiving assistance (the denominator). This ranged from 12% at Site C to 33.3% at Site A, and 37% at Site B. Fidelity to evidence-based principles was fair at Sites A and C and good at Site B. These results were below expectations based on international-controlled trials. The variation in site effectiveness appeared related to both fidelity to evidence-based principles and to other factors at each site, which could not be clearly identified. CONCLUSIONS: Delivering an effective supported employment program using an inter-agency partnership method is challenging. There are several roles in which occupational therapists can be involved that facilitate improving both the implementation and the effectiveness of supported employment for people with severe mental illness in Australia.

Accurate confidence limits for stratified clinical trials.

For stratified 2 × 2 tables, standard approximate confidence limits can perform poorly from a strict frequentist perspective, even for moderate-sized samples, yet they are routinely used. In this paper, I show how to use importance sampling to compute highly accurate limits in reasonable time. The methodology is very general and simple to implement, and orders of magnitude are faster than existing alternatives.

Improving adherence and health outcomes in testicular cancer survivors using a mobile health-based intervention: A mixed-methods pilot study.

Objective: Testicular cancer (TC) is one of the most common cancers among young men, with survival rates exceeding 97% due to effective treatments. Post-treatment follow-up care is important for long-term survival and monitoring psychosocial symptoms, yet TC survivors (TCS) show poor adherence to post-treatment care. Mobile-health-based interventions show high acceptability in men with cancer. This study will examine the feasibility of using the Zamplo health app to improve adherence to post-treatment care and support psychosocial outcomes in TCS. Methods: This mixed-methods, longitudinal, single-arm pilot study will recruit N = 30 patients with a diagnosis of TC who finished treatment within ≤ 6 months and are currently aged ≥18 years old. Adherence to follow-up appointments (e.g. blood work, scans) will be assessed (primary outcome), and measures for fatigue, depression, anxiety, sexual satisfaction and function, social roles satisfaction, general mental and physical health and body image (secondary outcomes) will be completed at four-time points: baseline, 3, 6 and 12 months. One-on-one semi-structured interviews will be conducted post-intervention (month 12). Results: Improvements in post-treatment follow-up appointment adherence and psychosocial outcomes will be analyzed using descriptive statistics, paired samples t-tests to determine changes across time points 1 through 4, and correlation analysis. Qualitative data will be analyzed using thematic analysis. Conclusion: Findings will inform future, larger trials that incorporate evaluation of sustainability and economic implications to improve adherence to TC follow-up guidelines. Findings will be disseminated via infographics, social media, publications and presentations conducted in partnership with TC support organizations and at conferences.

Earning and learning among Australian community residents with psychiatric disorders.

At a population level the extent that psychiatric disorders and other health conditions disrupt participation in education and employment is rarely considered simultaneously and remains largely unknown. This is an important issue because policy makers are as concerned with educational attainment, school to work transitions, and workforce skills, as they are with overall labour force participation. We investigated earning or learning, and educational attainment, among Australian community residents by age group and by category of psychiatric disorder. Data files were provided by the Australian Bureau of Statistics (ABS) from a population survey conducted in 2003 using a multi-stage probability sample (N=23,787). Adults with schizophrenia, depression, and anxiety disorders were compared to (1) working age adults with other non-psychiatric health conditions and disabilities; and (2) healthy adults of working age. Participation in formal education and employment was extensively disrupted by all health conditions and by psychiatric disorders in particular. The extent of career-related disruption provides benchmarks for policy makers and service providers attempting to increase participation in formal education and in the labour force.

The reliability of an education-related self-efficacy scale for people with psychiatric disabilities.

We investigated the reliability of the Education-related Self Efficacy Scale (ESS-40), a measure of self-efficacy at a core task level designed for people with psychiatric disabilities. Sixty community residents with schizophrenia or schizoaffective disorder participated. The ESS-40 was administered twice via telephone interview. Short cycle test-retest reliability was very good for the total score and most items. The measure demonstrated signs of a coherent internal structure, adequate face validity, good client acceptability, and promising utility. The reliability evidence supports its use in community mental health services and in psychiatric rehabilitation settings. Sensitivity and predictive validity require further investigation.

Reliability and validity of a measure of role functioning among people with psychiatric disabilities.

AIM: The aim was to investigate the reliability and validity of the Socially Valued Role Classification Scale (SRCS), a domain-specific measure of role functioning designed for use with community residents with psychiatric disabilities. Test-retest reliability, concurrent validity, face validity, consumer and clinician acceptability and utility were examined. METHODS: Sixty community residents with schizophrenia or schizoaffective disorder participated in this study where the SRCS was administered by telephone. RESULTS: Test-retest reliability showed good or very good agreement for subscale scores (intraclass correlations (ICCs): 0.78-0.89) and for items capturing amount of participation in domain-specific activities (ICC: 0.67-1.00). Greater variation was observed for items capturing assistance required with activities (κ: 0.40-0.75), and standard of activities performed (κ: 0.43-1.00). Concurrent validity was supported by moderate to very good associations in the directions expected. Face validity, user acceptability and utility in telephone interviews were adequate. CONCLUSIONS: These findings add to previous psychometric evidence and support the continued development of the SRCS for use in community mental health settings. The SRCS has promising utility for occupational therapists involved in psychiatric rehabilitation outcome measurement.

A comprehensive open-source library for exact required sample size in binary clinical trials.

We describe how we are creating a new and comprehensive R library solving the problem of exact sample size determination of RCTs. A crucial prerequisite for the trial protocol is a priori sample sizes that bound the test size below a target (often 5%) and the test power above a target (often 80%). Approximate formulas are available for binary trials but the target test size and power are often violated by standard methods for even quite large sample sizes. Moreover, adjusting standard tests to take account of their size bias can reduce power substantially. This has been well known for several decades. Exact and quasi-exact tests are now available and can be computed in a few seconds for a single data set. However, calculating the exact power and size of such tests requires computing them for all possible outcomes. Searching for minimum samples sizes that achieve a given target requires doing this for a wide range of sample sizes. This becomes computationally infeasible very quickly; to compute required sample sizes for a target size of 5% and power of 80% would, on a standard computer, take several months. Computation time increases as the size and clinically relevant difference decreases. After having presented the main operative challenges to creating this library, mainly due to the need of summarizing a very large amount of information, we put forward our innovative solutions to deal with this complex problem from a statistical viewpoint. The described library will be released in open source.

Bootstrap and second-order tests of risk difference.

Clinical trials data often come in the form of low-dimensional tables of small counts. Standard approximate tests such as score and likelihood ratio tests are imperfect in several respects. First, they can give quite different answers from the same data. Second, the actual type-1 error can differ significantly from nominal, even for quite large sample sizes. Third, exact inferences based on these can be strongly nonmonotonic functions of the null parameter and lead to confidence sets that are discontiguous. There are two modern approaches to small sample inference. One is to use so-called higher order asymptotics (Reid, 2003, Annal of Statistics 31, 1695-1731) to provide an explicit adjustment to the likelihood ratio statistic. The theory for this is complex but the statistic is quick to compute. The second approach is to perform an exact calculation of significance assuming the nuisance parameters equal their null estimate (Lee and Young, 2005, Statistic and Probability Letters 71, 143-153), which is a kind of parametric bootstrap. The purpose of this article is to explain and evaluate these two methods, for testing whether a difference in probabilities p(2) - p(1) exceeds a prechosen noninferiority margin δ(0) . On the basis of an extensive numerical study, we recommend bootstrap P-values as superior to all other alternatives. First, they produce practically identical answers regardless of the basic test statistic chosen. Second, they have excellent size accuracy and higher power. Third, they vary much less erratically with the null parameter value δ(0) .

Labour market conditions, labour force activity and prevalence of psychiatric disorders.

BACKGROUND: At a population level, the extent that labour market conditions influence labour force activity among people with psychiatric disorders, remains equivocal. Similarly equivocal is the hypothesised relationship between economic conditions and the reported prevalence of specific psychiatric disorders. We investigated these issues by examining the extent that labour market conditions were associated with change in labour force activity among people with anxiety disorders, affective disorders, and schizophrenia, in comparison to healthy working age adults. METHODS: Data files were provided by the Australian Bureau of Statistics (ABS) from a population survey conducted in 1998 and replicated in 2003. Multi-stage probability samples were obtained in 1998 (N(1) = 37,580) and 2003 (N(2) = 36,088). Adults with schizophrenia, depression, and anxiety disorders were compared to healthy working age adults. RESULTS: Greater labour demand in 2003 was positively associated with increased labour force participation among healthy adults. The proportions actively looking for work declined among healthy adults and among those with anxiety disorders. Full-time employment significantly increased among healthy working age residents. The proportions employed part-time significantly increased in all groups except among people with schizophrenia. CONCLUSION: These results support policies which remove disincentives and increase access to the more intensive evidence-based employment programs even when labour market conditions are improving.

A new exact and more powerful unconditional test of no treatment effect from binary matched pairs.

We consider the problem of testing for a difference in the probability of success from matched binary pairs. Starting with three standard inexact tests, the nuisance parameter is first estimated and then the residual dependence is eliminated by maximization, producing what I call an E+M P-value. The E+M P-value based on McNemar's statistic is shown numerically to dominate previous suggestions, including partially maximized P-values as described in Berger and Sidik (2003, Statistical Methods in Medical Research 12, 91-108). The latter method, however, may have computational advantages for large samples.

Comorbid physical health conditions hinder employment among people with psychiatric disabilities.

OBJECTIVE: To investigate whether comorbid physical health conditions hinder employment for people with psychiatric disabilities. METHOD: A secondary analysis of a 12-month longitudinal natural observation study. Community residents (n = 104) with schizophrenia or schizoaffective disorder were interviewed at baseline, 6 and 12 months. RESULTS: Comorbid physical health conditions were negatively associated with employment status. CONCLUSIONS: More attention to physical health conditions may improve outcomes in psychiatric vocational rehabilitation.

Musculoskeletal disorders and comorbid depression: implications for practice.

BACKGROUND: The physical demands of work have a substantial impact on the incidence of work-related musculoskeletal disorders. Depression is often associated with work-related injuries and may influence a person's success or otherwise return to work. There is pressure for occupational rehabilitation providers to produce good return-to-work outcomes in a timely and financially responsible manner. The aim was to examine current evidence for any added impact of depression on return-to-work prospects among people with work-related musculoskeletal disorders. METHODS: A review of the literature was conducted to determine the extent to which depression comorbid with musculoskeletal disorders affected labour force participation and the outcomes obtained in occupational rehabilitation. RESULTS: Australian population level data show that people of working age with depression comorbid with musculoskeletal disorders have extensive labour force disadvantage and reduced return-to-work outcomes when participating in occupational rehabilitation. CONCLUSIONS: Although more research is needed, there is already sufficient evidence to support the introduction of systems and practices to detect and integrate treatment for comorbid depression in order to prevent occupational rehabilitation failure.

Reliability of a composite measure of social inclusion for people with psychiatric disabilities.

AIM: To assess the reliability of the components of a proposed composite measure of social inclusion for people with psychiatric disabilities. METHOD: The interview covered sociodemographics, domain-specific socially valued role functioning, social support, stigma experiences, integration within the immediate psychosocial rehabilitation community, and integration within the wider neighbourhood community. Participants (n(1) = 28; n(2) = 26) were recruited from a psychosocial rehabilitation setting. The candidate measures were assessed for short-cycle test-retest reliability and internal consistency. RESULTS: Several items were identified for removal from the stigma experiences and community integration subscales because of low test-retest reliability or for having not sufficiently contributed to internal consistency. CONCLUSIONS: The promising test-retest and internal consistency results warrant continuing the psychometric development of the composite measures of social inclusion and its applicability to community residents with psychiatric disabilities.

A new method of identifying target groups for pronatalist policy applied to Australia.

A country's total fertility rate (TFR) depends on many factors. Attributing changes in TFR to changes of policy is difficult, as they could easily be correlated with changes in the unmeasured drivers of TFR. A case in point is Australia where both pronatalist effort and TFR increased in lock step from 2001 to 2008 and then decreased. The global financial crisis or other unobserved confounders might explain both the reducing TFR and pronatalist incentives after 2008. Therefore, it is difficult to estimate causal effects of policy using econometric techniques. The aim of this study is to instead look at the structure of the population to identify which subgroups most influence TFR. Specifically, we build a stochastic model relating TFR to the fertility rates of various subgroups and calculate elasticity of TFR with respect to each rate. For each subgroup, the ratio of its elasticity to its group size is used to evaluate the subgroup's potential cost effectiveness as a pronatalist target. In addition, we measure the historical stability of group fertility rates, which measures propensity to change. Groups with a high effectiveness ratio and also high propensity to change are natural policy targets. We applied this new method to Australian data on fertility rates broken down by parity, age and marital status. The results show that targeting parity 3+ is more cost-effective than lower parities. This study contributes to the literature on pronatalist policies by investigating the targeting of policies, and generates important implications for formulating cost-effective policies.