Interpreting the clinical utility of a pharmacogenomic marker based on observational association studies

The author accepted manuscript (post print) is made available in accordance with with publisher copyright policy.It is increasingly recognized that the clinical utility of a pharmacogenomic marker is a fundamental characteristic influencing the likelihood of successful clinical translation. Although appropriately designed and executed randomized controlled trials generally provide the most valid evidence for the clinical utility of a pharmacogenomic marker, such evidence may not always be available. Observational pharmacogenomic association studies are a common form of evidence available, but the assessment of clinical utility based on such evidence is often not straightforward. This paper aims to provide insight into this issue using a range of illustrative examples

Reducing perinatal mortality among Indigenous babies in Queensland: should the first priority be better primary health care or better access to hospital care during confinement?

BACKGROUND: The perinatal mortality rate among Indigenous Australians is still double that of the rest of the community. The aim of our study was to estimate the extent to which increased risk of low birthweight and preterm birth among Indigenous babies in Queensland account for their continuing mortality excess. If a large proportion of excess deaths can be explained by the unfavourable birthweight and gestational age distribution of Indigenous babies, then that would suggest that priority should be given to implementing primary health care interventions to reduce the risk of low birthweight and preterm birth (eg, interventions to reduce maternal smoking or genitourinary infections). Conversely, if only a small proportion is explained by birthweight and gestational age, then other strategies might need to be considered such as improving access to high-quality hospital care around the time of confinement. METHODOLOGY: Population-based, descriptive study of perinatal mortality rates among Indigenous and non-Indigenous babies, in Queensland, stratified by birthweight and gestational age. RESULTS: Indigenous babies are twice as likely to die as their non-Indigenous counterparts (rate ratio1998–2002: 2.01; 95%ci 1.77, 2.28). However, within separate strata of birth weight and gestational age, Indigenous and non-Indigenous rates are similar. The Mantel-Haenszel rate ratio adjusted for birth weight and gestational age was 1.13 (0.99, 1.28). This means that most of the excess mortality in Indigenous babies is largely due to their unfavourable birth weight and gestational-age distributions. If Indigenous babies had the same birth weight and gestational age distribution as their non-Indigenous counterparts, then the relative disparity would be reduced by 87% and 20 fewer Indigenous babies would die in Queensland each year. CONCLUSION: Our results suggest that Indigenous mothers at high risk of poor outcome (for example those Indigenous mothers in preterm labour) have good access to high quality medical care around the time of confinement. The main reason Indigenous babies have a high risk of death is because they are born too early and too small. Thus, to reduce the relative excess of deaths among Indigenous babies, priority should be given to primary health care initiatives aimed at reducing the prevalence of low birth weight and preterm birth

Influenza-like illness surveillance using a deputising medical service corresponds to surveillance from sentinel general practices

Standard sources of data for influenza surveillance include notifications of laboratory-confirmed cases and notifications from sentinel general practices. These data are not always available in a timely fashion, leading to proposals to use more immediate data sources such as over-the-counter drug sales, ambulance call-outs and web searches to monitor influenza-like illness (ILI). We aimed to assess data from a deputising medical service as another source of data for timely syndromic influenza surveillance. We measured the extent of agreement between the weekly percentage of patients with ILI reported from sentinel general practices and the corresponding weekly percentage reported from a deputising medical service in Victoria, Australia over ten years, from 1999 to 2008. There was good agreement between the two data sources, with suitably narrow limits of agreement. The deputising medical service did not use a standardised definition of ILI and is not supplemented by laboratory confirmation of suspected cases. Nevertheless, the results of this study show that such data can provide low cost and timely ILI surveillance

Survival of indigenous and non-Indigenous Queenslanders after a diagnosis of lung cancer: a matched cohort study

Objective: To compare survival of Indigenous and non-Indigenous lung cancer patients and to investigate any corresponding differences in stage, treatment and comorbidities.Design and setting: Cohort study of 158 Indigenous and 152 non-Indigenous patients (frequency-matched on age, sex and rurality) diagnosed with lung cancer between 1996 and 2002 and treated in Queensland public hospitals.Main outcome measures: Survival after diagnosis of lung cancer; effects of stage at diagnosis, treatment, comorbidities and histological subtype on lung cancer-specific survival.Results: Survival of Indigenous lung cancer patients was significantly lower than that of non-Indigenous patients (median survival, 4.3 v 10.3 months; hazard ratio, 1.48; 95% CI, 1.14–1.92). Of 158 Indigenous patients, 72 (46%) received active treatment with chemotherapy, radiotherapy or surgery compared with 109 (72%) of the 152 non-Indigenous patients, and this treatment disparity remained after adjusting for histological subtype, stage at diagnosis, and comorbidities (adjusted risk ratio, 0.65; 95% CI, 0.53–0.73). The treatment disparity explained most of the survival deficit: the hazard ratio reduced to 1.10 (95% CI, 0.83–1.44) after inclusion of treatment variables in the proportional hazards survival model. The remaining survival deficit was explained by the higher prevalence of comorbidities among Indigenous cancer patients, mainly diabetes.Conclusion: Survival after a diagnosis of lung cancer is worse for Indigenous patients than for non-Indigenous patients, and differences in treatment between the two groups are mainly responsible

Indirect estimation of the comparative treatment effect in pharmacogenomic subgroups

Evidence of clinical utility is a key issue in translating pharmacogenomics into clinical practice. Appropriately designed randomized controlled trials generally provide the most robust evidence of the clinical utility, but often only data from a pharmacogenomic association study are available. This paper details a method for reframing the results of pharmacogenomic association studies in terms of the comparative treatment effect for a pharmacogenomic subgroup to provide greater insight into the likely clinical utility of a pharmacogenomic marker, its' likely cost effectiveness, and the value of undertaking the further (often expensive) research required for translation into clinical practice. The method is based on the law of total probability, which relates marginal and conditional probability. It takes as inputs: the prevalence of the pharmacogenomic marker in the patient group of interest, prognostic effect of the pharmacogenomic marker based on observational association studies, and the unstratified comparative treatment effect based on one or more conventional randomized controlled trials. The critical assumption is that of exchangeability across the included studies. The method is demonstrated using a case study of cytochrome P450 (CYP) 2C19 genotype and the anti-platelet agent clopidogrel. Indirect subgroup analysis provided insight into relationship between the clinical utility of genotyping CYP2C19 and the risk ratio of cardiovascular outcomes between CYP2C19 genotypes for individuals using clopidogrel. In this case study the indirect and direct estimates of the treatment effect for the cytochrome P450 2C19 subgroups were similar. In general, however, indirect estimates are likely to have substantially greater risk of bias than an equivalent direct estimate.Michael J. Sorich, Michael Coory, Brita A. K. Pekarsk

Delays in lung cancer referral pathways between rural and urban patients in North Queensland: a mixed methods study

INTRODUCTION: Aims of this study were to examine time delays in lung cancer referral pathways in North Queensland (NQ), Australia, and explore patients' perspective of factors causing these delays. METHODS: Prospective study of patients attending three cancer centres in Townsville, Cairns and Mackay in NQ from 2009 to 2012. Times along referral pathway were divided as follows: Onset of symptoms to treatment (T1), symptoms to general practitioner(GP) (T2), GP to specialist (T3), and Specialist to treatment (T4). Quantitative and qualitative methods were used for analysis. RESULTS: 252 patients participated. T1 was influenced by remoteness (125 days in Townsville vs. 170 days for Remote, p=0.01), T2 by level of education (91 days for Primary education vs. 61 days for Secondary vs. 23 days for Tertiary/TAFE, p=0.006), and age group (14 days for 31-50 years, 61 days for 51-70 years, 45 days for >71 years, p=0.026), T3 by remoteness (15 days for Townville and 29.5 days for remote, p=0.02) and T4 by stage of disease (21 days for stage I, 11 days for Stage II, 34 days for Stage III 18 days for Stage IV, p=0.041). Competing priorities of family and work and cost & inconvenience of travel were perceived as rural barriers. CONCLUSION: Remoteness, age and level of education were related to delays in various time lines in lung cancer referral pathways in NQ. Provision of specialist services closer to home may decrease delays by alleviating burden of cost and inconvenience of travel

Find cancer early: Evaluation of a community education campaign to increase awareness of cancer signs and symptoms in people in regional Western Australians

Introduction: Cancer outcomes for people living in rural and remote areas are worse than for those living in urban areas. Although access to and quality of cancer treatment are important determinants of outcomes, delayed presentation has been observed in rural patients. Methods: Formative research with people from rural Western Australia (WA) led to the Find Cancer Early campaign. Find Cancer Early was delivered in three regions of WA, with two other regions acting as controls. Staff delivered the campaign using a community engagement approach, including promotion in local media. Television communications were not used to minimize contamination in the control regions. The campaign evaluation was undertaken at 20 months via a computer-assisted telephone interview (CATI) survey comparing campaign and control regions. The primary outcome variable was knowledge of cancer signs and symptoms. Results: Recognition and recall of Find Cancer Early and symptom knowledge were higher in the campaign regions. More than a quarter of those who were aware of the campaign reported seeing the GP as a result of their exposure. Conclusion: Despite limited use of mass media, Find Cancer Early successfully improved knowledge of cancer symptoms and possibly led to changes in behavior. Social marketing campaigns using community development can raise awareness and knowledge of a health issue in the absence of television advertising

Gestational age specific stillbirth risk among Indigenous and non-Indigenous women in Queensland, Australia: a population based study.

BACKGROUND: In Australia, significant disparity persists in stillbirth rates between Aboriginal and Torres Strait Islander (Indigenous Australian) and non-Indigenous women. Diabetes, hypertension, antepartum haemorrhage and small-for-gestational age (SGA) have been identified as important contributors to higher rates among Indigenous women. The objective of this study was to examine gestational age specific risk of stillbirth associated with these conditions among Indigenous and non-Indigenous women. METHODS: Retrospective population-based study of all singleton births of at least 20 weeks gestation or at least 400 grams birthweight in Queensland between July 2005 and December 2011 using data from the Queensland Perinatal Data Collection, which is a routinely-maintained database that collects data on all births in Queensland. Multivariate logistic regression was used to calculate adjusted odds ratios (aOR) and 95 % confidence intervals, adjusting for maternal demographic and pregnancy factors. RESULTS: Of 360987 births analysed, 20273 (5.6 %) were to Indigenous women and 340714 (94.4 %) were to non-Indigenous women. Stillbirth rates were 7.9 (95 % CI 6.8-9.2) and 4.1 (95 % CI 3.9-4.3) per 1000 births, respectively. For both Indigenous and non-Indigenous women across most gestational age groups, antepartum haemorrhage, SGA, pre-existing diabetes and pre-existing hypertension were associated with increased risk of stillbirth. There were mixed results for pre-eclampsia and eclampsia and a consistently raised risk of stillbirth was not seen for gestational diabetes. CONCLUSION: This study highlights gestational age specific stillbirth risk for Indigenous and non-Indigenous women; and disparity in risk at term gestations. Improving access to and utilisation of appropriate and responsive healthcare may help to address disparities in stillbirth risk for Indigenous women.Ibinabo Ibiebele is a recipient of the National Health and Medical Research Council Postgraduate Public Health scholarship and the University of Queensland Research Scholarship.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12884-016-0943-