Publications by authors named "Karen Tricker"

9 Publications

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Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Eur Urol 2019 12 16;76(6):831-842. Epub 2019 Sep 16.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

Design, Setting, And Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.

Outcome Measurements And Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.

Results And Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).

Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.

Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
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http://dx.doi.org/10.1016/j.eururo.2019.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880781PMC
December 2019

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Br J Cancer 2018 01 4;118(2):266-276. Epub 2018 Jan 4.

Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.

Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.

Results: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.

Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.
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http://dx.doi.org/10.1038/bjc.2017.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785754PMC
January 2018

The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine.

Value Health 2014 Jan-Feb;17(1):22-33

The University of Manchester, Manchester, UK. Electronic address:

Background: Thiopurine-methyl transferase (TPMT) testing prior to the prescription of azathioprine in autoimmune diseases is one of the few examples of a pharmacogenetic test that has made the transition from research into clinical practice. TPMT testing could lead to improved prescribing of azathioprine resulting in a reduction in adverse drug reactions as well as an improvement in effectiveness. When allocating scarce resources robust evidence on cost-effectiveness is required.

Objective: This study aimed to evaluate the cost-effectiveness of a TPMT genotyping test to inform azathioprine prescribing in autoimmune diseases. The secondary aim of this study was to demonstrate the complexity of undertaking a trial-based evaluation of a pharmacogenetic test.

Methods: A prospective economic evaluation was conducted alongside the TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study, a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT genotyping before azathioprine (n = 167) or current practice (n = 166). Assuming the UK health service perspective and a time horizon of 4 months, resource-use and health status data were collected prospectively for all recruited patients.

Results: The mean incremental cost for TPMT genotyping and subsequent care pathways compared with current practice for the 4-month follow-up was -£421.06 (95% confidence interval -£925.15 to £89.75). Mean incremental quality-adjusted life-years were close to zero but negative: -0.008 (95% confidence interval -0.017 to 0.0002). Assuming a threshold of £20,000 per quality-adjusted life-year, the expected incremental net benefit of introducing the test is £256.89 (95% CI -£425.94 to £932.86).

Conclusions: TPMT genotyping potentially offers a less expensive alternative than current practice, but it may also have a small but negative effect on health status. These findings are associated with significant uncertainty, and the causal effect of TPMT genotyping on changes in health status and health care resource use remains uncertain. The results from this study therefore pose a difficult challenge to decision makers.
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http://dx.doi.org/10.1016/j.jval.2013.10.007DOI Listing
March 2014

A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study.

Pharmacogenomics 2011 Jun 3;12(6):815-26. Epub 2011 May 3.

Genetic Medicine, Manchester Academic Health Science Centre (MAHSC), University of Manchester and Central Manchester NHS Foundation Trust, UK.

Aim: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs).

Methods: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping.

Results: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia.

Conclusion: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine.
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http://dx.doi.org/10.2217/pgs.11.32DOI Listing
June 2011

Valuing pharmacogenetic testing services: a comparison of patients' and health care professionals' preferences.

Value Health 2011 Jan;14(1):121-34

The University of Manchester, Manchester, UK.

Objective: The study compared the preferences of patients and health-care professionals for the key attributes of a pharmacogenetic testing service to identify a patient's risk of developing a side effect (neutropenia) from the immunosuppressant, azathioprine.

Methods: A discrete choice experiment was posted to a sample of patients (n=309) and health-care professionals (HCPs) (n=410), as part of the TARGET study. Five attributes, with four levels each, described the service as follows: level of information given; predictive ability of the test; how the sample is collected; turnaround time for a result; who explains the test result. Data from each sample were first analyzed separately and responses were compared by 1) identifying the impact of the scale parameter, and 2) estimating marginal rates of substitution.

Results: The final analysis included 159 patients and 138 HCPs (50% & 34% response rates). Estimated attribute coefficients from the patient and HCP sample differed in size, after taking into account the impact of the scale parameter. Patients and HCPs had similar preferences for predictive accuracy of the test and were willing to wait 2 days for a 1% improvement in test accuracy. Patients preferred to obtain more information and were willing to wait 19 days compared to 8 days for HCPs for providing higher levels of information.

Conclusions: Patients demanded accurate and timely information from health-care professionals about why it was necessary to have a pharmacogenetic test and what the test results mean. In contrast, health-care professionals appear to focus more exclusively or entirely upon the predictive accuracy and waiting time for a test result.
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http://dx.doi.org/10.1016/j.jval.2010.10.007DOI Listing
January 2011

Patients' and healthcare professionals' views on pharmacogenetic testing and its future delivery in the NHS.

Pharmacogenomics 2007 Nov;8(11):1511-9

Nowgen - A Centre for Genetics in Healthcare, The Nowgen Centre, 29 Grafton Street, Manchester M13 9WU, UK.

Introduction: There is limited empirical evidence on patients' and healthcare professionals' views on the provision of pharmacogenetic testing services. These opinions may be used to shape the development of emerging pharmacogenetic services and inform healthcare professionals' future educational requirements.

Objectives: To explore patients' and healthcare professionals' views about pharmacogenetic testing services and their future development.

Methods: Semi-structured interviews were conducted with patients who had been prescribed azathioprine for autoimmune conditions and prevention of acute rejection in renal transplantation. Focus groups were conducted with a range of healthcare professionals. Interviews and focus groups were recorded and transcribed verbatim. Data were analyzed using the constant comparative method.

Results: The views of 42 individuals - 25 patients and 17 healthcare professionals - were explored in depth. Key themes emerging from the data were: patients' and healthcare professionals' knowledge and experience of pharmacogenetics; expectations about how such a testing service could be used; and characteristics of service delivery. Knowledge and experience of pharmacogenetics varied. Pharmacogenetics was perceived to be of benefit by both groups. Patients gave opinions about pharmacogenetic services based on their experiences of illness, taking medicines and using healthcare services. Healthcare professionals based their opinions on how existing services are provided and access to limited healthcare resources. Patients had strong feelings about how this service should be delivered and expected high standards of explanation about potential pharmacogenetic tests. None of the healthcare professionals questioned expected to have responsibility for the future delivery of pharmacogenetic testing services.

Conclusion: There is no clear model of how pharmacogenetic tests will be delivered in clinical practice. Patients expect to receive pharmacogenetic services from healthcare professionals who are able to explain the test, and interpret the implications for prescribing, with confidence. The gap between patients' high expectations for information and healthcare professionals' current knowledge and reluctance to deliver pharmacogenetic services highlights the urgent need for better education and training of healthcare professionals in pharmacogenetics.
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http://dx.doi.org/10.2217/14622416.8.11.1511DOI Listing
November 2007

Is shared care with annual hospital review better value for money than predominantly hospital-based care in patients with established stable rheumatoid arthritis?

Ann Rheum Dis 2007 May 23;66(5):658-63. Epub 2006 Nov 23.

Health Economics Research at Manchester, University of Manchester, Manchester, UK.

Objective: To assess the cost effectiveness and cost effectiveness acceptability of symptom control delivered by shared care (SCSC) and aggressive treatment delivered in hospital (ATH) for established rheumatoid arthritis (RA).

Methods: Economic data were collected within the British Rheumatoid Outcome Study Group randomised controlled trial of SCSC and ATH. A broad perspective was used (UK National Health Service, social support services and patients). Cost per quality adjusted life year (QALY) gained, net benefit statistics and cost effectiveness acceptability curves were estimated. Costs and outcomes were discounted at 3.5%. Sensitivity analysis tested the robustness of the results to analytical assumptions.

Results: The mean (SD) cost per person was 4540 pounds (4700) in the SCSC group and 4440 pounds (4900) in the ATH group. The mean (SD) QALYs per person for 3 years were 1.67 (0.56) in the SCSC group and 1.60 (0.60) in the ATH group. If decision makers are prepared to pay > or = 2000 pounds to gain 1 QALY, SCSC is likely to be cost effective in 60-90% of cases.

Conclusions: The primary economic analysis and sensitivity analyses indicate that SCSC is likely to be more cost effective than ATH in 60-90% of cases. This result seems to be robust to assumptions required by the analysis. This study is one of a limited number of randomised controlled trials to collect detailed resource use and health status data and estimate the costs and QALYs of treatment for established RA. This trial is one of the largest RA studies to use the EuroQol.
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http://dx.doi.org/10.1136/ard.2006.061234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1954606PMC
May 2007

The relationship between social deprivation, disease outcome measures, and response to treatment in patients with stable, long-standing rheumatoid arthritis.

J Rheumatol 2005 Dec;32(12):2330-6

ARC Epidemiology Unit, The University of Manchester, Manchester, UK.

Objective: Patients with rheumatoid arthritis (RA) with lower socioeconomic status (SES) are known to have more severe disease, more comorbidity, and higher mortality. It is not known whether SES influences response to treatment in RA. We examined the relationship between area of residence (as a surrogate for SES) and baseline outcome measures and response to treatment, using data from the British Rheumatoid Outcome Study Group randomized controlled trial of aggressive versus symptomatic treatment of long-standing, stable RA.

Methods: A total of 466 patients from 5 centers were recruited to the trial. Baseline data included age, sex, smoking status, and comorbidity. Patients were assigned a Townsend score (a measure of social deprivation) according to their area of residence. Outcome measures including the Disease Activity Score (DAS28), Health Assessment Questionnaire, Medical Outcomes Study Short Form-36, and EuroQol (EQ5D) were recorded at the beginning and end of the 3 year trial. The baseline, 3 year values, and change data were examined by Townsend quintile adjusting for each treatment arm.

Results: Significant relationships between increasing social deprivation by area of residence and higher disease activity, higher pain, poorer physical function, poorer emotional aspects of mental health, and lower quality of life were found at baseline (adjusted for age, sex, disease duration, current smoking, treatment center, and treatment group). During the 3 year trial period, patients from the most deprived areas showed greater improvement, with statistically significant greater improvement on DAS28 (p = 0.041) and 28 tender joint count (p = 0.015).

Conclusion: Area of residence is related to the severity of RA at recruitment and is a predictor of response in a clinical trial situation. The results suggest that measures of SES should be recorded for patients enrolled in clinical trials, longitudinal observational studies, and in the clinical setting.
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December 2005