Katarina L. Matthes

Isoform prefiltering improves performance of count-based methods for analysis of differential transcript usage

BackgroundRNA-seq has been a boon to the quantitative analysis of transcriptomes. A notable application is the detection of changes in transcript usage between experimental conditions. For example, discovery of pathological alternative splicing may allow the development of new treatments or better management of patients. From an analysis perspective, there are several ways to approach RNA-seq data to unravel differential transcript usage, such as annotation-based exon-level counting, differential analysis of the percentage spliced in, or quantitative analysis of assembled transcripts. The goal of this research is to compare and contrast current state-of-the-art methods, and to suggest improvements to commonly used work flows.ResultsWe assess the performance of representative work flows using synthetic data and explore the effect of using non-standard counting bin definitions as input to DEXSeq, a state-of-the-art inference engine. Although the canonical counting provided the best results overall, several non-canonical approaches were as good or better in specific aspects and most counting approaches outperformed the evaluated event- and assembly-based methods. We show that an incomplete annotation catalog can have a detrimental effect on the ability to detect differential transcript usage in transcriptomes with few isoforms per gene and that isoform-level prefiltering can considerably improve false discovery rate control.ConclusionCount-based methods generally perform well in the detection of differential transcript usage. Controlling the false discovery rate at the imposed threshold is difficult, particularly in complex organisms, but can be improved by prefiltering the annotation catalog.

The risk of prostate cancer mortality and cardiovascular mortality of nonmetastatic prostate cancer patients: A population-based retrospective cohort study

PURPOSEnTo assess the risk of prostate cancer (PCa) specific mortality (PCSM) compared to cardiovascular disease mortality (CVDM), or other-cause mortality (OCM) of men with nonmetastatic PCa according to PCa risk groups, primary treatment, and age.nnnPATIENTS AND METHODSnThis retrospective population-based cohort study identified 1,908 nonmetastatic PCa patients in the cancer registry Zurich and Zug, diagnosed between 2000 and 2009 living in the City of Zurich. Multiple imputation methods were applied to handle missing PCa information. Fine and Gray competing risk regression analysis was used to estimate subdistribution hazard ratios for the outcomes PCSM, CVDM, or OCM RESULTS: Ten years after diagnosis the cumulative probability of PCSM and CVDM was 16.4% and 10.0%, respectively. We observed an increased adjusted risk of PCSM in men treated with androgen deprivation therapy (ADT) compared to surgery, but could not observe an association between ADT and CVDM. The probability of PCSM was significantly higher for patients on active surveillance or watchful waiting, compared to surgery. Age and PCa risk categories were positively associated with risk of PCSM, whereas there was no evidence for an association with CVDM or OCM based on risk groups.nnnCONCLUSIONSnOverall, men with PCa were more likely to die from non-PCa related outcomes. Nevertheless, the analyses showed a high proportion of PCSM among men on ADT, older men and men with a high-risk tumor. However, further research is needed to understand comprehensively the benefits of the respective treatments.

Impact of comorbidities at diagnosis on prostate cancer treatment and survival

BackgroundThe aim of this study was to assess the associations of comorbidities with primary treatment of prostate cancer (PCa) patients and of comorbidities with PCa-specific mortality (PCSM) compared to other-cause mortality (OCM) in Switzerland.Patients and methodsWe included 1527 men diagnosed with PCa in 2000 and 2001 in the canton of Zurich. Multiple imputation methods were applied to missing data for stage, grade and comorbidities. Multinomial logistic regression analyses were used to explore the associations of comorbidities with treatment. Cox regression models were used to estimate all-cause mortality, and Fine and Gray competing risk regression models to estimate sub-distribution hazard ratios for the outcomes PCSM and OCM.ResultsIncreasing age was associated with a decreasing probability of receiving curative treatment, whereas an increasing Charlson Comorbidity Index (CCI) did not influence the treatment decision as strongly as age. The probability of OCM was higher for patients with comorbidities compared to those without comorbidities [CCI 1: hazard ratio 2.07 (95% confidence interval 1.51–2.85), CCI 2+: 2.34 (1.59–3.44)]; this was not observed for PCSM [CCI 1: 0.79 (0.50–1.23), CCI 2+: 0.97 (0.59–1.59)]. In addition, comorbidities had a greater impact on the patients’ mortality than age.ConclusionsThe results of the current study suggest that chronological age is a stronger predictor of treatment choices than comorbidities, although comorbidities have a larger influence on patients’ mortality. Hence, inclusion of comorbidities in treatment choices may provide more appropriate treatment for PCa patients to counteract over- or undertreatment.

Primary Treatment Choice Over Time and Relative Survival of Prostate Cancer Patients: Influence of Age, Grade, and Stage

Background: The aim of this study was to assess associations of stage, grade, and age with the primary treatment of prostate cancer (PCa) patients comparing the incidence years 2000/2001 and 2012/2013, and to estimate the relative survival (RS) for patients diagnosed in 2000/2001. Methods: We included 1,541 men diagnosed in 2000/2001 and 1,605 men diagnosed in 2012/2013. Multiple imputation methods were applied to missing data for stage and grade. Multinomial logistic regression analyses were used to explore the associations of stage, grade, and age with treatment. RS was estimated using the Ederer II approach. Results: In 2000/2001, older patients were more likely to choose active surveillance (AS)/watchful waiting (WW) or to receive androgen deprivation therapy (ADT) compared to surgery; in 2012/2013, this association was only observed for ADT but not for AS/WW. In 2000/2001, the overall 1-, 5-, and 10-year RS was approximately 99, 94, and 92%, respectively. RS was highest for patients who underwent surgical procedures or radiotherapy and considerably lower for patients with ADT. Conclusion: Our data show that today AS/WW is an option not only for patients with a life expectancy of < 10 years but also for younger men with localized PCa. PCa patients have a good RS if the cancer is diagnosed at an early stage.

Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling

Cancer of unknown primary (CUP) is a distinct clinicopathological entity with poor prognosis, frequently resistant to chemotherapy. Comprehensive genomic profiling (CGP) by next‐generation sequencing potentially identifies novel treatment options for CUP patients. The objective of this study was to determine incidence and survival trends and to discuss the value of CGP in CUP patients.

Trends in prostate cancer incidence between 1996 and 2013 in two Swiss regions by age, grade, and T-stage

PurposeTo investigate differences in prostate cancer incidence between two distinct Swiss regions from 1996 to 2013 stratified by age group, grade, and T-stage.MethodsThe dataset included 17,495 men living in Zurich and 3,505 men living in Ticino, diagnosed with prostate cancer between 1996 and 2013. We computed age-standardized incidence rates per 100,000 person-years using the European Standard Population. Trends were assessed using JoinPoint regression analysis Software.ResultsAge-standardized incidence rates were generally higher in Zurich compared to Ticino but the difference decreased over time. Incidence rates increased significantly up to 2002 in Zurich and 2007 in Ticino and then decreased. A statistically significant increase was observed for men agedu2009<u200965 years, for grade 3 tumors, and for T-stage 2 and 3 tumors. The largest decrease was seen for grade 1 tumors. Furthermore, the incidence of tumors of unknown grade or T-stage decreased significantly in both regions.ConclusionsThe trends in prostate cancer incidence rates were similar in both regions, although on a higher level in Zurich compared to Ticino. However, the difference decreased over time. The distribution of T-stage and grade did not explain the difference in incidence rates. Different use of opportunistic screening may play a role.

Indicators of Data Quality at the Cancer Registry Zurich and Zug in Switzerland

Data quality is an important issue in cancer registration. This paper provides a comprehensive overview of the four main data quality indicators (comparability, validity, timeliness, and completeness) for the Cancer Registry Zurich and Zug (Switzerland). We extracted all malignant cancer cases (excluding non-melanoma skin cancer) diagnosed between 1980 and 2014 in the canton of Zurich. Methods included the proportion of morphologically verified cases (MV%), the proportion of DCN and DCO cases (2009–2014), cases with primary site uncertain (PSU%), the stability of incidence rates over time, age-specific incidence rates for childhood cancer, and mortality:incidence (MI) ratios. The DCO rate decreased from 6.4% in 1997 to 0.8% in 2014 and was <5% since 2000. MV% was 95.5% in 2014. PSU% was <3% over the whole period. The incidence rate of all tumours increased over time with site-specific fluctuations. The overall M:I ratio decreased from 0.58 in 1980 to 0.37 in 2014. Overall, data quality of the Cancer Registry Zurich and Zug was acceptable according to the methods presented in this review. Most indicators improved over time with low DCO rates, high MV%, low PSU%, relatively low M:I ratios and age-specific incidence of childhood cancer within reference ranges.