Susanne Rosthøj

Competing risks as a multi-state model:

This paper deals with the competing risks model as a special case of a multi-state model. The properties of the model are reviewed and contrasted to the so-called latent failure time approach. The relation between the competing risks model and right-censoring is discussed and regression analysis of the cumulative incidence function briefly reviewed. Two real data examples are presented and a guide to the practitioner is given.

SAS macros for estimation of the cumulative incidence functions based on a Cox regression model for competing risks survival data.

When considering competing risks survival data, the cause specific hazard functions are often modelled by the proportional hazards Cox regression model. First, we present how to estimate the parameters in this model when some of the covariates are allowed to have exactly the same effect on several causes of failure. In many cases, the focus is not on the parameter estimates, but rather on the probability of observing a failure from a specific cause for individuals with specified covariate values. These probabilities, the cumulative incidences, are not simple functions of the parameters and they are, so far, not provided by the standard statistical software packages. We present two SAS macros: a SAS macro named CumInc for estimation of the cumulative incidences and a SAS macro named CumIncV for estimation of the cumulative incidences and the variances of the estimated cumulative incidences. The use of the macros is demonstrated through an example.

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

PURPOSE Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). RESULTS After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). CONCLUSION Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

The epidemiology of febrile malaria episodes in an area of unstable and seasonal transmission

This study investigated the epidemiology of uncomplicated falciparum malaria in an area of unstable and seasonal transmission in eastern Sudan. About 90% of malaria morbidity in this region occurs in the months of September to November, and very few malaria cases occur during the intensely arid Sudanese dry season and during years of drought. The malaria situation in the study site, the village of Daraweesh, was analysed during 3 consecutive malaria seasons in 1993-95 during which the 457 inhabitants suffered at total of 436 episodes of falciparum malaria. Using an Andersen-Gill proportional hazard model for recurrent events stratified by family, we have calculated the relative hazard for clinical malaria episodes by age, sex, haemoglobin genotype, blood type and infection in the previous season. The malaria risk was significantly lower in individuals aged 20-88 years than in the 5-19 years age-group. The relative protection due to adulthood varied between seasons (relative risk, RR, 0x34 to 0x67). Serological data were not consistent with the hypothesis that the age difference in incidence was due to differences in exposure. During the 1993 season the malaria incidence in males was lower than in females (RR = 0x75), during the 1994 season the incidences were comparable, whereas males had an increased risk of malaria in 1995 (RR = 1x87). The relative risk in individuals carrying the haemoglobin AS genotype compared to homozygous AA individuals was 0x57.

Impact of age and sex on sudden cardiovascular death following myocardial infarction

Objective: To evaluate and compare the risk of sudden cardiovascular death (SCD) and non-SCD after myocardial infarction (MI) associated with age and sex. Design: Cohort study of patients admitted with an enzyme verified acute MI and discharged alive. Patients were followed up for up to four years. Patients: 5983 consecutive hospital survivors of acute MI were enrolled in the TRACE (trandolapril cardiac evaluation) registry from 1990–92. Four age groups were prespecified: < 56, 56–65, 66–75, and ≥ 76 years. Main outcome measures: SCD was defined as cardiovascular death within one hour of onset of symptoms. Results: There were 536 SCD and 725 non-SCD. SCD mortality was 4.8% in the youngest and 15.7% in the oldest age groups. Non-SCD mortality was 3.5% and 25%, respectively. The ratio of SCD to non-SCD mortality varied from 1.44 in the youngest (< 56 years) to 0.55 in the oldest patients (≥ 76 years). Age significantly increased both SCD and non-SCD risk (p < 0.0001), but the increase in non-SCD risk was 40% higher (p < 0.0001). Male sex was associated with increased risk of SCD independently of age (risk ratio 1.34, p < 0.005). However, the absolute three year probability of SCD among women older than 66 years exceeded 10%. Conclusions: Compared with non-SCD the risk of SCD is relatively highest in the younger age groups, but the absolute risk of SCD is much higher among the upper age groups than the younger. The risk of SCD was slightly lower in women but not enough to warrant a different treatment strategy.

Simulation-based multiprofessional obstetric anaesthesia training conducted in situ versus off-site leads to similar individual and team outcomes: a randomised educational trial

Objective To investigate the effect of in situ simulation (ISS) versus off-site simulation (OSS) on knowledge, patient safety attitude, stress, motivation, perceptions of simulation, team performance and organisational impact. Design Investigator-initiated single-centre randomised superiority educational trial. Setting Obstetrics and anaesthesiology departments, Rigshospitalet, University of Copenhagen, Denmark. Participants 100 participants in teams of 10, comprising midwives, specialised midwives, auxiliary nurses, nurse anaesthetists, operating theatre nurses, and consultant doctors and trainees in obstetrics and anaesthesiology. Interventions Two multiprofessional simulations (clinical management of an emergency caesarean section and a postpartum haemorrhage scenario) were conducted in teams of 10 in the ISS versus the OSS setting. Primary outcome Knowledge assessed by a multiple choice question test. Exploratory outcomes Individual outcomes: scores on the Safety Attitudes Questionnaire, stress measurements (State-Trait Anxiety Inventory, cognitive appraisal and salivary cortisol), Intrinsic Motivation Inventory and perceptions of simulations. Team outcome: video assessment of team performance. Organisational impact: suggestions for organisational changes. Results The trial was conducted from April to June 2013. No differences between the two groups were found for the multiple choice question test, patient safety attitude, stress measurements, motivation or the evaluation of the simulations. The participants in the ISS group scored the authenticity of the simulation significantly higher than did the participants in the OSS group. Expert video assessment of team performance showed no differences between the ISS versus the OSS group. The ISS group provided more ideas and suggestions for changes at the organisational level. Conclusions In this randomised trial, no significant differences were found regarding knowledge, patient safety attitude, motivation or stress measurements when comparing ISS versus OSS. Although participant perception of the authenticity of ISS versus OSS differed significantly, there were no differences in other outcomes between the groups except that the ISS group generated more suggestions for organisational changes. Trial registration number NCT01792674.

Risk factors of recurrent anal sphincter ruptures: a population-based cohort study

Please cite this paper as: Jangö H, Langhoff‐Roos J, Rosthøj S, Sakse A. Risk factors of recurrent anal sphincter ruptures: a population‐based cohort study. BJOG 2012;119:1640–1647.

Sedentary work—Associations between five-year changes in occupational sitting time and body mass index

OBJECTIVE The aim of this study is to investigate the association between five-year changes in occupational sitting and body mass index (BMI) in working adults. METHODS We analyzed data from The Danish Work Environment Cohort Study (2005 and 2010, n=3.482). Data on occupational sitting, weight, height and several potential confounders were self-reported. The association between change in occupational sitting (hours) (categorized as large decrease <-7.5, moderate decrease -7.5 to <-2.5, no change -2.5 to 2.5, moderate increase >2.5 to 7.5 and large increase >7.5) and change in BMI was explored by multiple linear regression analyses. RESULTS 43.0% men and 36.1% women had high occupational sitting time (≥25h per week) at baseline. 31.8% men and 27.2% women decreased while 30.0% men and 33.0% women increased occupational sitting. The proportion of obese (BMI≥30) increased almost 3% for both genders. BMI changed 0.13 (CI: 0.06; 0.20, p=0.0003), per category of change in occupational sitting in women, but no association was found in men. CONCLUSION In women, there is a positive association between five-year changes in occupational sitting and BMI.

Gene dose effects of GSTM1, GSTT1 and GSTP1 polymorphisms on outcome in childhood acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) react very differently to chemotherapy. One explanation for this is inherited genetic variation. The glutathione S-transferase (GST) enzymes inactivate a number of chemotherapeutic drugs administered in childhood ALL therapy. Two multiplexing methods were applied for genotyping the GSTM1 and GSTT1 genes (distinguishing between 0, 1, or 2 gene copies) and the GSTP1 313 A>G polymorphism, simultaneously. A total of 263 childhood ALL patients were genotyped. No gene dose effect on outcome was demonstrated with either GST polymorphisms. Grouping of GSTM1 and GSTT1 into poor (0 or 1 gene copy)—and good metabolizers (at least 2 gene copies)—showed that the poor metabolizers had a trend toward a better outcome (event-free survival =91.8%) compared with the good metabolizers (event-free survival =83.2%). Similarly, in the adjusted analysis the good metabolizers demonstrated a 2.2-fold higher risk trend of experiencing an event (resistant disease or relapse) compared with the poor metabolizers (P=0.066; hazard ratio =2.248; 95% confidence interval, 0.948-5.327). In conclusion, our results suggest that the combined gene dose of GSTM1 and GSTT1 may influence outcome in childhood ALL.

Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: Influence on cure rates and risk of second cancer

Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMTLA) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild‐type (TPMTWT) when treated with 6MP maintenance therapy starting doses of 75 mg/m2/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m2/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.