Interpreting and comparing risks in the presence of competing events

Competing events are common in medical research. Ignoring them in the statistical analysis can easily lead to flawed results and conclusions. This article uses a real dataset and a simple simulation to show how standard analysis fails and how such data should be analysed

Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the *NIS-LAMS** cohort

Background: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these compet ng events have not been previously assessed using competing-risks regression models. Objectives: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariaies associated with these competing events. Study Design and Methods: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). Results: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance of ASCUS+Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. Conclusions: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.

Multilevel competing risk models to evaluate the risk of nosocomial infection

Introduction Risk factor analyses for nosocomial infections (NIs) are complex. First, due to competing events for NI, the association between risk factors of NI as measured using hazard rates may not coincide with the association using cumulative probability (risk). Second, patients from the same intensive care unit (ICU) who share the same environmental exposure are likely to be more similar with regard to risk factors predisposing to a NI than patients from different ICUs. We aimed to develop an analytical approach to account for both features and to use it to evaluate associations between patient- and ICU-level characteristics with both rates of NI and competing risks and with the cumulative probability of infection. Methods We considered a multicenter database of 159 intensive care units containing 109,216 admissions (813,739 admission-days) from the Spanish HELICS-ENVIN ICU network. We analyzed the data using two models: an etiologic model (rate based) and a predictive model (risk based). In both models, random effects (shared frailties) were introduced to assess heterogeneity. Death and discharge without NI are treated as competing events for NI. Results There was a large heterogeneity across ICUs in NI hazard rates, which remained after accounting for multilevel risk factors, meaning that there are remaining unobserved ICU-specific factors that influence NI occurrence. Heterogeneity across ICUs in terms of cumulative probability of NI was even more pronounced. Several risk factors had markedly different associations in the rate-based and risk-based models. For some, the associations differed in magnitude. For example, high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were associated with modest increases in the rate of nosocomial bacteremia, but large increases in the risk. Others differed in sign, for example respiratory vs cardiovascular diagnostic categories were associated with a reduced rate of nosocomial bacteremia, but an increased risk. Conclusions A combination of competing risks and multilevel models is required to understand direct and indirect risk factors for NI and distinguish patient-level from ICU-level factors.

Interventions to control nosocomial infections : study designs and statistical issues

There is a wide range of potential study designs for intervention studies to decrease nosocomial infections in hospitals. The analysis is complex due to competing events, clustering, multiple timescales and time-dependent period and intervention variables. This review considers the popular pre-post quasi-experimental design and compares it with randomized designs. Randomization can be done in several ways: randomization of the cluster [intensive care unit (ICU) or hospital] in a parallel design; randomization of the sequence in a cross-over design; and randomization of the time of intervention in a stepped-wedge design. We introduce each design in the context of nosocomial infections and discuss the designs with respect to the following key points: bias, control for nonintervention factors, and generalizability. Statistical issues are discussed. A pre-post-intervention design is often the only choice that will be informative for a retrospective analysis of an outbreak setting. It can be seen as a pilot study with further, more rigorous designs needed to establish causality. To yield internally valid results, randomization is needed. Generally, the first choice in terms of the internal validity should be a parallel cluster randomized trial. However, generalizability might be stronger in a stepped-wedge design because a wider range of ICU clinicians may be convinced to participate, especially if there are pilot studies with promising results. For analysis, the use of extended competing risk models is recommended.

Training Volume and Methods of Athletes Competing at a Mixed Martial Arts Events

This study surveyed 32 athletes competing at a mixed martial arts (MMA) event held in Butte, Montana. The survey attempted to gather information regarding overall training volume, supplement use, volume change and specific exercises used. The survey return rate was 100 percent (32/32). Twenty-five of 32 athletes supplemented their training with strength training. Overall frequency of strength training ranged from one to six sessions/week, and overall frequency of fighting-specific training sessions/weel ranged from two to 10. Two of the 32 athletes used/had used anabolic-androgenic steroids. Sixteen MMA athletes performed exercises specifically for the neck musculature, and eight use the power clean within their strength-training program. Results suggested that strength and conditioning speciialists should educate the importance of, volume variation and periodization, balanced training, effective exercises, and the side effects of anabolic steroid use.

Stochastic modelling of T cell homeostasis for two competing clonotypes via the master equation

Stochastic models for competing clonotypes of T cells by multivariate, continuous-time, discrete state, Markov processes have been proposed in the literature by Stirk, Molina-París and van den Berg (2008). A stochastic modelling framework is important because of rare events associated with small populations of some critical cell types. Usually, computational methods for these problems employ a trajectory-based approach, based on Monte Carlo simulation. This is partly because the complementary, probability density function (PDF) approaches can be expensive but here we describe some efficient PDF approaches by directly solving the governing equations, known as the Master Equation. These computations are made very efficient through an approximation of the state space by the Finite State Projection and through the use of Krylov subspace methods when evolving the matrix exponential. These computational methods allow us to explore the evolution of the PDFs associated with these stochastic models, and bimodal distributions arise in some parameter regimes. Time-dependent propensities naturally arise in immunological processes due to, for example, age-dependent effects. Incorporating time-dependent propensities into the framework of the Master Equation significantly complicates the corresponding computational methods but here we describe an efficient approach via Magnus formulas. Although this contribution focuses on the example of competing clonotypes, the general principles are relevant to multivariate Markov processes and provide fundamental techniques for computational immunology.

Dialogic Evidence: Documentation of Ephemeral Events

Performance and documentation have long been characterised as oppositional practices, separated by competing voices which argue the virtues of disappearance and reproducibility. In response to this state of affairs, the recently completed Dialogic Evidence project was designed to explore the possibility (and the limits) of a productive co-existence between performance and documentation practices. In this paper I reflect on this project’s processes and outcomes, particular highlighting the potential of social web technologies as a collaborative means to archive, discuss and remember live performance.

Competing for attentional priority: temporary goals versus threats

Numerous studies have shown that attention is biased toward threatening events. More recent evidence has also found attentional biases for stimuli that are relevant to the current and temporary goals of an individual. We examined whether goal-relevant information still evokes an attentional bias when this information competes with threatening events. In three experiments, participants performed a dot probe task combined with a separate task that induced a temporary goal. The results of Experiment 1 showed that attention was oriented to goal-relevant pictures in the dot probe task when these pictures were simultaneously presented with neutral or threatening pictures. Whether goal-relevant pictures themselves were threatening or neutral did not influence the results. Experiment 2 replicated these findings in a sample of highly trait-anxious participants. Experiment 3 showed that attention was automatically deployed to stimuli relevant to a temporary goal even in the presence of stimuli that signal imminent and genuine threat (i.e., a colored patch signaling the presentation of an aversive noise). These findings further corroborate the conclusion that an individual's current and temporary goals guide early attentional processes

Covariates of high-risk human papillomavirus (HPV) infections are distinct for incident CIN1, CIN2 and CIN3 as disclosed by competing-risks regression models

Background: In addition to the oncogenic human papillomavirus (HPV), several cofactors are needed in cervical carcinogenesis, but whether the HPV covariates associated with incident i) CIN1 are different from those of incident ii) CIN2 and iii) CIN3 needs further assessment. Objectives: To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV covariates associated with incident CIN1, CIN2, and CIN3. Study Design and Methods: HPV covariates associated with progression to CIN1, CIN2 and CIN3 were analysed in the combined cohort of the NIS (n = 3,187) and LAMS study (n = 12,114), using competing-risks regression models (in panel data) for baseline HR-HPV-positive women (n = 1,105), who represent a sub-cohort of all 1,865 women prospectively followed-up in these two studies. Results: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2, and CIN3, respectively. Among these baseline HR-HPV-positive women, the risk profiles of incident GIN I, CIN2 and CIN3 were unique in that completely different HPV covariates were associated with progression to CIN1, CIN2 and CIN3, irrespective which categories (non-progression, CIN1, CIN2, CIN3 or all) were used as competing-risks events in univariate and multivariate models. Conclusions: These data confirm our previous analysis based on multinomial regression models implicating that distinct covariates of HR-HPV are associated with progression to CIN1, CIN2 and CIN3. This emphasises true biological differences between the three grades of GIN, which revisits the concept of combining CIN2 with CIN3 or with CIN1 in histological classification or used as a common end-point, e.g., in HPV vaccine trials.

Influenza A virus ribonucleoproteins modulate host recycling by competing with Rab11 effectors

Influenza A virus assembly is an unclear process, whereby individual virion components form an infectious particle. The segmented nature of the influenza A genome imposes a problem to assembly because it requires packaging of eight distinct RNA particles (vRNPs). It also allows genome mixing from distinct parental strains, events associated with influenza pandemic outbreaks. It is important to public health to understand how segmented genomes assemble, a process that is dependent on the transport of components to assembly sites. Previously, it has been shown that vRNPs are carried by recycling endosome vesicles, resulting in a change of Rab11 distribution. Here, we describe that vRNP binding to recycling endosomes impairs recycling endosome function, by competing for Rab11 binding with family-interacting proteins, and that there is a causal relationship between Rab11 ability to recruit family-interacting proteins and Rab11 redistribution. This competition reduces recycling sorting at an unclear step, resulting in clustering of single- and double-membraned vesicles. These morphological changes in Rab11 membranes are indicative of alterations in protein and lipid homeostasis during infection. Vesicular clustering creates hotspots of the vRNPs that need to interact to form an infectious particle.

Excess in cardiovascular events on mondays: a meta-analysis analysis and prospective study

The aim of this paper was to summarise the reported excess in coronary events on Mondays, and examine the evidence for three competing explanations: stress, alcohol consumption, or registration errors. A review of the literature found 28 studies covering 16 countries and over 1.6 million coronary events. The overall Monday excess was small; in a population experiencing 100 coronary events per week there was one more event on Monday than other days. The excess was larger in men and in studies including sudden cardiac death or cardiac arrests. In a prospective study an increase in events on Mondays was associated with greater alcohol consumption, lower rainfall, and the month of January. The excess in coronary events on Mondays is a persistent phenomenon. The size of the effect varies widely between populations. There is some evidence of an association with alcohol consumption, but a definitive explanation remains elusive and is likely to remain so because of the smallness of the effect and the paucity of high quality data.

Relating two simultaneous events in discourse: the role of on-goingness devices in L1 Tunisian Arabic, L1 French and L2 French by Tunisian learners

Our PhD study focuses on the role of aspectual marking in expressing simultaneity of events in Tunisian Arabic as a first language, French as a first language, as well as in French as a second language by Tunisian learners at different acquisitional stages. We examine how the explicit markers of on-goingness qa:’id and «en train de» in Tunisian Arabic and in French respectively are used to express this temporal relation, in competition with the simple forms, the prefixed verb form in Tunisian Arabic and the présent de l’indicatif in French. We use a complex verbal task of retelling simultaneous events sharing an interval on the time axis based on eight videos presenting two situations happening in parallel. Two types of simultaneity are exploited: perfect simultaneity (when the two situations are parallel to each other) and inclusion (one situation is framed by the second one). Our informants in French and in Tunisian Arabic have two profiles, highly educated and low educated speakers. We show that the participants’ response to the retelling task varies according to their profiles, and so does their use of the on-goingness devices in the expression of simultaneity. The differences observed between the two profile groups are explained by the degree to which the speakers have developed a habit of responding to tasks. This is a skill typically acquired during schooling. We notice overall that the use of qa:’id as well as of «en train de» is less frequent in the data than the use of the simple forms. However, qa:’id as well as «en train de» are employed to play discursive roles that go beyond the proposition level. We postulate that despite the shared features between Tunisian Arabic and French regarding marking the concept of on-goingness, namely the presence of explicit lexical, not fully grammaticalised markers competing with other non-marked forms, the way they are used in the discourse of simultaneous events shows clear differences. We explain that «en train de» plays a more contrastive role than qa:’id and its use in discourse obeys a stricter rule. In cases of the inclusion type of simultaneity, it is used to construe the ‘framing’ event that encloses the second event. In construing perfectly simultaneneous events, and when both «en train de» and présent de l’indicatif are used, the proposition with «en train de» generally precedes the proposition with présent de l’indicatif, and not the other way around. qa:id obeys, but to a less strict rule as it can be used interchangeably with the simple form regardless of the order of propositions. The contrastive analysis of French L1 and L2 reveals learners’ deviations from natives’ use of on-goingness devices. They generalise the use of «en train de» and apply different rules to the interaction of the different marked and unmarked forms in discourse. Learners do not master its role in discourse even at advanced stages of acquisition despite its possible emergence around the basic and intermediate varieties. We conclude that the native speakers’ use of «en train de» involves mastering its role at the macro-structure level. This feature, not explicitly available to learners in the input, might persistently present a challenge to L2 acquisition of the periphrasis.