Sick leave due to SARS-CoV-2 infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused a high burden of sick leave worldwide. Long-term sick leave for COVID-19 may be longer than for other influenza-like syndromes. The real impact of long COVID on absenteeism remains uncertain. AIMS: To investigate the burden of sick leave, especially >12 weeks, in Belgian workers with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from July 2020 to September 2021 and to compare these figures with sick leave for other infectious diseases. METHODS: We coupled a database of SARS-CoV-2-positive workers and workers who were absent for other infections with objective absence data. Predictors of prolonged sickness were evaluated by negative binomial regression, Cox proportional hazards regression and ordinal logistic regression. RESULTS: The study population involved 2569 workers who tested positive for SARS-CoV-2 and 392 workers who were absent for other infectious diseases. In total, 16% (95% CI 14-17%) of workers with a positive SARS-CoV-2 test had no sick leave registered. Fourteen out of 1000 (95% CI 9-20‰) workers with absenteeism for COVID-19 experienced sick leave >12 weeks as compared to 43 out of 1000 workers (95% CI 3-69‰) with absenteeism due to other infections. When including PCR-positive workers without sick leave, the prevalence of long-term sick leave decreased to 12 per 1000 (95% CI8-17‰). Long-term sick leave was associated with older age, high previous sick leave and low educational level. CONCLUSIONS: The prevalence of long-term sick leave was lower than estimated in earlier investigations regardless of worrying reports about post-COVID-19 syndrome.

Generalized pairwise comparison methods to analyze (non)prioritized composite endpoints.

In the analysis of composite endpoints in a clinical trial, time to first event analysis techniques such as the logrank test and Cox proportional hazard test do not take into account the multiplicity, importance, and the severity of events in the composite endpoint. Several generalized pairwise comparison analysis methods have been described recently that do allow to take these aspects into account. These methods have the additional benefit that all types of outcomes can be included, such as longitudinal quantitative outcomes, to evaluate the full treatment effect. Four of the generalized pairwise comparison methods, ie, the Finkelstein-Schoenfeld, the Buyse, unmatched Pocock, and adapted O'Brien test, are summarized. They are compared to each other and to the logrank test by means of simulations while specifically evaluating the effect of correlation between components of the composite endpoint on the power to detect a treatment difference. These simulations show that prioritized generalized pairwise comparison methods perform very similarly, are sensitive to the priority rank of the components in the composite endpoint, and do not measure the true treatment effect from the second priority-ranked component onward. The nonprioritized pairwise comparison test does not suffer from these limitations and correlation affects only its variance.

Community-acquired pneumonia (CAP) hospitalizations and deaths: is there a role for quality improvement through inter-hospital comparisons?

OBJECTIVE: To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement. DESIGN: We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit. SETTING: All Belgian hospital discharge records from 2004 to 2007. STUDY PARTICIPANTS: A total of 111 776 adult patients were admitted for CAP. MAIN OUTCOME MEASURE: Risk-adjusted standardized in-hospital mortality ratios. RESULTS: Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. CONCLUSIONS: Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality.

Implementation of pattern-mixture models in randomized clinical trials.

Modern analysis of incomplete longitudinal outcomes involves formulating assumptions about the missingness mechanisms and then using a statistical method that produces valid inferences under this assumption. In this manuscript, we define missingness strategies for analyzing randomized clinical trials (RCTs) based on plausible clinical scenarios. Penalties for dropout are also introduced in an attempt to balance benefits against risks. Some missingness mechanisms are assumed to be non-future dependent, which is a subclass of missing not at random. Non-future dependent stipulates that missingness depends on the past and the present information but not on the future. Missingness strategies are implemented in the pattern-mixture modeling framework using multiple imputation (MI), and it is shown how to estimate the marginal treatment effect. Next, we outline how MI can be used to investigate the impact of dropout strategies in subgroups of interest. Finally, we provide the reader with some points to consider when implementing pattern-mixture modeling-MI analyses in confirmatory RCTs. The data set that motivated our investigation comes from a placebo-controlled RCT design to assess the effect on pain of a new compound. Copyright © 2016 John Wiley & Sons, Ltd.

[Risk factors and protective factors relating to suicide in the Netherlands and Flanders]. / Risicofactoren en beschermende factoren inzake suïcide in Nederland en Vlaanderen.

BACKGROUND: The suicide rate is 82% higher in the Flanders region of Belgium than in the Netherlands. AIM: To investigate to what extent Flanders and the Netherlands differ with regard to the risk factors and protective factors relating to suicide and attempted suicide. METHOD: By means of a structured postal questionnaire, we collected data on the following topics from 2999 Flemish and Dutch people between 18 and 64 years: mental well-being and earlier attempts to commit suicide, the help they had received and their intention to seek help for psychological problems, awareness of the mental health care available, satisfaction with the help received, and attitudes to suicide. RESULTS: The incidence of psychological problems and suicidality did not differ significantly between Flanders and the Netherlands. Compared to Flemish people, Dutch people with psychological problems had received more psychological help and more often expressed the intention to seek help in the future. Furthermore, the Dutch were better informed about mental health care, and patient satisfaction was higher in the Netherlands. Compared to the Flemish people, the Dutch had more positive and understanding attitude to suicide. CONCLUSION: In general, risk factors for suicide were similar in the Netherlands and Flanders. However, the Dutch were characterised by more protective factors. We attempt to explain these differences and suggest ways of improving suicidal prevention policy.

Maternal venous Doppler characteristics are abnormal in pre-eclampsia but not in gestational hypertension.

OBJECTIVE: To compare functional characteristics of maternal thoraco-abdominal arteries and veins in proteinuric and non-proteinuric hypertension in pregnancy. METHODS: This retrospective study included women with singleton pregnancies during the third trimester, which were either uncomplicated or complicated with different clinical types of hypertension: non-proteinuric gestational hypertension (GH), early-onset pre-eclampsia (PE) diagnosed < 34 weeks or late-onset PE diagnosed ≥ 34 weeks. Demographic maternal and neonatal data were recorded, together with maternal serum and urine analytes. All women underwent standardized automated blood-pressure measurement, together with non-invasive impedance cardiography (ICG), for measurement of cardiac output (CO), aortic flow velocity index (VI) and aortic flow acceleration index (ACI). A standardized combined Doppler-electrocardiography assessment of maternal venous hemodynamics was performed to measure renal interlobar vein impedance index (RIVI), hepatic vein impedance index (HVI) and venous pulse transit time (VPTT) in liver and kidneys. Finally, resistance index (RI), pulsatility index (PI) and arterial pulse transit time (APTT) were measured in the uterine arcuate arteries. Mann-Whitney U-tests and Fisher's exact tests were used for intergroup comparisons, and linear dependence between variables was assessed using Pearson's correlation coefficient (r). RESULTS: A total of 150 pregnancies were evaluated: 22 with uncomplicated pregnancy, 41 GH, 31 early PE and 56 late PE. Aortic VI and ACI were lower in GH, early PE and late PE than in uncomplicated pregnancy. Both early PE and late PE differed from GH by having shorter APTT in the uterine arcuate arteries and higher RIVI. Hemodynamic abnormalities were most pronounced in early PE, during which uterine arcuate artery RI was higher and VPTT in kidneys was shorter than in late PE. There was a significant correlation between degree of proteinuria and RIVI for the left (r = 0.381) and right (r = 0.347) kidney in late PE, but this was not true for early PE. CONCLUSIONS: There is a gradient of worsening arterial and venous hemodynamic abnormalities from GH to late PE and then to early PE. Venous hemodynamic abnormalities are present only in PE, with a linear correlation between proteinuria and RIVI in late PE. The role of the maternal venous compartment in the pathophysiology and etiology of PE-related symptoms may be much more important than considered at present.

Simulation-based study comparing multiple imputation methods for non-monotone missing ordinal data in longitudinal settings.

The application of multiple imputation (MI) techniques as a preliminary step to handle missing values in data analysis is well established. The MI method can be classified into two broad classes, the joint modeling and the fully conditional specification approaches. Their relative performance for the longitudinal ordinal data setting under the missing at random (MAR) assumption is not well documented. This article intends to fill this gap by conducting a large simulation study on the estimation of the parameters of a longitudinal proportional odds model. The two MI methods are also illustrated in quality of life data from a cancer clinical trial.

Attitudes and stigma in relation to help-seeking intentions for psychological problems in low and high suicide rate regions.

PURPOSE: Accessibility and availability of mental health care services are necessary but not sufficient for people to seek help for psychological problems. Attitudes and stigma related to help seeking also determine help seeking intentions. The aim of this study is to investigate how cross-national differences in attitudes and stigma within the general population are related to professional and informal help seeking intentions in low and high suicide rate regions. METHODS: By means of a postal structured questionnaire, data of 2999 Dutch and Flemish respondents between 18 and 65 years were gathered. Attitudes toward help seeking, perceived stigma, self-stigma, shame and intention to seek help were assessed. RESULTS: People in the Netherlands, where suicide rates are low, have more positive attitudes toward help seeking and experience less self stigma and shame compared to the people in Flanders, where suicide rates are relatively high. These attitudinal factors predicted professional as well as informal help seeking intentions. Perceived stigma was negatively associated with informal help seeking. Shame was positively associated with higher intention to use psychotropic drugs and perceived stigma was negatively associated with the intention to seek help from a psychotherapist in Flanders but not in the Netherlands. CONCLUSION: Help seeking for psychological problems prevent these problems to aggravate and it is assumed to be a protective factor for suicide. Our results stress the importance of the promotion of positive attitudes and the reduction of stigma within the general population to facilitate help seeking from professional providers and informal networks. Focusing on these attitudinal factors is believed to be a key aspect of universal mental health and suicide prevention policies.

Registration of aggressive incidents in an adolescent forensic psychiatric unit and implications for further practice.

Although aggression is part of daily life in psychiatric units for adolescents, empirical data on its prevalence are sparse. Only few studies have described prevalence of aggressive incidents in adolescent psychiatric wards, and data in forensic psychiatric care are even more limited. Available studies reported high prevalence rates of aggression, ranging from 0.4 to 2.4 incidents of aggression per day across (forensic) child and adolescent psychiatric units. Between 27 and 78 % of all admitted youth committed an aggressive act. In this study, we collected systematically registered data of all aggressive incidents from the first 2 years (2010-2012) on a newly established forensic adolescent psychiatric unit, which used a formal aggression management program embedded in the social competence model, which is based on early intervention in the 'chain of behavior' to prevent any further escalation. The inclusion of also minor aggressive incidents is unique in the literature and the clinical relevance is highlighted. A mean of one incident a day took place, with each adolescent involved in at least one incident. Notably, 1.7 aggressive incidents per month made seclusion of restraint use necessary. Based on the social competence theory, the aggression management model suggests intervening early in the cascade of aggression, in order to prevent further escalation and reduce the need for intrusive interventions. Evidence supported that aggression is a contextual event, as external factors clearly influence the incidence of aggression. Aggression management should be built on both relational and structural security.

Analysis of an incomplete binary outcome derived from frequently recorded longitudinal continuous data: application to daily pain evaluation.

Randomized clinical trials increasingly collect daily data, frequently using electronic diaries. Such data are usually summarized into an 'intermediate' continuous outcome (such as the mean of the daily values in a period before a scheduled clinic visit). These are in turn often summarized further into a binary outcome, for example, indicating whether the intermediate continuous outcome has improved by a prespecified amount from randomization. This article compares and contrasts statistical approaches for analyzing such binary outcomes when the underlying study is subject to dropout so that some of the underlying diary data are missing. Such analysis involves rigorous rules for the derivation of outcomes, a thorough data exploration for the selection of covariates, and an elucidation of the missingness mechanism. The investigated statistical methods for treatment-effect analysis are based on direct modeling and on multiple imputation and are applied either to the binary outcome or the intermediate continuous outcome or to the daily diary data. These are compared on the basis of criteria for inferences at prespecified times during the follow-up. We show that multiple-imputation methods are particularly well adapted to our context and that missing data imputation on the daily diary data, rather than the derived outcomes, makes best use of the available information. The data set, which motivated our investigation, comes from a placebo-controlled clinical trial to assess the effect on pain of a new compound.

Time interval between maternal electrocardiogram and venous Doppler waves in normal pregnancy and preeclampsia: a pilot study.

PURPOSE: To evaluate the time interval between maternal electrocardiogram (ECG) and venous Doppler waves at different stages of uncomplicated pregnancy (UP) and in preeclampsia (PE). MATERIALS AND METHODS: Cross-sectional pilot study in 40 uncomplicated singleton pregnancies, categorized in four groups of ten according to gestational age: 10 - 14 weeks (UP1), 18 - 23 weeks (UP2), 28 - 33 weeks (UP3) and ≥ 37 weeks (UP4) of gestation. A fifth group of ten women with PE was also included. A Doppler flow examination at the level of renal interlobar veins (RIV) and hepatic veins (HV) was performed according to a standard protocol, in association with a maternal ECG. The time interval between the ECG P-wave and the corresponding A-deflection of the venous Doppler waves was measured (PA), and expressed relative to the duration of the cardiac cycle (RR), and labeled PA/RR. RESULTS: In hepatic veins, the PA/RR is longer in UP 4 than in UP 1 (0.48 ± 0.15 versus 0.29 ± 0.09, p ≤ 0.001). When all UP groups were compared, the PA/RR increased gradually with gestational age. In PE, the HV PA/RR is shorter than in UP 3 (0.25 ± 0.09 versus 0.42 ± 0.14, p < 0.01) and this difference persisted under anti-hypertensive treatment (0.28 ± 0.06 versus 0.42 ± 0.14, p ≤ 0.01, n = 6). Similar results were found in both kidneys. In UP 1 but not in UP 3 or UP 4, the HV PA/RR is shorter in the liver than in the left and right kidney (0.29 ± 0.09 versus 0.38 ± 0.12, p < 0.01, and versus 0.36 ± 0.09, p ≤ 0.01). CONCLUSION: The PA/RR is organ-specific and gestation-dependent, and is considered to relate to venous vascular tone and/or intravascular filling. Increased values at advanced gestational stages are consistent with known features of maternal cardiovascular adaptation. Shorter values in preeclampsia are consistent with maternal cardiovascular maladaptation mechanisms. Our pilot study invites more research of the relevance of the time interval between maternal ECG and venous Doppler waves as a new parameter for studying the gestational cardiovascular (patho)physiology of the maternal venous compartment by duplex sonography.

A structured approach to choosing estimands and estimators in longitudinal clinical trials.

An important evolution in the missing data arena has been the recognition of need for clarity in objectives. The objectives of primary focus in clinical trials can often be categorized as assessing efficacy or effectiveness. The present investigation illustrated a structured framework for choosing estimands and estimators when testing investigational drugs to treat the symptoms of chronic illnesses. Key issues were discussed and illustrated using a reanalysis of the confirmatory trials from a new drug application in depression. The primary analysis used a likelihood-based approach to assess efficacy: mean change to the planned endpoint of the trial assuming patients stayed on drug. Secondarily, effectiveness was assessed using a multiple imputation approach. The imputation model-derived solely from the placebo group-was used to impute missing values for both the drug and placebo groups. Therefore, this so-called placebo multiple imputation (a.k.a. controlled imputation) approach assumed patients had reduced benefit from the drug after discontinuing it. Results from the example data provided clear evidence of efficacy for the experimental drug and characterized its effectiveness. Data after discontinuation of study medication were not required for these analyses. Given the idiosyncratic nature of drug development, no estimand or approach is universally appropriate. However, the general practice of pairing efficacy and effectiveness estimands may often be useful in understanding the overall risks and benefits of a drug. Controlled imputation approaches, such as placebo multiple imputation, can be a flexible and transparent framework for formulating primary analyses of effectiveness estimands and sensitivity analyses for efficacy estimands.

Impedance cardiography in uncomplicated pregnancy and pre-eclampsia: a reliability study.

It has been reported that cardiac contractility is altered in pre-eclampsia compared with normal pregnancy. Because of the non-invasive nature of impedance cardiography (ICG), this method is gaining popularity in the obstetric field. We assessed the reliability of ICG measurements in uncomplicated 3rd trimester pregnancies (UP) and pre-eclamptic pregnancies (PE). ICG measurements were recorded before and after three position changes, and this examination was done twice (session 1 and 2) per subject. For each of the 22 haemodynamic parameters, inter- and intrasession Pearson's correlation coefficients (PCC) were calculated for mean values of 30 measurements per position per subject. PCC was consistently ≥ 0.80 for contractility parameters 'acceleration-', 'velocity-' and 'heather-index' in both UP and PE. These data illustrate that correlation between repeated ICG measurements of cardiac contractility is high under standardised conditions, and that ICG may be useful to study changes of cardiac contractility in pregnancy.

Geographical variation of COVID-19 vaccination coverage, ethnic diversity and population composition in Flanders.

The vaccination coverage in Flanders is high, but some regions show lower vaccination willingness as compared to the overall vaccination coverage. Beginning November of 2021, the vaccination rate in Flanders was above 93% in age groups above 45 years, and around 85% in the age groups 12 to 44 years. Apart from Flanders as a whole, focus here is on the health sector Maasland, which has a slightly lower vaccination rate, especially in the age groups 12 to 44 years. In the Maasland region, located on the eastern border of Flanders, there are between 1% and 10% less vaccinated individuals than expected according to the vaccination rate in the whole of Flanders, with lowest vaccination rates in the south of the Maasland region. We study the impact of ethnic diversity in the population, population composition with respect to the ethnicity of individuals (in the sense of how the local population composition differs from the Flemish average), and socio-economic status on the vaccination rate at the level of the statistical sector, apart from the effect of age. We explain the statistical methods to investigate geographical differences and illustrate how one can deal with incomplete information in vaccination registries. Ethnic diversity in a region is associated with lower vaccination rates, as is a lower regional socio-economic status. The composition of the population in Maasland is associated with a 35% reduction in the odds to get vaccinated as compared to the overall Flemish population.

Maternal renal interlobar vein impedance index is higher in early- than in late-onset pre-eclampsia.

OBJECTIVES: To test the hypothesis that Doppler characteristics of maternal renal interlobar veins (RIV) are different between pregnancies affected by early-onset pre-eclampsia (EP) and those affected by late-onset pre-eclampsia (LP). METHODS: A gestational age of 34 weeks was considered to differentiate EP from LP. All women had a renal duplex scan according to a standard protocol, with known intraobserver correlation coefficient (0.88). Maximum (Vmax) and minimum (Vmin) RIV velocities were measured on two occasions (between 28 and 32 and between 34 and 37 weeks) in 18 women with uncomplicated pregnancy (UP). In women with EP (n = 32) or LP (n = 41), these variables were measured once, within 3 days following hospital admission. Delta velocity (DeltaV) was calculated as Vmax - Vmin and the RIV impedance index (RIVI) was calculated as DeltaV/Vmax. Data on neonatal outcome and maternal renal function were obtained for UP and those with EP and LP, and group-specific means +/- SD were calculated and compared. RESULTS: Compared with UP, the RIVI of both left and right kidneys was higher in those with EP (0.49 +/- 0.13 vs. 0.36 +/- 0.04, P = 0.0001, and 0.46 +/- 0.15 vs. 0.33 +/- 0.04, P = 0.0008) and in those with LP (0.41 +/- 0.07 vs. 0.37 +/- 0.06, P = 0.04, and 0.38 +/- 0.12 vs. 0.30 +/- 0.05, P = 0.009). RIVI was higher in pregnancies with EP than in those with LP (P < or = 0.01), and this difference was associated with lower median birth-weight percentiles (22.5 (interquartile range (IQR), 15-35) vs. 40.0 (IQR, 12-55), P = 0.01), higher maternal serum uric acid concentrations (419 +/- 84 vs. 374 +/- 85 micromol/L, P = 0.03) and higher proteinuria (4131 +/- 3885 vs. 1190 +/- 1133 mg/24 h, P < 0.0001). CONCLUSION: Maternal vascular maladaption in pre-eclampsia is associated with abnormal Doppler findings in the venous compartment. RIVI is higher in EP than in LP pregnancies and this is associated with lower birth-weight percentiles and higher proteinuria.

Aligning Estimators With Estimands in Clinical Trials: Putting the ICH E9(R1) Guidelines Into Practice.

The draft ICH E9(R1) addendum stipulates that an estimator should align with its associated estimand and yield an estimate that facilitates reliable interpretations. The addendum further stipulates that assumptions should be justifiable and plausible, and that the extent of assumptions is an important consideration for whether an estimate will be robust because assumptions are often unverifiable. The draft addendum specifies 5 strategies for dealing with intercurrent events. The intent of this paper is to provide conceptual considerations and technical details for various estimators that align with these strategies. We include focus on how the nature and extent of assumptions influences the potential robustness of the various estimators. The content reflects the knowledge, experience, and opinions of the Drug Information Association's Scientific Working Group on Missing Data. This group includes experienced statisticians from across industry and academia, primarily in the US and European Union.

Impact of a short period of pre-enrichment on detection and bacterial loads of methicillin-resistant Staphylococcus aureus from screening specimens.

We compared the impacts of direct plating on a chromogenic medium and of plating after enrichment (4 h and overnight) on the detection of methicillin-resistant Staphylococcus aureus (MRSA) from 52 patient screening samples. MRSA colony counts for approximately 70% of samples after overnight pre-enrichment were >20-fold higher than the counts after the other two treatments. The qualitative differences (sample was MRSA positive/negative) between the results of the direct plating and 4-h pre-enrichment treatments were not significant, indicating no advantage of the latter; however, the number of samples positive for MRSA increased significantly after an overnight sample pre-enrichment (P < 0.005).

The correlated and shared gamma frailty model for bivariate current status data: an illustration for cross-sectional serological data.

Frailty models are often used to study the individual heterogeneity in multivariate survival analysis. Whereas the shared frailty model is widely applied, the correlated frailty model has gained attention because it elevates the restriction of unobserved factors to act similar within clusters. Estimating frailty models is not straightforward due to various types of censoring. In this paper, we study the behavior of the bivariate-correlated gamma frailty model for type I interval-censored data, better known as current status data. We show that applying a shared rather than a correlated frailty model to cross-sectionally collected serological data on hepatitis A and B leads to biased estimates for the baseline hazard and variance parameters.

Interlobar venous flow is different between left and right kidney in uncomplicated third trimester pregnancy.

AIM: To investigate Doppler flow patterns of renal interlobar veins (RIV) in left (L) and right (R) kidney in relation to gestational age and to intrarenal pyelocalyceal diameters (PCD). METHODS: Cross-sectional study involving 6 groups of women: (1) non-pregnant women, women pregnant between weeks (2) 11-14, (3) 18-23, (4) 28-33, (5) 37-40 and (6) women <5 days post delivery. During standardized renal duplex ultrasound scan, PCD (mm) was measured and venous impedance index (VI = [peak flow (PV) - presystolic flow]/PV) of RIV was defined. Comparison between L and R kidney was performed by repeated-measures analysis of variance for VI and by t tests for PCD. RESULTS: A total of 150 women were examined, 25 in each group. In the early third trimester of pregnancy, L VI was significantly higher than R VI (0.38 +/- 0.01 vs. 0.33 +/- 0.01, p < 0.0001) and L PCD was significantly lower than R PCD (3.90 +/- 3.68 vs. 6.25 +/- 4.03, p = 0.03). CONCLUSION: RIV Doppler flow is different between left and right kidney only in the third trimester of pregnancy. This difference is inversely related to PCD, which may be explained by pelvic compression from the gravid uterus.

Random-effects models for multivariate repeated measures.

Mixed models are widely used for the analysis of one repeatedly measured outcome. If more than one outcome is present, a mixed model can be used for each one. These separate models can be tied together into a multivariate mixed model by specifying a joint distribution for their random effects. This strategy has been used for joining multivariate longitudinal profiles or other types of multivariate repeated data. However, computational problems are likely to occur when the number of outcomes increases. A pairwise modeling approach, in which all possible bivariate mixed models are fitted and where inference follows from pseudo-likelihood arguments, has been proposed to circumvent the dimensional limitations in multivariate mixed models. An analysis on 22-variate longitudinal measurements of hearing thresholds illustrates the performance of the pairwise approach in the context of multivariate linear mixed models. For generalized linear mixed models, a data set containing repeated measurements of seven aspects of psycho-cognitive functioning will be analyzed.