AimTo examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and... Show moreAimTo examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.Methods and resultsIn the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study.ConclusionA small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study.The ability of the deep circulating proteome to predict future heart failure (HF) events, including its primary subtypes, in relation to event time and known HF-associated clinical factors was studied in two prospective population-based cohorts. AGES-RS, Age, Gene/Environment Susceptibility Reykjavik Study; CHS, Cardiovascular Health Study; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LASSO, least absolute shrinkage and selection operator; ROC, receiver operating characteristic.dagger image Show less
Carryover of previous treatment outcomes to subsequent medical treatment outcomes seems to be pervasive. The influence of a treatment history can generalize across treatments and across symptoms.... Show moreCarryover of previous treatment outcomes to subsequent medical treatment outcomes seems to be pervasive. The influence of a treatment history can generalize across treatments and across symptoms. These generalization effects in clinical practice have been studied experimentally in placebo and nocebo effects, which are beneficial and adverse effects that do not arise from active treatment components, respectively. The aim of this thesis was to answer the question of whether previously learned placebo and nocebo effects can generalize within and across somatosensory sensations. Additionally, the thesis also explored the role of individual characteristics as predictors (e.g., anxiety, stress, attention, catastrophizing) for the generalization of placebo and nocebo effects. The findings of the thesis have showed that placebo and nocebo effects can generalize within pain and itch modalities, but can not generalize from pain to itch and from itch to touch. The generalization effects of placebo and nocebo effects can not be predicted by psychological characteristics (e.g., anxiety- and stress symptoms) in healthy individuals. Moreover, the dissertation addresses the limitations of the work and directions for future research, as well as giving implications for clinic practice. Show less
Population-scale expression profiling studies can provide valuable insights into biological and disease-underlying mechanisms. The availability of phenotypic traits is essential for studying... Show morePopulation-scale expression profiling studies can provide valuable insights into biological and disease-underlying mechanisms. The availability of phenotypic traits is essential for studying clinical effects. Therefore, missing, incomplete, or inaccurate phenotypic information can make analyses challenging and prevent RNA-seq or other omics data to be reused. A possible solution are predictors that infer clinical or behavioral phenotypic traits from molecular data. While such predictors have been developed based on different omics data types and are being applied in various studies, metabolomics-based surrogates are less commonly used than predictors based on DNA methylation profiles.In this study, we inferred 17 traits, including diabetes status and exposure to lipid medication, using previously trained metabolomic predictors. We evaluated whether these metabolomic surrogates can be used as an alternative to reported information for studying the respective phenotypes using expression profiling data of four population cohorts. For the majority of the 17 traits, the metabolomic surrogates performed similarly to the reported phenotypes in terms of effect sizes, number of significant associations, replication rates, and significantly enriched pathways.The application of metabolomics-derived surrogate outcomes opens new possibilities for reuse of multi-omics data sets. In studies where availability of clinical metadata is limited, missing or incomplete information can be complemented by these surrogates, thereby increasing the size of available data sets. Additionally, the availability of such surrogates could be used to correct for potential biological confounding. In the future, it would be interesting to further investigate the use of molecular predictors across different omics types and cohorts. Show less
BACKGROUND: Missing data is a typical problem in clinical studies, where the value of variables of interest is not measured or collected for some patients. This article aimed to review imputation... Show moreBACKGROUND: Missing data is a typical problem in clinical studies, where the value of variables of interest is not measured or collected for some patients. This article aimed to review imputation approaches for missing values and their application in neurosurgery.METHODS: We reviewed current practices on detecting missingness patterns and applications of multiple imputation approaches under different scenarios. Statistical considerations and importance of sensitivity analysis were explained. Various imputation methods were applied to a retrospective cohort.RESULTS: For illustration purposes, a retrospective cohort of 609 patients harboring both ruptured and unruptured intracranial aneurysms and undergoing microsurgical clip reconstruction at Erasmus MC University Medical Center, Rotterdam, The Netherlands, between 2000 and 2019 was used. modified Rankin Scale score at 6 months was the clinical outcome, and potential predictors were age, sex, size of aneurysm, hypertension, smoking, World Federation of Neurosurgical Societies grade, and aneurysm location. Associations were investigated using different imputation approaches, and the results were compared and discussed.CONCLUSIONS: Missing values should be treated carefully. Advantages and disadvantages of multiple imputation methods along with imputation in small and big data should be considered depending on the research question and specifics of the study. Show less
Physical and sexual abuse during childhood can have long lasting consequences such as posttraumatic stress disorder (PTSD). Prolonged Exposure (PE) is an established and effective guideline... Show morePhysical and sexual abuse during childhood can have long lasting consequences such as posttraumatic stress disorder (PTSD). Prolonged Exposure (PE) is an established and effective guideline treatment for PTSD. Nevertheless, a considerable number of patients drop out from treatment or do not (completely) recover from PTSD during PE. It has been suggested that patients with PTSD resulting from childhood abuse are specifically at risk for suboptimal treatment outcomes. We carried out a randomized controlled trial with 149 patients with childhood abuse-related PTSD comparing PE with two innovations: intensified PE (iPE) and skills training in affective and interpersonal regulation followed by PE (STAIR+PE). We found that all treatments were safe and resulted in large improvements in PTSD symptoms. iPE and STAIR+PE did not improve treatment outcomes of PE, although iPE led to faster symptom improvements. Not all patients benefitted from the allocated treatment, but we found no contra-indications for the treatments. We found that a combination of patient characteristics was predictive of a larger effect size of PTSD symptom improvement in PE and iPE or STAIR+PE. We conclude that the three forms of exposure therapy were effective treatments for patients with childhood abuse-related PTSD. Show less
Wit, A.E. de; Giltay, E.J.; Boer, M.K. de; Nathan, M.; Wiley, A.; Crawford, S.; Joffe, H. 2021
Objective: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with... Show moreObjective: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with depressive symptoms during perimenopause, more insight is needed into reproductive hormone dynamics and other factors that predispose perimenopausal women to irritable mood. Methods: Among 50 mildly depressed perimenopausal women (mean (SD) age 48.4 (3.9) years), severity of irritability symptoms (on Symptom Questionnaire Hostility subscale, range 0-23) was assessed weekly for eight weeks, concurrent with potential predictors. Associations between these were examined using generalized estimating equating models.Results: Most women (82.0%) reported having moderate to severe irritability at least once. However, the severity of irritability was highly variable from week-to-week (between-subject mean coefficient of variation [CV] 72.9% and within-subject mean CV 63.7%). In multivariate analyses, less variable serum estradiol levels (standardized beta within-person CV-0.23 95%CI [-0.32,-0.14], p < 0.001), greater depression severity (0.45 [0.35, 0.56], p < 0.001), younger age (-0.23, [-0.28,-0.09], p < 0.001), and more frequent vasomotor symptoms (0.14 [0.05, 0.23], p = 0.002) were associated with more irritability. Depression severity explained the largest portion of the variance in irritability, but still not more than 20.3%. Neither crude values, weekly change in, or variability of progesterone or FSH levels were associated with irritability.Conclusions: Irritability was highly prevalent among mildly depressed perimenopausal women. In contrast to depressive symptoms, decreased rather than increased variability in estradiol levels was associated with more irritability. This highlights that irritable mood can be disentangled from depressive symptoms in perimenopausal women and might be linked with different estradiol dynamics. Show less
Miah, I.P.; Tank, Y.; Rosendaal, F.R.; Peul, W.C.; Dammers, R.; Lingsma, H.F.; ... ; Gaag, N.A. van der 2020
Purpose Chronic subdural hematoma (CSDH) is associated with high recurrence rates. Radiographic prognostic factors may identify patients who are prone for recurrence and who might benefit further... Show morePurpose Chronic subdural hematoma (CSDH) is associated with high recurrence rates. Radiographic prognostic factors may identify patients who are prone for recurrence and who might benefit further optimization of therapy. In this meta-analysis, we systematically evaluated pre-operative radiological prognostic factors of recurrence after surgery. Methods Electronic databases were searched until September 2020 for relevant publications. Studies reporting on CSDH recurrence in symptomatic CSDH patients with only surgical treatment were included. Random or fixed effects meta-analysis was used depending on statistical heterogeneity. Results Twenty-two studies were identified with a total of 5566 patients (mean age 69 years) with recurrence occurring in 801 patients (14.4%). Hyperdense components (hyperdense homogeneous and mixed density) were the strongest prognostic factor of recurrence (pooled RR 2.83, 95% CI 1.69-4.73). Laminar and separated architecture types also revealed higher recurrence rates (RR 1.37, 95% CI 1.04-1.80 and RR 1.76 95% CI 1.38-2.16, respectively). Hematoma thickness and midline shift above predefined cut-off values (10 mm and 20 mm) were associated with an increased recurrence rate (RR 1.79, 95% CI 1.45-2.21 and RR 1.38, 95% CI 1.11-1.73, respectively). Bilateral CSDH was also associated with an increased recurrence risk (RR 1.34, 95% CI 0.98-1.84). Limitations Limitations were no adjustments for confounders and variable data heterogeneity. Clinical factors could also be predictive of recurrence but are beyond the scope of this study. Conclusions Hyperdense hematoma components were the strongest prognostic factor of recurrence after surgery. Awareness of these findings allows for individual risk assessment and might prompt clinicians to tailor treatment measures. Show less
Najafabadi, A.H.Z.; Meer, P.B. van der; Boele, F.W.; Taphoorn, M.J.B.; Klein, M.; Peerdeman, S.M.; ... ; Dirven, L. 2020
Introduction Meningioma is a heterogeneous disease and patients may suffer from long-term tumor- and treatment-related sequelae. To help identify patients at risk for these late effects, we first... Show moreIntroduction Meningioma is a heterogeneous disease and patients may suffer from long-term tumor- and treatment-related sequelae. To help identify patients at risk for these late effects, we first assessed variables associated with impaired long-term health-related quality of life (HRQoL) and impaired neurocognitive function on group level (i.e. determinants). Next, prediction models were developed to predict the risk for long-term neurocognitive or HRQoL impairment on individual patient-level. Methods Secondary data analysis of a cross-sectional multicenter study with intracranial WHO grade I/II meningioma patients, in which HRQoL (Short-Form 36) and neurocognitive functioning (standardized test battery) were assessed. Multivariable regression models were used to assess determinants for these outcomes corrected for confounders, and to build prediction models, evaluated with C-statistics. Results Data from 190 patients were analyzed (median 9 years after intervention). Main determinants for poor HRQoL or impaired neurocognitive function were patients' sociodemographic characteristics, surgical complications, reoperation, radiotherapy, presence of edema, and a larger tumor diameter on last MRI. Prediction models with a moderate/good ability to discriminate between individual patients with and without impaired HRQoL (C-statistic 0.73, 95% CI 0.65 to 0.81) and neurocognitive function (C-statistic 0.78, 95%CI 0.70 to 0.85) were built. Not all predictors (e.g. tumor location) within these models were also determinants. Conclusions The identified determinants help clinicians to better understand long-term meningioma disease burden. Prediction models can help early identification of individual patients at risk for long-term neurocognitive or HRQoL impairment, facilitating tailored provision of information and allocation of scarce supportive care services to those most likely to benefit. Show less
In this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was... Show moreIn this thesis, longitudinal analyses have been performed on the PROPARK-Cohort, a hospital-based cohort of 421 patients followed for a period of five years. The main focus of this thesis was to determine which predictors and associated factors contributed to the development of certain non-motor symptoms in Parkinson’s disease (PD). Strengths of our cohort study include the length of the follow-up period, broad clinical characterization, limited loss-to-follow-up and the large cohort size. The following non-motor symptoms have been addressed in this thesis: psychosis (hallucinations), dementia, excessive daytime sleepiness (EDS), insomnia, depression and anxiety. We found that while certain non-motor symptoms are inherent components of PD that increase in severity as the disease progresses, others symptoms such as excessive daytime sleepiness are inarguably caused by antiparkinsonian medication. For the future, we hope to see more longitudinal data on the disease progression in PD from large cohorts. Knowledge from longitudinal studies does not only contribute to more insight in the underlying pathobiology of PD, but it could also help the caregiver to monitor patients with particular risk factors more closely and adjust treatment if necessary. Show less
The main subject of this thesis is pelvic pain in women in secondary and/or tertiary medical care. Studies aim to examine: 1. The clinical course of acute abdominal pain and risks of pain... Show moreThe main subject of this thesis is pelvic pain in women in secondary and/or tertiary medical care. Studies aim to examine: 1. The clinical course of acute abdominal pain and risks of pain persistence. 2. The clinical course of chronic pelvic pain (CPP) and predictors of recovery. 3. The moderating and /or mediating factors of sexual functioning. 4. The reliability of videotaped compared to real-time laparoscopic findings. Results show that pain persisted in 30% of women after an acute episode of abdominal pain. A low education level and an abuse history at a younger age were risks for chronicity. Recovery from pain was observed in 20% to 25% of women with CPP. Only a decrease in catastrophizing pain was associated with an improvement in pain and adjustment. Women with CPP reported more sexual problems than pain free controls. Anxiety and depression moderated sexual problems, while sexual abuse was a non-specific predictor. Finally, the evaluations of videotaped laparoscopies to score endometriosis were reliable, apart from ovarian lesions. In case of adhesions such evaluations were inconsistent. Main conclusion: CPP in women has to be considered as a chronic pain condition in general. A model to assess women with CPP and facilitate pain management is suggested. Show less