Etiological research aims to uncover causal effects, whilst prediction research aims to forecast an outcome with the best accuracy. Causal and prediction research usually require different methods,... Show moreEtiological research aims to uncover causal effects, whilst prediction research aims to forecast an outcome with the best accuracy. Causal and prediction research usually require different methods, and yet their findings may get conflated when reported and interpreted. The aim of the current study is to quantify the frequency of conflation between etiological and prediction research, to discuss common underlying mistakes and provide recommendations on how to avoid these. Observational cohort studies published in January 2018 in the top-ranked journals of six distinct medical fields (Cardiology, Clinical Epidemiology, Clinical Neurology, General and Internal Medicine, Nephrology and Surgery) were included for the current scoping review. Data on conflation was extracted through signaling questions. In total, 180 studies were included. Overall, 26% (n = 46) contained conflation between etiology and prediction. The frequency of conflation varied across medical field and journal impact factor. From the causal studies 22% was conflated, mainly due to the selection of covariates based on their ability to predict without taking the causal structure into account. Within prediction studies 38% was conflated, the most frequent reason was a causal interpretation of covariates included in a prediction model. Conflation of etiology and prediction is a common methodological error in observational medical research and more frequent in prediction studies. As this may lead to biased estimations and erroneous conclusions, researchers must be careful when designing, interpreting and disseminating their research to ensure this conflation is avoided. Show less
Hond, A. de; Raven, W.; Schinkelshoek, L.; Gaakeer, M.; Avest, E. ter; Sir, O.; ... ; Groot, B. de 2021
Objective: Early identification of emergency department (ED) patients who need hospitalization is essential for quality of care and patient safety. We aimed to compare machine learning (ML) models... Show moreObjective: Early identification of emergency department (ED) patients who need hospitalization is essential for quality of care and patient safety. We aimed to compare machine learning (ML) models predicting the hospitalization of ED patients and conventional regression techniques at three points in time after ED registration.Methods: We analyzed consecutive ED patients of three hospitals using the Netherlands Emergency Department Evaluation Database (NEED). We developed prediction models for hospitalization using an increasing number of data available at triage, similar to 30 min (including vital signs) and similar to 2 h (including laboratory tests) after ED registration, using ML (random forest, gradient boosted decision trees, deep neural networks) and multivariable logistic regression analysis (including spline transformations for continuous predictors). Demographics, urgency, presenting complaints, disease severity and proxies for comorbidity, and complexity were used as covariates. We compared the performance using the area under the ROC curve in independent validation sets from each hospital.Results: We included 172,104 ED patients of whom 66,782 (39 %) were hospitalized. The AUC of the multi-variable logistic regression model was 0.82 (0.78-0.86) at triage, 0.84 (0.81-0.86) at similar to 30 min and 0.83 (0.75-0.92) after similar to 2 h. The best performing ML model over time was the gradient boosted decision trees model with an AUC of 0.84 (0.77-0.88) at triage, 0.86 (0.82-0.89) at similar to 30 min and 0.86 (0.74-0.93) after similar to 2 h.Conclusions: Our study showed that machine learning models had an excellent but similar predictive performance as the logistic regression model for predicting hospital admission. In comparison to the 30-min model, the 2-h model did not show a performance improvement. After further validation, these prediction models could support management decisions by real-time feedback to medical personal. Show less
Background Notwithstanding the firmly established cross-sectional association of happiness with psychiatric disorders and their symptom severity, little is known about their temporal relationships.... Show moreBackground Notwithstanding the firmly established cross-sectional association of happiness with psychiatric disorders and their symptom severity, little is known about their temporal relationships. The goal of the present study was to investigate whether happiness is predictive of subsequent psychiatric disorders and symptom severity (and vice versa). Moreover, it was examined whether changes in happiness co-occur with changes in psychiatric disorder status and symptom severity. Methods In the Netherlands Study of Depression and Anxiety (NESDA), happiness (SRH: Self-Rated Happiness scale), depressive and social anxiety disorder (CIDI: Composite Interview Diagnostic Instrument) and depressive and anxiety symptom severity (IDS: Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory; and FQ: Fear Questionnaire) were measured in 1816 adults over a three-year period. Moreover, we focused on occurrence and remittance of 6-month recency Major Depressive Disorder (MDD) and Social Anxiety Disorders (SAD) as the two disorders most intertwined with subjective happiness. Results Interindividual differences in happiness were quite stable (ICC of .64). Higher levels of happiness predicted recovery from depression (OR = 1.41; 95% CI = 1.10-1.80), but not social anxiety disorder (OR = 1.31; 95%CI = .94-1.81), as well as non-occurrence of depression (OR = 2.41; 95%CI = 1.98-2.94) and SAD (OR = 2.93; 95%CI = 2.29-3.77) in participants without MDD, respectively SAD at baseline. Higher levels of happiness also predicted a reduction of IDS depression (sr = - 0.08; 95%CI = -0.10 - -0.04), and BAI (sr = - 0.09; 95%CI = -0.12 - -0.05) and FQ (sr = - 0.06; 95%CI = -0.09 - -0.04) anxiety symptom scores. Conversely, presence of affective disorders, as well as higher depression and anxiety symptom severity at baseline predicted a subsequent reduction of self-reported happiness (with marginal to small sr values varying between -.04 (presence of SAD) to -.17 (depression severity on the IDS)). Moreover, changes in happiness were associated with changes in psychiatric disorders and their symptom severity, in particular with depression severity on the IDS (sr = - 0.46; 95%CI = -.50 - -.42). Conclusions Results support the view of rather stable interindividual differences in subjective happiness, although level of happiness is inversely associated with changes in psychiatric disorders and their symptom severity, in particular depressive disorder and depression severity. Show less
Tio-Coma, M.; Kielbasa, S.M.; Eeden, S.J.F. van den; Mei, H.L.; Roy, J.C.; Wallinga, J.; ... ; Geluk, A. 2021
Background: Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late-or misdiag-nosed leading to irreversible disabilities. Blood transcriptomic biomarkers that... Show moreBackground: Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late-or misdiag-nosed leading to irreversible disabilities. Blood transcriptomic biomarkers that prospectively predict those who progress to leprosy (progressors) would allow early diagnosis, better treatment outcomes and facilitate interventions aimed at stopping bacterial transmission. To identify potential risk signatures of leprosy, we collected whole blood of household contacts (HC, n=5,352) of leprosy patients, including individuals who were diagnosed with leprosy 4-61 months after sample collection.Methods: We investigated differential gene expression (DGE) by RNA-Seq between progressors before pres-ence of symptoms (n=40) and HC (n=40), as well as longitudinal DGE within each progressor. A prospective leprosy signature was identified using a machine learning approach (Random Forest) and validated using reverse transcription quantitative PCR (RT-qPCR). Findings: Although no significant intra-individual longitudinal variation within leprosy progressors was iden-tified, 1,613 genes were differentially expressed in progressors before diagnosis compared to HC. We identi-fied a 13-gene prospective risk signature with an Area Under the Curve (AUC) of 95.2%. Validation of this RNA-Seq signature in an additional set of progressors (n=43) and HC (n=43) by RT-qPCR, resulted ina final 4 -gene signature, designated RISK4LEP (MT-ND2, REX1BD, TPGS1, UBC) (AUC=86.4%).Interpretation: This study identifies for the first time a prospective transcriptional risk signature in blood pre-dicting development of leprosy 4 to 61 months before clinical diagnosis. Assessment of this signature in con-tacts of leprosy patients can function as an adjunct diagnostic tool to target implementation of interventions to restrain leprosy development. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Plas-Krijgsman, W.G. van der; Boer, A.Z. de; Jong, P. de; Bastiaannet, E.; Bos, F. van den; Mooijaart, S.P.; ... ; Glas, N.A. de 2021
The number of older patients with breast cancer has increased due to the aging of the general population. The use of a geriatric assessment in this population has been advocated in many studies and... Show moreThe number of older patients with breast cancer has increased due to the aging of the general population. The use of a geriatric assessment in this population has been advocated in many studies and guidelines as it can be used to identify high risk populations for early mortality and toxicity. Additionally, geriatric parameters could predict relevant outcome measures. This systematic review summarizes all available evidence on predictive factors for various outcomes (disease-related and survival, toxicity, and patient-reported outcomes), with a special focus on geriatric parameters and patient-reported outcomes, in older patients with breast cancer. Studies were identified through systematic review of the literature published up to September 1st 2019 in the PubMed database and EMBASe. A total of 173 studies were included. Most studies investigated disease-related and survival outcomes (n = 123, 71%). Toxicity was investigated in 40 studies (23%) and a mere 15% (n = 26) investigated patient-reported outcomes. Various measures that can be derived from a geriatric assessment were predictive for survival endpoints. Furthermore, geriatric parameters were among the most frequently found predictors for toxicity and patient-reported outcomes. In conclusion, this study shows that geriatric parameters can predict survival, toxicity, and patient-reported outcomes in older patients with breast cancer. These findings can be used in daily clinical practice to identify patients at risk of early mortality, high risk of treatment toxicity or poor functional outcome after treatment. A minority of studies used relevant outcome measures for older patients, showing the need for studies that are tailored to the older population.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
There is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor... Show moreThere is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor-stroma ratio (TSR) in colorectal cancer, focusing on expanding current clinical-pathological standards and combining TSR with other diagnostic parameters. The TSR is a microscopy scoring method performed on hematoxylin-eosin stained tissue slides used for routine pathology assessment, and has proven to be a robust prognostic maker. Here, we investigate whether the TSR also exhibits predictive value with regard to adjuvant targeted therapy in stage II and III colon cancer. Moreover, exploring the value of collagen fiber organization in the intratumoral stroma, as well as combining this parameter with the TSR. Finally, expanding the application of the TSR with radiological diagnostics in rectal cancer. Assessing is there is a correlation between TSR and apparent diffusion coefficient values obtained from diagnostically performed MRI-DWI scans, in order to determine if there is potential with regards to neoadjuvant treatment choices or patient follow-up. Show less
Patients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to... Show morePatients with diabetes mellitus have the highest mortality risk within the dialysis population. The presence of chronic kidney disease (CKD) in patients with diabetes is also strongly related to impaired quality of life. Research is warranted to prevent progressive diabetic kidney disease, improve quality of life and reduce mortality in this vulnerable population. In order to improve survival, more knowledge about which patients have the highest mortality risk and which risk factors and co-morbid conditions contribute to this increased mortality risk is essential. In this thesis we focussed on clinical aspects of the relation between diabetes mellitus and kidney disease, from hyperfiltration to dialysis. In chapter 2 we assessed many different measures of glucose metabolism and their association with kidney function among Dutch middle-aged adults. In chapter three and four we compared survival of dialysis patients with diabetes mellitus as underlying cause of the renal failure versus dialysis patients with diabetes mellitus as a co-morbid condition only. In chapter five we aimed to develop a prediction model for 1-year mortality in diabetic dialysis patients. Furthermore in chapter six we compared survival after amputation in diabetic dialysis patients to non-diabetic dialysis patients. Show less
Risk prediction is one of the central goals of medicine. However, ultimate prediction-perfectly predicting whether individuals will actually get a disease-is still out of reach for virtually all... Show moreRisk prediction is one of the central goals of medicine. However, ultimate prediction-perfectly predicting whether individuals will actually get a disease-is still out of reach for virtually all conditions. One crucial assumption of ultimate personalized prediction is that individual risks in the relevant sense exist. In the present paper we argue that perfect prediction at the individual level will fail-and we will do so by providing pragmatic, epistemic, conceptual, and ontological arguments. Show less
Souwer, E.T.D.; Bastiaannet, E.; Steyerberg, E.W.; Dekker, J.W.T.; Bos, F. van den; Portielje, J.E.A. 2020
Background: An increasing number of patients with Colorectal Cancer (CRC) is 65 years or older. We aimed to systematically review existing clinical prediction models for postoperative outcomes of... Show moreBackground: An increasing number of patients with Colorectal Cancer (CRC) is 65 years or older. We aimed to systematically review existing clinical prediction models for postoperative outcomes of CRC surgery, study their performance in older patients and assess their potential for preoperative decision making.Methods: A systematic search in Pubmed and Embase for original studies of clinical prediction models for outcomes of CRC surgery. Bias and relevance for preoperative decision making with older patients were assessed using the CHARMS guidelines.Results: 26 prediction models from 25 publications were included. The average age of included patients ranged from 61 to 76. Two models were exclusively developed for 65 and older. Common outcomes were mortality (n = 10), anastomotic leakage (n = 7) and surgical site infections (n = 3). No prediction models for quality of life or physical functioning were identified. Age, gender and ASA score were common predictors; 12 studies included intraoperative predictors. For the majority of the models, bias for model development and performance was considered moderate to high.Conclusions: Prediction models are available that address mortality and surgical complications after CRC surgery. Most models suffer from methodological limitations, and their performance for older patients is uncertain. Models that contain intraoperative predictors are of limited use for preoperative decision making. Future research should address the predictive value of geriatric characteristics to improve the performance of prediction models for older patients. (C) 2020 The Authors. Published by Elsevier Ltd. Show less
This thesis describes the detailed method of scoring the tumor-stroma ratio and the different possibilities to use it in routine clinical diagnostics, for different types of cancer. It can be used... Show moreThis thesis describes the detailed method of scoring the tumor-stroma ratio and the different possibilities to use it in routine clinical diagnostics, for different types of cancer. It can be used not only for prognostic purposes, but it might also be useful for predicting the response on neo-adjuvant therapy. As it is an easy and cheap method, based on routine hematoxylin-eosin stained tissue slides used for daily pathology routine, it can be implemented in clinical diagnostics with little effort. Show less
In this thesis, the transition from a population-based approach to individualized therapy for the prevention of VT following lower-leg cast immobilization and knee arthroscopy is discussed.
Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury.Study Design and Setting: We... Show moreObjective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury.Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified.Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study.Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations. (C) 2020 The Authors. Published by Elsevier Inc. Show less
One of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse... Show moreOne of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse effects can be limited while still maintaining high cure rates or to identify those patients for whom treatment is expected to have limited benefit. Furthermore, to identify high-risk patients in which treatment needs to be intensified to improve outcome. Selection of risk groups and adjusted treatment allows for early decision making, will help to improve future outcomes and assists in clinical trial design. Additionally, treatment of Ewing sarcoma is multimodal and surgery, if feasible, is crucial for curative management. However, accurate detection and localization of tumor boundaries, especially in anatomical complex locations such as the pelvic is challenging. Inadequate surgical margins lead to a higher risk of local recurrence which has major impact on oncological outcome. Developments in intra-operative imaging, like CT-based navigation systems and near infrared (NIR)fluorescence guided surgery (FGS) make accurate defining and localization of surgical margins possible. They represent a whole new field of precision medicine and provide new treatment options for patients, thereby improving function outcome and healthcare quality. Show less
With increasing age, associations between traditional risk factors (TRFs) and cardiovascular disease (CVD) shift. It is unknown which mid-life risk factors remain relevant predictors for CVD in... Show moreWith increasing age, associations between traditional risk factors (TRFs) and cardiovascular disease (CVD) shift. It is unknown which mid-life risk factors remain relevant predictors for CVD in older people.We systematically searched PubMed and EMBASE on August 16th 2019 for studies assessing predictive ability of > 1 of fourteen TRFs for fatal and non-fatal CVD, in the general population aged 60 + .We included 12 studies, comprising 11 unique cohorts. TRF were evaluated in 2 to 11 cohorts, and retained in 0-70% of the cohorts: age (70%), diabetes (64%), male sex (57%), systolic blood pressure (SBP) (50%), smoking (36%), high-density lipoprotein cholesterol (HDL) (33%), left ventricular hypertrophy (LVH) (33%), total cholesterol (22%), diastolic blood pressure (20%), antihypertensive medication use (AHM) (20%), body mass index (BMI) (0%), hypertension (0%), low-density lipoprotein cholesterol (0%). In studies with low to moderate risk of bias, systolic blood pressure (SBP) (80%), smoking (80%) and HDL cholesterol (60%) were more often retained. Model performance was moderate with C-statistics ranging from 0.61 to 0.77.Compared to middle-aged adults, in people aged 60 + different risk factors predict CVD and current prediction models perform only moderate at best. According to most studies, age, sex and diabetes seem valuable predictors of CVD in old-age. SBP, HDL cholesterol and smoking may also have predictive value. Other blood pressure and cholesterol related variables, BMI, and LVH seem of very limited or no additional value. Without competing risk analysis, predictors are overestimated. Show less
Nemeth, B.; Douillet, D.; Cessie, S. le; Penaloza, A.; Moumneh, T.; Roy, P.M.; Cannegieter, S. 2020
Background: Patients with lower-limb trauma requiring immobilization have an increased risk of venous thromboembolism (VTE). While thromboprophylaxis for all patients seems not effective, targeted... Show moreBackground: Patients with lower-limb trauma requiring immobilization have an increased risk of venous thromboembolism (VTE). While thromboprophylaxis for all patients seems not effective, targeted thromboprophylaxis in high risk patients may be an appropriate alternative. Therefore, we aimed to develop and validate a risk assessment model for VTE risk: the TRiP(cast) score (Thrombosis Risk Prediction following cast immobilization).Methods: In this prediction model study, for development, data were used from the MEGA study (case-control study into the etiology of VTE) and for validation, data from the POT-CAST trial (randomized trial on the effectiveness of thromboprophylaxis following cast immobilization) were used. Model discrimination was calculated by estimating the Area Under the Curve (AUC). For model calibration, observed and predicted risks were assessed.Findings: The TRiP( cast) score includes 14 items; one item for trauma severity (or type), one for type of immobilization and 12 items related to patients' characteristics. Validation analyses showed an AUC of 0.74 (95%CI 0.61-0.87) in the complete dataset (n = 1250) and 0.72 (95%CI 0.60-0.84) in the imputed data set (n = 1435). The calibration plot shows the degree of agreement between the observed and predicted risks (intercept 0.0016 and slope 0.933). Using a cut-off score of 7 points in the POT-CAST trial (incidence 1.6%), the sensitivity, specificity, positive and negative predictive values were 76.1%, 51.2%, 2.5%, and 99.2%, respectively.Interpretation: The TRiP(cast) score provides a helpful tool in daily clinical practice to accurately stratify patients in high versus low-risk categories in order to guide thromboprophylaxis prescribing. To accommodate implementation in clinical practice a mobile phone application has been developed. (C) 2020 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. (http://creativecommon.org/licenses/by-nc-nd/4.0/) Show less
Pelt, G.W. van; Krol, J.A.; Lips, I.M.; Peters, F.P.; Klaveren, D. van; Boonstra, J.J.; ... ; Slingerland, M. 2020
Psychomotor symptoms are core features of melancholic depression. This study investigates whether psychomotor disturbance predicts the outcome of electroconvulsive therapy (ECT) and how the... Show morePsychomotor symptoms are core features of melancholic depression. This study investigates whether psychomotor disturbance predicts the outcome of electroconvulsive therapy (ECT) and how the treatment modulates psychomotor disturbance. In 73 adults suffering from major depressive disorder psychomotor functioning was evaluated before, during and after ECT using the observer-rated CORE measure and objective measures including accelerometry and a drawing task. Regression models were fitted to assess the predictive value of melancholic depression (CORE >= 8) and the psychomotor variables on ECT outcome, while effects on psychomotor functioning were evaluated through linear mixed models. Patients with CORE-defined melancholic depression (n = 41) had a 4.9 times greater chance of reaching response than those (n = 24) with non-melancholic depression (Chi-Square = 7.5, P = 0.006). At baseline, both higher total CORE scores (AUC = 0.76; P = 0.001) and needing more cognitive (AUC = 0.78; P = 0.001) and motor time (AUC = 0.76; P = 0.003) on the drawing task corresponded to superior ECT outcomes, as did lower daytime activity levels (AUC = 0.76) although not significantly so after Bonferroni correction for multiple testing. A greater CORE-score reduction in the first week of ECT was associated with higher ECT effectiveness. ECT reduced CORE-assessed psychomotor symptoms and improved activity levels only in those patients showing the severer baseline retardation. Although the sample was relatively small, psychomotor symptoms were clearly associated with beneficial outcome of ECT in patients with major depression, indicating that monitoring psychomotor deficits can help personalise treatment. Show less
Postpartum haemorrhage, in this thesis defined as blood loss above 1000mL within the first 24 hours after birth, remains a major cause of maternal morbidity and mortality with an incidence that... Show morePostpartum haemorrhage, in this thesis defined as blood loss above 1000mL within the first 24 hours after birth, remains a major cause of maternal morbidity and mortality with an incidence that seems to be increasing over the last decade. In this thesis we focussed on improvement of prognostic and diagnostic strategies for major obstetric haemorrhage, which may subsequently lead to a reduction of severe maternal morbidity, mortality and need for surgical interventions. In pursuit of this aim, research questions were posed corresponding to all three phases leading up to adverse outcome due to postpartum haemorrhage: pregnancy (prior to childbirth), early postpartum haemorrhage and persistent postpartum haemorrhage. In the first part of this thesis we focused on prediction of postpartum haemorrhage.Bleeding assessment tools were found to have no predictive value for postpartum haemorrhage. The change of coagulation parameters during the course of postpartum haemorrhage was described, and fibrinogen was found to be an early predictor of a worse outcome of postpartum haemorrhage. The association between fibrinogen measured by the Clauss method and ROTEM Fibtem was described in this thesis. Show less
