Search

Purpose: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process., Methods: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure., Results: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of ≥60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris., Conclusions: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objective: Congenital heart disease (CHD) is associated with decreased birthweight (BW) compared to population-based references. The aim of this study was to compare the BW of isolated CHD cases to their siblings, thus controlling for unknown and unmeasured confounders within the family., Methods: All isolated CHD cases in the Leiden University Medical Center were included (2002-2019). Generalized estimated equation models were constructed to compare BW z scores of CHD neonates with their siblings. Cases were clustered to minor or severe CHD and stratified according to the aortic flow and oxygenation to the brain., Results: The overall BW z score of siblings was 0.032 (n = 471). The BW z score was significantly lower in CHD cases (n = 291) compared to their siblings (-0.20, p = 0.005). The results were consistent in the subgroup analysis of severe and minor CHD (BW z score difference -0.20 and -0.10), but did not differ significantly (p = 0.63). Stratified analysis regarding flow and oxygenation showed no BW difference between the groups (p = 0.1)., Conclusion: Isolated CHD cases display a significantly lower BW z score compared to their siblings. As the siblings of these CHD cases show a BW distribution similar to the general population, this suggests that shared environmental and maternal influences between siblings do not explain the difference in BW., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Introduction: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development., Methods: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme., Results: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses., Conclusion: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objectives: Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software., Methods: We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses., Results: A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases., Conclusion: The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance., (© 2020 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Introduction: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and are therefore prone to delay in cortical maturation. The aim of this study was to determine the difference in fetal brain age between consecutive congenital heart defect cases and controls in the second and third trimester using ultrasound., Material and Methods: Since 2014, we have included 90 isolated severe congenital heart defect cases in the Heart And Neurodevelopment (HAND)-study. Every 4 weeks, detailed neurosonography was performed in these fetuses, including the recording of a 3D volume of the fetal brain, from 20 weeks onwards. In all, 75 healthy fetuses underwent the same protocol to serve as a control group. The volumes were analyzed by automated age prediction software which determines gestational age by the assessment of cortical maturation., Results: In total, 477 volumes were analyzed using the age prediction software (199 volumes of 90 congenital heart defect cases; 278 volumes of 75 controls). Of these, 16 (3.2%) volume recordings were excluded because of imaging quality. The age distribution was 19-33 weeks. Mixed model analysis showed that the age predicted by brain maturation was 3 days delayed compared with the control group (P = .002)., Conclusions: This study shows that fetuses with isolated cases of congenital heart defects show some delay in cortical maturation as compared with healthy control cases. The clinical relevance of this small difference is debatable. This finding was consistent throughout pregnancy and did not progress during the third trimester., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., (© 2019 CSL Behring. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.)

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.]., (© 2019 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.)

Several studies have shown the relationship between symptoms of posttraumatic stress disorder (PTSD), somatic symptoms, and the mediating effect of depression and anxiety. The following study was conducted to investigate the relationship between PTSD symptoms and somatic complaints through underlying symptoms of depression and anxiety. The participants of the study were 2,799 veterans who were examined after a 6-month deployment. They were assessed using the PTSD Checklist (PCL-5) and Patient Health Questionnaire (PHQ) for depression, anxiety, and somatic complaints. To check the indirect effect of PTSD on somatic complaints through depression and anxiety, mediation model 4 (parallel mediation) of the SPSS PROCESS macro was used. There was a significant total indirect effect of PTSD through depression and anxiety on somatic complaints, b = 0.14, 95% confidence interval (CI) [0.12, 0.16], from which an indirect effect of PTSD on somatic complaints through depression was b = 0.08, 95% CI [0.06, 0.10], and through anxiety it equaled b = 0.06, 95% CI [0.04, 0.07]. The ratio of indirect to total effect was 0.66, 95% CI [0.59, 0.75]. The present study helps us to understand the role of depression and anxiety symptoms when the symptoms of PTSD and somatic complaints are present. These new findings may have implications for the management as well as treatment of PTSD because they recognize the importance of symptoms of anxiety and depression when somatic complaints are present., (Copyright © 2017 International Society for Traumatic Stress Studies.)

The Kaplan-Meier, Nelson-Aalen and Breslow estimators are widely used in the analysis of right-censored time to event data in medical applications. These methods are fully non-parametric and do not put any restriction on the shape of the hazard curve. In some applications, this leads to implausible estimates of the hazard course over time. With non-parametric shape-constrained estimation techniques, one can facilitate an increasing or decreasing hazard and thus generate estimators that better match the biological reasoning, without being as restrictive as parametric methods. We illustrate the advantage of such techniques in the analysis of a large clinical trial in cardiology. Simulation results show that in case the true hazard is monotone, the non-parametric shape-constrained estimators are more accurate than the traditional estimators on the hazard level. On the (cumulative) distribution function level, the shape-constrained estimators show similar performance as the traditional ones., (Copyright © 2012 John Wiley & Sons, Ltd.)

Research into the diagnostic accuracy of clinical tests is often hampered by single or double partial verification mechanisms, that is, not all patients have their disease status verified by a reference test, neither do all patients receive all tests under evaluation (index tests). We show methods that reduce verification bias introduced when omitting data from partially tested patients. Adjustment techniques are well established when there are no missing index tests and when the reference test is 'missing at random'. However, in practice, index tests tend to be omitted, and the choice of applying a reference test may depend on unobserved variables related to disease status, that is, verification may be missing not at random (MNAR). We study double partial verification in a clinical example from reproductive medicine in which we analyse the diagnostic values of the chlamydia antibody test and the hysterosalpingography in relation to a diagnostic laparoscopy. First, we plot all possible combinations of sensitivity and specificity of both index tests in two test ignorance regions. Then, we construct models in which we impose different assumptions for the verification process. We allow for missing index tests, study the influence of patient characteristics and study the accuracy estimates if an MNAR mechanism would operate. It is shown that data on tests used in the diagnostic process of the same population are preferably studied jointly and that the influence of an MNAR verification process was limited in a clinical study where more than half of the patients did not have the reference test., (Copyright © 2011 John Wiley & Sons, Ltd.)