Real-World Evidence to Inform Regulatory Decision Making: A Scoping Review.

Real-world evidence (RWE) is increasingly considered in regulatory decision making. When, and to which extent, RWE is considered relevant by regulators likely depends on many factors. This review aimed to identify factors that make RWE necessary or desirable to inform regulatory decision making. A scoping review was conducted using literature databases (PubMed, Embase, Emcare, Web of Science, and Cochrane Library) and websites of regulatory agencies, health technology assessment agencies, research institutes, and professional organizations involved with RWE. Articles were included if: (1) they discussed factors or contexts that impact whether RWE could be necessary or desirable in regulatory decision making; (2) focused on pharmacological or biological interventions in humans; and (3) considered decision making in Europe or North America, or without a focus on a specific region. We included 118 articles in the scoping review. Two major themes and six subthemes were identified. The first theme concerns questions addressable with RWE, with subthemes epidemiology and benefit-risk assessment. The second theme concerns contextual factors, with subthemes feasibility, ethical considerations, limitations of available evidence, and disease and treatment-specific aspects. Collectively, these themes encompassed 43 factors influencing the need for RWE in regulatory decisions. Although single factors may not make RWE fully necessary, their cumulative influence could make RWE essential and pivotal in regulatory decision making. This overview contributes to ongoing discussions emphasizing the nuanced interplay of factors influencing the necessity or desirability of RWE to inform regulatory decision making.

Clinical risk assessment model to predict venous thromboembolism risk after immobilization for lower-limb trauma.

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 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. FUNDING: ZonMW VIMP grant:17110200011.

Evaluating the Effectiveness and Cost-Effectiveness of Seizure Dogs in Persons With Medically Refractory Epilepsy in the Netherlands: Study Protocol for a Stepped Wedge Randomized Controlled Trial (EPISODE).

Background: Epilepsy is associated with a high disease burden, impacting the lives of people with epilepsy and their caregivers and family. Persons with medically refractory epilepsy experience the greatest burden, suffering from profound physical, psychological, and social consequences. Anecdotal evidence suggests these persons may benefit from a seizure dog. As the training of a seizure dog is a substantial investment, their accessibility is limited in the absence of collective reimbursement as is seen in the Netherlands. Despite sustained interest in seizure dogs, scientific knowledge on their benefits and costs remains scarce. To substantiate reimbursement decisions stronger evidence is required. The EPISODE study aims to provide this evidence by evaluating the effectiveness and cost-effectiveness of seizure dogs in adults with medically refractory epilepsy. Methods: The study is designed as a stepped wedge randomized controlled trial that compares the use of seizure dogs in addition to usual care, with usual care alone. The study includes adults with epilepsy for whom current treatment options failed to achieve seizure freedom. Seizure frequency of participants should be at least two seizures per week, and the seizures should be associated with a high risk of injury or dysfunction. During the 3 year follow-up period, participants receive a seizure dog in a randomized order. Outcome measures are taken at multiple time points both before and after receiving the seizure dog. Seizure frequency is the primary outcome of the study and will be recorded continuously using a seizure diary. Questionnaires measuring seizure severity, quality of life, well-being, resource use, productivity, social participation, and caregiver burden will be completed at baseline and every 3 months thereafter. The study is designed to include a minimum of 25 participants. Discussion: This protocol describes the first randomized controlled trial on seizure dogs. The study will provide comprehensive data on the effectiveness and cost-effectiveness of seizure dogs in adults with medically refractory epilepsy. Broader benefits of seizure dogs for persons with epilepsy and their caregivers are taken into account, as well as the welfare of the dogs. The findings of the study can be used to inform decision-makers on the reimbursement of seizure dogs.

Assessment of reproducibility and biological variability of fasting and postprandial plasma metabolite concentrations using 1H NMR spectroscopy.

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research. OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples. METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (<6 months) and long-term (>3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements. RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66. CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.

Combining multiple imputation and bootstrap in the analysis of cost-effectiveness trial data.

In healthcare cost-effectiveness analysis, probability distributions are typically skewed and missing data are frequent. Bootstrap and multiple imputation are well-established resampling methods for handling skewed and missing data. However, it is not clear how these techniques should be combined. This paper addresses combining multiple imputation and bootstrap to obtain confidence intervals of the mean difference in outcome for two independent treatment groups. We assessed statistical validity and efficiency of 10 candidate methods and applied these methods to a clinical data set. Single imputation nested in the bootstrap percentile method (with added noise to reflect the uncertainty of the imputation) emerged as the method with the best statistical properties. However, this method can require extensive computation times and the lack of standard software makes this method not accessible for a larger group of researchers. Using a standard unpaired t-test with standard multiple imputation without bootstrap appears to be a robust alternative with acceptable statistical performance for which standard multiple imputation software is available.

Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma.

The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p ≤ 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p ≤ 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk.

Economic analysis comparing induction of labour and expectant management for intrauterine growth restriction at term (DIGITAT trial).

OBJECTIVE: Pregnancies complicated by intrauterine growth restriction (IUGR) are at increased risk for neonatal morbidity and mortality. The Dutch nationwide disproportionate intrauterine growth intervention trial at term (DIGITAT trial) showed that induction of labour and expectant monitoring were comparable with respect to composite adverse neonatal outcome and operative delivery. In this study we compare the costs of both strategies. STUDY DESIGN: A cost analysis was performed alongside the DIGITAT trial, which was a randomized controlled trial in which 650 women with a singleton pregnancy with suspected IUGR beyond 36 weeks of pregnancy were allocated to induction or expectant management. Resource utilization was documented by specific items in the case report forms. Unit costs for clinical resources were calculated from the financial reports of participating hospitals. For primary care costs Dutch standardized prices were used. All costs are presented in Euros converted to the year 2009. RESULTS: Antepartum expectant monitoring generated more costs, mainly due to longer antepartum maternal stays in hospital. During delivery and the postpartum stage, induction generated more direct medical costs, due to longer stay in the labour room and longer duration of neonatal high care/medium care admissions. From a health care perspective, both strategies generated comparable costs: on average €7106 per patient for the induction group (N=321) and €6995 for the expectant management group (N=329) with a cost difference of €111 (95%CI: €-1296 to 1641). CONCLUSION: Induction of labour and expectant monitoring in IUGR at term have comparable outcomes immediately after birth in terms of obstetrical outcomes, maternal quality of life and costs. Costs are lower, however, in the expectant monitoring group before 38 weeks of gestation and costs are lower in the induction of labour group after 38 weeks of gestation. So if induction of labour is considered to pre-empt possible stillbirth in suspected IUGR, it is reasonable to delay until 38 weeks, with watchful monitoring.

Multiple SNP testing improves risk prediction of first venous thrombosis.

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

Food questionnaire for the assessment of gluten intake by children 1 to 4 years old.

OBJECTIVES: A food questionnaire (FQ) to assess gluten intake in infants 0 to 12 months old has been developed and validated (FQ-gluten), but an instrument to assess gluten intake in children 1 to 4 years is not available. Development and validation of such an instrument (FQ-gluten4) was the aim of the present study. METHODS: The FQ-gluten was adapted according to age-related food consumption. The results of this FQ-gluten4 were compared with the results of a 2-day food record. RESULTS: Seventy-one parents filled in both instruments. The mean amount of gluten consumption calculated from the FQ-gluten4 was comparable with that of the food record, but significant differences were found in the amount of gluten intake in 1- to 2-year-old children and in the percentage of gluten from porridge among the 1- to 3-year-olds. The Blant-Altman limits of agreement with standard deviation of 2600 mg were -5118 to 5630 mg. CONCLUSIONS: The new, short, standardized, validated, and easy-to-use FQ-gluten4 may be a useful instrument in the assessment of gluten intake in young children. Using this standardized method provides opportunity for better comparison of the results of gluten consumption in studies throughout the world. Furthermore, such an instrument can be used to quantify the gluten intake in individuals suspected to have celiac disease but in whom the diagnoses cannot be confirmed.

Long-term impact of delay in assessment of patients with early arthritis.

OBJECTIVE: During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD-free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed. METHODS: A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined. RESULTS: The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C-reactive protein, and the presence of autoantibodies were associated with longer total delay. CONCLUSION: Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD-free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA.

Follow-up outcomes at 1 and 2 years of infants born less than 32 weeks after Newborn Individualized Developmental Care and Assessment Program.

OBJECTIVE: This was a randomized, controlled trial to investigate the effect of Newborn Individualized Developmental Care and Assessment Program on growth, cognitive, psychomotor, and neuromotor development at 1 and 2 years in infants born at <32 weeks' gestational age. METHODS: Infants were randomly assigned within 48 hours of birth to the newborn individualized developmental care and assessment program group (intervention) or basic developmental care group (control group [ie, incubator covers and nests]). At 1 and 2 years' corrected age, growth was measured and standardized neurologic examinations were administered. Mental and psychomotor development was assessed by using the Dutch version of the Bayley Scales of Infant Development II. Neurologic outcome, Psychomotor Developmental Index, and Mental Developmental Index scores were combined a total outcome measure. RESULTS: One hundred sixty-eight infants were recruited (intervention: 84; control: 84). Four infants (newborn intervention: 3; control: 1) were excluded because they were admitted less than or died within the first 5 days, leaving a total of 164 infants who met inclusion criteria. In-hospital mortality was 8 of 81 in the intervention group and 3 of 83 in the control group. At 1 year of age 148 children (intervention: 70; control: 78) and at 2 years of age 146 children (intervention: 68; control: 78) were assessed. There was no significant difference in growth at 1 and 2 years of age. There was no significant difference found in neurologic outcomes or mental and psychomotor development at 1 and 2 years of age. When neurologic outcome, Mental Developmental Index and Psychomotor Developmental Index scores were combined, there still remained no significant difference. CONCLUSIONS: Newborn individualized developmental care and assessment program developmental care showed no effect on growth or neurologic, mental, or psychomotor development at 1 and 2 years of age in infants born at <32 weeks. Duration of the intervention was not associated with neurologic and developmental outcome.

Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors.

The distinction between benign and malignant cartilaginous tumors of bone is one of the most difficult subjects in surgical pathology. The grading of chondrosarcoma also seems to vary considerably among pathologists. However, clinical management differs. The purpose of this study was (1) to investigate interobserver variability in histological diagnosis and grading of central cartilaginous tumors and (2) to assess the diagnostic value of defined histologic parameters in differentiating enchondroma and central grade I chondrosarcoma. The interobserver variability was assessed using a set of 16 cases evaluated by 18 specialized pathologists. Subsequently, 20 enchondromas and 37 central grade I chondrosarcomas diagnosed in a multidisciplinary team with full clinical, radiologic, and pathologic data available with 10 years of follow-up were collected. Cytologic and tissue-architectural features were assessed to find an optimal set of parameters to differentiate enchondroma from central grade I chondrosarcoma. We demonstrate considerable variation in the histologic assessment of cartilaginous tumors (weighted kappa=0.78). The distinction between enchondroma and grade I chondrosarcoma was shown to be the most disconcordant (kappa coefficient=0.54), and also the differentiation between grade I and grade II chondrosarcoma was subjected to variation (kappa coefficient=0.80). The application of a combination of 5 parameters (high cellularity, presence of host bone entrapment, open chromatin, mucoid matrix quality, and age above 45 y) allowed optimal differentiation between enchondromas and central grade I chondrosarcomas. With a classification tree based on 2 parameters (mucoid matrix degeneration more than 20% and/or host bone entrapment present), 54 of the 57 (94.7%) cases were assessed correctly (sensitivity 95% and specificity 95%). Our study confirms the low reliability of the diagnosis and grading of central chondrosarcoma. However, these classifications guide therapeutic decision making in daily practice. Therefore, we propose a classification model that, combined with a tailored radiologic assessment, may improve reliability of the diagnosis of cartilaginous tumors.

Pre-conception counselling in primary care: prevalence of risk factors among couples contemplating pregnancy.

The outcome of pregnancy can be influenced by several risk factors. Women who are informed about these risks during pre-conception counselling (PCC) have an opportunity to take preventive measures in time. Several studies have shown that high-risk populations have a high prevalence of such risk factors. However, prevalence in the general population, which is assumed to be low risk, is largely unknown. We therefore provided a systematic programme of PCC for the general population and studied the prevalence of risk factors using the risk-assessment questionnaire which was part of the PCC. None of the couples reported no risk factors at all and only 2% of the couples reported risk factors for which written information was considered to be sufficient. Therefore, 98% of all couples reported one or more risk factors for which at least personal counselling by a general practitioner (GP) was indicated. Many of these factors were related to an unhealthy lifestyle. Women with a low level of education reported more risk factors than women with a high level of education. There is a great need for PCC as shown by the fact that almost all couples reported risk factors for which personal counselling was indicated. Pre-conception counselling may reduce the risk of adverse pregnancy outcome by enabling couples to avoid these risks. PCC can be provided by GPs, who have the necessary medical knowledge and background information to counsel couples who wish to have a baby.

Food questionnaire for assessment of infant gluten consumption.

BACKGROUND: In light of the possibly preventive role of timing and amount of gluten in celiac disease, it would be helpful to have a questionnaire to assess the gluten intake in infants. AIMS: Development and validation of a food questionnaire to assess gluten consumption in healthy infants aged 0-12 months (FQ-gluten). METHODS: A food frequency questionnaire, previously developed for the Generation R study, was adapted for the assessment of gluten intake. The results of a 2-day food record (FR) were compared with the results of this FQ-gluten. RESULTS: Eighty-seven parents filled in the FR and the FQ-gluten. The number of children who consume gluten and who are breast-fed is higher, reported in the FQ-gluten. The amount of gluten is comparable from the age of 3 up to 10 months, but at 11 and 12 months a higher gluten intake is reported using the FR, probably due to a larger variety of food products not detectable by the FQ-gluten. However, there is a high agreement in the food groups (Cohens' kappa=0.6-0.8). CONCLUSIONS: This new, short, standardized, validated and easy to use FQ-gluten may be a useful instrument to assess gluten intake in infants, both at the individual and at the population level. The use of this method by investigators in other countries provides the opportunity for a better comparison of the results of gluten consumption in (co-operative) studies throughout different countries.