Missing not at random in end of life care studies: multiple imputation and sensitivity analysis on data from the ACTION study

Background: Missing data are common in end-of-life care studies, but there is still relatively little exploration of which is the best method to deal with them, and, in particular, if the missing at random (MAR) assumption is valid or missing not at random (MNAR) mechanisms should be assumed. In this paper we investigated this issue through a sensitivity analysis within the ACTION study, a multicenter cluster randomized controlled trial testing advance care planning in patients with advanced lung or colorectal cancer. Methods: Multiple imputation procedures under MAR and MNAR assumptions were implemented. Possible violation of the MAR assumption was addressed with reference to variables measuring quality of life and symptoms. The MNAR model assumed that patients with worse health were more likely to have missing questionnaires, making a distinction between single missing items, which were assumed to satisfy the MAR assumption, and missing values due to completely missing questionnaire for which a MNAR mechanism was hypothesized. We explored the sensitivity to possible departures from MAR on gender differences between key indicators and on simple correlations. Results: Up to 39% of follow-up data were missing. Results under MAR reflected that missingness was related to poorer health status. Correlations between variables, although very small, changed according to the imputation method, as well as the differences in scores by gender, indicating a certain sensitivity of the results to the violation of the MAR assumption. Conclusions: The findings confirmed the importance of undertaking this kind of analysis in end-of-life care studies

Children Achieving: Philadelphia\u27s Education Reform, Year Two Report

Children Achieving Progress Report Series 1996-1997. In February 1995, The Annenberg Foundation designated Philadelphia as one of a small number of American cities to receive a five-year $50 million Annenberg Challenge grant to improve public education. CPRE and its partners, Research for Action and OMG Center for Collaborative Learning, conducted a four-year evaluation of Philadelphia\u27s Children Achieveing initiative, funded by the Annenberg Challenge grant. This summary describes finding from Year 2

Heterogeneity of postpartum depression: a latent class analysis

Background—Maternal depression in the postpartum period confers substantial morbidity and mortality, but the definition of postpartum depression remains controversial. We investigated the heterogeneity of symptoms with the aim of identifying clinical subtypes of postpartum depression. Methods—Data were aggregated from the international perinatal psychiatry consortium Postpartum Depression: Action Towards Causes and Treatment, which represents 19 institutions in seven countries. 17 912 unique subject records with phenotypic data were submitted. We applied latent class analyses in a two-tiered approach to assess the validity of empirically defined subtypes of postpartum depression. Tier one assessed heterogeneity in women with complete data on the Edinburgh postnatal depression scale (EPDS) and tier two in those with postpartum depression case status. Findings—6556 individuals were assessed in tier one and 4245 in tier two. A final model with three latent classes was optimum for both tiers. The most striking characteristics associated with postpartum depression were severity, timing of onset, comorbid anxiety, and suicidal ideation. Women in class 1 had the least severe symptoms (mean EPDS score 10·5), followed by those in class 2 (mean EPDS score 14·8) and those in class 3 (mean EPDS score 20·1). The most severe symptoms of postpartum depression were significantly associated with poor mood (mean EPDS score 20·1), increased anxiety, onset of symptoms during pregnancy, obstetric complications, and suicidal ideation. In class 2, most women (62%) reported symptom onset within 4 weeks postpartum and had more pregnancy complications than in other two classes (69% vs 67% in class 1 and 29% in class 3). Interpretation—PPD seems to have several distinct phenotypes. Further assessment of PPD heterogeneity to identify more precise phenotypes will be important for future biological and genetic investigations

Personalised biopsy schedules based on risk of Gleason upgrading for patients with low-risk prostate cancer on active surveillance.

OBJECTIVE: To develop a model and methodology for predicting the risk of Gleason upgrading in patients with prostate cancer on active surveillance (AS) and using the predicted risks to create risk-based personalised biopsy schedules as an alternative to one-size-fits-all schedules (e.g. annually). Furthermore, to assist patients and doctors in making shared decisions on biopsy schedules, by providing them quantitative estimates of the burden and benefit of opting for personalised vs any other schedule in AS. Lastly, to externally validate our model and implement it along with personalised schedules in a ready to use web-application. PATIENTS AND METHODS: Repeat prostate-specific antigen (PSA) measurements, timing and results of previous biopsies, and age at baseline from the world's largest AS study, Prostate Cancer Research International Active Surveillance (PRIAS; 7813 patients, 1134 experienced upgrading). We fitted a Bayesian joint model for time-to-event and longitudinal data to this dataset. We then validated our model externally in the largest six AS cohorts of the Movember Foundation's third Global Action Plan (GAP3) database (>20 000 patients, 27 centres worldwide). Using the model predicted upgrading risks; we scheduled biopsies whenever a patient's upgrading risk was above a certain threshold. To assist patients/doctors in the choice of this threshold, and to compare the resulting personalised schedule with currently practiced schedules, along with the timing and the total number of biopsies (burden) planned, for each schedule we provided them with the time delay expected in detecting upgrading (shorter is better). RESULTS: The cause-specific cumulative upgrading risk at the 5-year follow-up was 35% in PRIAS, and at most 50% in the GAP3 cohorts. In the PRIAS-based model, PSA velocity was a stronger predictor of upgrading (hazard ratio [HR] 2.47, 95% confidence interval [CI] 1.93-2.99) than the PSA level (HR 0.99, 95% CI 0.89-1.11). Our model had a moderate area under the receiver operating characteristic curve (0.6-0.7) in the validation cohorts. The prediction error was moderate (0.1-0.2) in theGAP3 cohorts where the impact of the PSA level and velocity on upgrading risk was similar to PRIAS, but large (0.2-0.3) otherwise. Our model required re-calibration of baseline upgrading risk in the validation cohorts. We implemented the validated models and the methodology for personalised schedules in a web-application (http://tiny.cc/biopsy). CONCLUSIONS: We successfully developed and validated a model for predicting upgrading risk, and providing risk-based personalised biopsy decisions in AS of prostate cancer. Personalised prostate biopsies are a novel alternative to fixed one-size-fits-all schedules, which may help to reduce unnecessary prostate biopsies, while maintaining cancer control. The model and schedules made available via a web-application enable shared decision-making on biopsy schedules by comparing fixed and personalised schedules on total biopsies and expected time delay in detecting upgrading

Missing not at random in end of life care studies : multiple imputation and sensitivity analysis on data from the ACTION study

Background: Missing data are common in end-of-life care studies, but there is still relatively little exploration of which is the best method to deal with them, and, in particular, if the missing at random (MAR) assumption is valid or missing not at random (MNAR) mechanisms should be assumed. In this paper we investigated this issue through a sensitivity analysis within the ACTION study, a multicenter cluster randomized controlled trial testing advance care planning in patients with advanced lung or colorectal cancer. Methods: Multiple imputation procedures under MAR and MNAR assumptions were implemented. Possible violation of the MAR assumption was addressed with reference to variables measuring quality of life and symptoms. The MNAR model assumed that patients with worse health were more likely to have missing questionnaires, making a distinction between single missing items, which were assumed to satisfy the MAR assumption, and missing values due to completely missing questionnaire for which a MNAR mechanism was hypothesized. We explored the sensitivity to possible departures from MAR on gender differences between key indicators and on simple correlations. Results: Up to 39% of follow-up data were missing. Results under MAR reflected that missingness was related to poorer health status. Correlations between variables, although very small, changed according to the imputation method, as well as the differences in scores by gender, indicating a certain sensitivity of the results to the violation of the MAR assumption. Conclusions: The findings confirmed the importance of undertaking this kind of analysis in end-of-life care studies

Motives to Report Adverse Drug Reactions to the National Agency:A Survey Study among Healthcare Professionals and Patients in Croatia, The Netherlands, and the UK

Introduction Healthcare professionals (HCPs) and patients have various motives to report adverse drug reactions (ADRs) to their national agency. These motives may differ between countries. Objective The aim of this study was to assess to what extent motives of HCPs and patients to report ADRs differ between countries. Methods HCPs and patients from Croatia (HR), The Netherlands (NL), and the UK were asked to complete a web-based survey containing questions regarding demographics and ADR reporting. HCPs and patients could select all motives for reporting that applied to them, with a total of 23 and 24 motives, respectively. Descriptive statistics are presented and Chi-square tests were used to test for differences across the countries, with effect sizes calculated using Cramer's V. Results In total, 296 HCPs and 423 patients were included (60% and 32% from Croatia, 19% and 44% from NL, and 21% and 24% from the UK, respectively). For most of the motives to report or not to report an ADR, there were no differences between countries. Most HCPs from all countries would be motivated to report an ADR if there was a strong suspicion of causality (89%), if it concerned a severe/serious ADR (86%), and if it concerned an ADR for a new, recently marketed drug (77%). Most patients from all countries agreed that they would report an ADR if it concerned a severe ADR (96%), if the ADR influenced their daily activities (91%), and if they were worried about their own situation (90%). Differences across the countries (p V &gt;= 0.21) were observed for three and four of the HCP and patient motives, respectively. For HCPs, these differences were seen in motives related to legal obligation (65% HR, 24% NL, 38% UK), black triangle medicines (27% HR, 4% NL, 77% UK), and the reporting of well-known ADRs (53% HR, 85% NL, 69% UK). For patients, these differences were seen in motives related to a linkage between the ADR report and the medical notes (59% HR, 60% NL, 30% UK), complexity and time taken to report (25% HR, 13% NL, 40% UK), medicines purchased on the internet (59% HR, 39% NL, 65% UK), and the reporting of embarrassing ADRs (32% HR, 11% NL, 35% UK). Conclusions HCPs' and patients' motives to report or not to report ADRs to the national agency were mostly similar across the three countries. Such motives can be used in general strategies to promote and increase ADR reporting. The observed differences provide guidance to further fine-tune ADR reporting at a national level.</p

Content analysis of Advance Directives completed by patients with advanced cancer as part of an Advance Care Planning intervention: insights gained from the ACTION trial

Purpose: Writing an Advance Directive (AD) is often seen as a part of Advance Care Planning (ACP). ADs may include specific preferences regarding future care and treatment and information that provides a context for healthcare professionals and relatives in case they have to make decisions for the patient. The aim of this study was to get insight into the content of ADs as completed by patients with advanced cancer who participated in ACP conversations. Methods: A mixed methods study involving content analysis and descriptive statistics was used to describe the content of completed My Preferences forms, an AD used in the intervention arm of the ACTION trial, testing the effectiveness of the ACTION Respecting Choices ACP intervention. Results: In total, 33% of 442 patients who received the ACTION RC ACP intervention completed a My Preferences form. Document completion varied per country: 10.4% (United Kingdom), 20.6% (Denmark), 29.2% (Belgium), 41.7% (the Netherlands), 61.3% (Italy) and 63.9% (Slovenia). Content analysis showed that \u2018maintaining normal life\u2019 and \u2018experiencing meaningful relationships\u2019 were important for patients to live well. Fears and worries mainly concerned disease progression, pain or becoming dependent. Patients hoped for prolongation of life and to be looked after by healthcare professionals. Most patients preferred to be resuscitated and 44% of the patients expressed maximizing comfort as their goal of future care. Most patients preferred \u2018home\u2019 as final place of care. Conclusions: My Preferences forms provide some insights into patients\u2019 perspectives and preferences. However, understanding the reasoning behind preferences requires conversations with patients

Feasibility and Coverage of Implementing Intermittent Preventive Treatment of Malaria in Pregnant women Contacting Private or Public Clinics in Tanzania: Experience-based Viewpoints of Health Managers in Mkuranga and Mufindi districts.

Evidence on healthcare managers' experience on operational feasibility of malaria intermittent preventive treatment for malaria during pregnancy (IPTp) using sulphadoxine-pyrimethamine (SP) in Africa is systematically inadequate. This paper elucidates the perspectives of District Council Health Management Team (CHMT)s regarding the feasibility of IPTp with SP strategy, including its acceptability and ability of district health care systems to cope with the contemporary and potential challenges. The study was conducted in Mkuranga and Mufindi districts. Data were collected between November 2005 and December 2007, involving focus group discussion (FGD) with Mufindi CHMT and in-depth interviews were conducted with few CHMT members in Mkuranga where it was difficult to summon all members for FGD. Participants in both districts acknowledged the IPTp strategy, considering the seriousness of malaria in pregnancy problem; government allocation of funds to support healthcare staff training programmes in focused antenatal care (fANC) issues, procuring essential drugs distributed to districts, staff remuneration, distribution of fANC guidelines, and administrative activities performed by CHMTs. The identified weaknesses include late arrival of funds from central level weakening CHMT's performance in health supervision, organising outreach clinics, distributing essential supplies, and delivery of IPTp services. Participants anticipated the public losing confidence in SP for IPTp after government announced artemither-lumefantrine (ALu) as the new first-line drug for uncomplicated malaria replacing SP. Role of private healthcare staff in IPTp services was acknowledged cautiously because CHMTs rarely supplied private clinics with SP for free delivery in fear that clients would be required to pay for the SP contrary to government policy. In Mufindi, the District Council showed a strong political support by supplementing ANC clinics with bottled water; in Mkuranga such support was not experienced. A combination of health facility understaffing, water scarcity and staff non-adherence to directly observed therapy instructions forced healthcare staff to allow clients to take SP at home. Need for investigating in improving adherence to IPTp administration was emphasised. High acceptability of the IPTp strategy at district level is meaningless unless necessary support is assured in terms of number, skills and motivation of caregivers and availability of essential supplies

Prostate Cancer Patients Under Active Surveillance with a Suspicious Magnetic Resonance Imaging Finding Are at Increased Risk of Needing Treatment: Results of the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) Consortium.

BACKGROUND: The inclusion criterion for active surveillance (AS) is low- or intermediate-risk prostate cancer. The predictive value of the presence of a suspicious lesion at magnetic resonance imaging (MRI) at the time of inclusion is insufficiently known. OBJECTIVE: To evaluate the percentage of patients needing active treatment stratified by the presence or absence of a suspicious lesion at baseline MRI. DESIGN SETTING AND PARTICIPANTS: A retrospective analysis of the data from the multicentric AS GAP3 Consortium database was conducted. The inclusion criteria were men with grade group (GG) 1 or GG 2 prostate cancer combined with prostate-specific antigen <20 ng/ml. We selected a subgroup of patients who had MRI at baseline and for whom MRI results and targeted biopsies were used for AS eligibility. Suspicious MRI was defined as an MRI lesion with Prostate Imaging Reporting and Data System (PI-RADS)/Likert ≥3 and for which targeted biopsies did not exclude the patient for AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was treatment free survival (FS). The secondary outcomes were histological GG progression FS and continuation of AS (discontinuation FS). RESULTS AND LIMITATIONS: The study cohort included 2119 patients (1035 men with nonsuspicious MRI and 1084 with suspicious MRI) with a median follow-up of 23 (12-43) mo. For the whole cohort, 3-yr treatment FS was 71% (95% confidence interval [CI]: 69-74). For nonsuspicious MRI and suspicious MRI groups, 3-yr treatment FS rates were, respectively, 80% (95% CI: 77-83) and 63% (95% CI: 59-66). Active treatment (hazard ratio [HR] = 2.0, p < 0.001), grade progression (HR = 1.9, p < 0.001), and discontinuation of AS (HR = 1.7, p < 0.001) were significantly higher in the suspicious MRI group than in the nonsuspicious MRI group. CONCLUSIONS: The risks of switching to treatment, histological progression, and AS discontinuation are higher in cases of suspicious MRI at inclusion. PATIENT SUMMARY: Among men with low- or intermediate-risk prostate cancer who choose active surveillance, those with suspicious magnetic resonance imaging (MRI) at the time of inclusion in active surveillance are more likely to show switch to treatment than men with nonsuspicious MRI

Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes

   Objective Proteomic profiling can identify useful biomarkers. Monozygotic(MZ) twins, discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well characterised cohorts. Research Design and Methods A broad, multiplex analysis of 4068 proteins in sera from MZ twins concordant (n=43) and discordant for type 1 diabetes (n=27) identified major differences which were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n=39) and discordant (n=42) for type 1 diabetes, individuals at-risk (n=195) and with type 1 diabetes (n=990), as well as with non-insulin requiring adult-onset diabetes diagnosed as either autoimmune (n=96) or type 2 (n=291). Results Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite strong correlation between twins, whether concordant or discordant for type 1 diabetes (p Conclusions Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and non-genetically determined factors. Exocrine/endocrine interactions are important under-investigated factors in type 1 diabetes.</p