Point and Interval Estimators of the Target Dose in Clinical Dose-Finding Studies with Active Control.

In a clinical dose finding study with active control a new drug with several dose levels is compared with an active comparator drug. The main focus of such studies often lies on the estimation of a target dose that leads to the same efficacy as the control. This article investigates the finite sample properties of the maximum likelihood estimation of the target dose and compares several approaches for constructing corresponding confidence intervals under the assumption of a linear dose-response curve and normal error terms. Furthermore, the impact of deviations from the model assumptions regarding the error distribution is explored.

Clinical presentation of pediatric multiple sclerosis before puberty.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) onset before puberty is extremely rare and establishment of diagnosis is often difficult due to atypical presentation. The study aims to identify the typical presentation of MS in this age group. METHODS: Pediatric MS patients were identified from the database of the Center for Multiple Sclerosis in Childhood and Adolescence at the University Medical Center Göttingen, Germany. Inclusion criteria were a relapsing-remitting initial disease course and minimum disease duration of 4 years. RESULTS: Forty-seven pre-pubertal (<11 years) and 41 post-pubertal (14-16 years) MS patients were compared. Before puberty an even gender ratio was found. The pre-pubertal patients were more likely to have a polysymptomatic severe first attack with motor and brainstem involvement, sphincter dysfunction, cognitive disturbances and milder residual neurological sequelae after the first episode whilst the post-pubertal patients predominantly presented with optic neuritis and sensory symptoms. The initial symptom pattern prevailed over the first 2 years of disease. Presentation of pre-pubertal boys and girls did not differ significantly. CONCLUSIONS: To facilitate early diagnosis it is important to recognize that pre-pubertal MS presents with a specific pattern of symptoms that is maintained over the first two disease years.

Blinded sample size re-estimation for recurrent event data with time trends.

The use of an internal pilot study for blinded sample size re-estimation (BSSR) allows to reduce uncertainty on the appropriate sample size compared with conventional fixed sample size designs. Recently BSSR procedures for recurrent event data were proposed and investigated. These approaches assume treatment-specific constant event rates that might not always be appropriate as found in relapsing multiple sclerosis. On the basis of a proportional intensity frailty model, we propose methods for BSSR in situations where a time trend of the event rates is present. For the sample size planning and the final analysis standard negative binomial methods can be used, as long as the patient follow-up time is approximately equal in the treatment groups. To re-estimate the sample size at interim, however, a full likelihood analysis is necessary. Operating characteristics such as rejection probabilities and sample size distribution are evaluated in a simulation study motivated by a systematic review in relapsing multiple sclerosis. The key factors affecting the operating characteristics are the study duration and the length of the recruitment period. The proposed procedure for BSSR controls the type I error rate and maintains the desired power against misspecifications of the nuisance parameters.

Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials.

Liver transplant recipients are at high risk of developing acute and chronic renal failure. Moreover, introduction of the model for end-stage liver disease (MELD) score for primary allocation of liver grafts favors patients with pretransplant kidney dysfunction, which in turn have a higher risk of posttransplant renal failure. Calcineurin inhibitors (CNI) further increase the risk of renal failure and therefore sparing CNI with the use of mycophenolate mofetil (MMF) may improve renal function. MMF may either be used de novo in the immediate posttransplant period in combination with low-dose CNI (scenario 1) or patients that receive immunosuppression based on CNI may be converted to MMF in combination with minimization or elimination of CNI (scenario 2). Although many retrospective cohort studies and nonrandomized trials have implicated efficacy of this approach the evidence from randomized controlled studies has not been summarized. In the current review we report the results of a systematic review and meta-analysis of randomized controlled trials.

A conditional error function approach for subgroup selection in adaptive clinical trials.

Growing interest in personalised medicine and targeted therapies is leading to an increase in the importance of subgroup analyses. If it is planned to view treatment comparisons in both a predefined subgroup and the full population as co-primary analyses, it is important that the statistical analysis controls the familywise type I error rate. Spiessens and Debois (Cont. Clin. Trials, 2010, 31, 647-656) recently proposed an approach specific for this setting, which incorporates an assumption about the correlation based on the known sizes of the different groups, and showed that this is more powerful than generic multiple comparisons procedures such as the Bonferroni correction. If recruitment is slow relative to the length of time taken to observe the outcome, it may be efficient to conduct an interim analysis. In this paper, we propose a new method for an adaptive clinical trial with co-primary analyses in a predefined subgroup and the full population based on the conditional error function principle. The methodology is generic in that we assume test statistics can be taken to be normally distributed rather than making any specific distributional assumptions about individual patient data. In a simulation study, we demonstrate that the new method is more powerful than previously suggested analysis strategies. Furthermore, we show how the method can be extended to situations when the selection is not based on the final but on an early outcome. We use a case study in a targeted therapy in oncology to illustrate the use of the proposed methodology with non-normal outcomes.

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis.

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.

HLA-A2 subtypes are functionally distinct in peptide binding and presentation.

Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A*0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A*0201, A*0202, A*0205, A*0214, and A*6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A*0201-restricted peptides can also bind to A*0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A*0202 has a similar peptide motif to A*0201, but that A*0205, A*0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.

dfpk: An R-package for Bayesian dose-finding designs using pharmacokinetics (PK) for phase I clinical trials.

BACKGROUND AND OBJECTIVE: Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. METHODS: All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. RESULTS: For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. CONCLUSION: The developed user-friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information.

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

A note on testing for intervention effects on binary responses.

OBJECTIVES: In some circumstances controlled trials are not feasible and treatments can only be evaluated using clinical databases. Here we consider the situation where treatment is introduced at a particular calendar time and can only be evaluated by comparison with historical controls. In these circumstances Heuer and Abel recommended using change-point methods to search for change in characteristics over the whole study period rather than simply comparing treated and untreated patients. Their recommendation is to only conclude that the intervention had an effect if a change-point could be demonstrated close in time to the introduction of the new treatment. This reduces the risk of false positives caused by confounding changes in population characteristics or changes in patient management. For binary data we develop a method that follows their philosophy and apply it to an observational study in the treatment of pin sites after orthopaedic surgery. METHODS: Tests for change in binomial probabilities based on Brownian bridge and Hansen's approximation for maximally selected chi(2) statistics are compared to an exact test by Worsley. The approximate method is generalized to logistic regression models allowing for covariates. RESULTS: The agreement of the exact and approximate method is good for sample sizes of 100 or more. The actual test size of the Hansen approximate test allowing for covariates is close to the nominal level, whereas the Brownian bridge approximation is slightly conservative. The change in pin site treatment significantly reduces the risk of infection for both adults and children. CONCLUSIONS: We consider the Hansen approximation to provide a very good and very simple method for obtaining the p-value when testing for a change in binary data event probabilities, with or without covariates.

Natural ligand motifs of closely related HLA-DR4 molecules predict features of rheumatoid arthritis associated peptides.

Rheumatoid arthritis (RA), one of the most common autoimmune disorders, is believed to be mediated via. T lymphocytes and genetic studies have shown that it is strongly associated with HLA-DR4. The DR4 subtypes DR4Dw4, DR4Dw14 and DR4Dw15 represent increased risk factors for RA, whereas DR4Dw10 is not associated with the disorder. Our study determines and compares the natural ligand motifs of these MHC class II molecules and identifies 60 natural ligands. At relative position 4 (P4), only the RA-associated DR4 molecules allow, or even prefer, negatively charged amino acids, but do not allow those which are positively charged (Arg, Lys). In the case of DR4Dw10 the preference for these amino acids is reversed. The results predict features of the putative RA-inducing peptide(s). A remarkable specificity, almost exclusively for negative charges (Asp, Glu), is found at P9 of the DR4Dw15 motif. This specificity can be ascribed to amino acid beta57 of the DR beta chain, and gives an important insight into the beta57-association of another autoimmune disease, insulin-dependent diabetes mellitus type I.

HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection.

Recent studies have shown that the risk conferred by the high-risk DQA1*03-DQB1*0302 (DQ8) haplotype is modified by the DRB1*04 allele that is also carried by this haplotype. However, many of these studies suffer from lack of sufficient numbers of DQ-matched control subjects, which are necessary because there is a strong linkage disequilibrium between genes in the HLA complex. In the present study, using a large material of IDDM patients and DQ-matched control subjects, we have addressed the contribution of DR4 subtypes to IDDM susceptibility. Our data, together with recent data from others, clearly demonstrate that some DR4-DQ8 haplotypes are associated with disease susceptibility, while others are associated with protection, depending on the DRB1*04 allele carried by the same haplotype. In particular, our data demonstrate that DRB1*0401 confers a higher risk than DRB1*0404. Based on combined available data on the genetic susceptibility encoded by various DR4-DQ8 haplotypes and the amino acid composition of the involved DRbeta*04 chains as well as the ligand motifs for these DR4 subtypes, we have developed a unifying hypothesis explaining the different risks associated with different DR4-DQ8 haplotypes. We suggest that disease susceptibility is mainly conferred by DQ8 while DR4 subtypes confer different degrees of protection. Some DR4 subtypes (i.e., DRB1*0405, 0402, and 0401) confer little or no protection, while others (i.e., DRB1*0404, 0403, and 0406) cause an increasing degree of protection, possibly by binding a common protective peptide. Features of a protective peptide that fit such a model are briefly discussed.

Recognition of peptides corresponding to the joining region of p210BCR-ABL protein by human T cells.

In chronic myeloid leukemia (CML) the proto-oncogene c-abl from chromosome 9 q34 is translocated to the breakpoint cluster region (bcr) gene on chromosome 22 q11. This translocation results in a BCR-ABL fusion gene, which encodes chimeric fusion oncoproteins p210BCR-ABL. Here we demonstrate that a peptide with joining region sequence ATGFKQSSKALQRPVAS (eight amino acids (aa) encoded by BCR exon 3; one novel lysine, encoded by the fusion codon; eight aa encoded by ABL exon 2) is immunogenic to human T cells. Primary immune response induction with this peptide resulted in a HLA DR2(DRB1*1501) restricted CD4+ BCR-ABL peptide specific T cell line P1. Responses of P1 were negatively affected by individual aa replacement by alanine at eight aa positions within the 17mer peptide (F4, K5, Q6, K9, L11, Q12, R13, P14). These findings were supported by experiments with a panel of overlapping 11mer b3a2 peptides. Only two of these peptides with an aa sequence encompassing all residues which could not be replaced by alanine induced P1 proliferation. Since presentation of cytosolic oncoproteins as peptides by DR molecules has been observed, the present findings provide a possible explanation for post interferon-alpha persisting remissions in spite of the presence of BCR-ABL PCR positive progenitors.

Memorandum "Open Metadata". Open Access to Documentation Forms and Item Catalogs in Healthcare.

At present, most documentation forms and item catalogs in healthcare are not accessible to the public. This applies to assessment forms of routine patient care as well as case report forms (CRFs) of clinical and epidemiological studies. On behalf of the German chairs for Medical Informatics, Biometry and Epidemiology six recommendations to developers and users of documentation forms in healthcare were developed. Open access to medical documentation forms could substantially improve information systems in healthcare and medical research networks. Therefore these forms should be made available to the scientific community, their use should not be unduly restricted, they should be published in a sustainable way using international standards and sources of documentation forms should be referenced in scientific publications.

Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery.

BACKGROUND AND PURPOSE: Moderate hypothermia has been found to reduce intracranial pressure (ICP) significantly in patients who have severe middle cerebral artery infarction. However, during passive rewarming, ICP continuously rises and some patients suffer transtentorial herniation. METHODS: We investigated the question of whether slower rewarming leads to slower increase in ICP and slower decrease in cerebral perfusion pressure (CPP). Furthermore, we studied feasibility of slow, controlled rewarming. ICP, CPP, and core body temperature were monitored continuously. Achievement of rewarming protocol was assessed by hit rate of temperature target intervals. Side effects of hypothermia were assessed. RESULTS: Rates of change of both ICP and CPP were correlated significantly with increase in temperature (ICP r=0.62, P=0.002; CPP r=-0.50, P=0.017). In feasibility analysis of 13 controlled rewarmed patients, hit rate of temperature target intervals was 63% (median; range 48% to 81%); hit rate within the target interval or below was 79% (median; range 62% to 94%). CONCLUSIONS: Slow, controlled rewarming is feasible and may be used for ICP and CPP control after moderate hypothermia for space-occupying infarction.

Peptide motif of a cattle MHC class I molecule.

A consensus motif for a bovine major histocompatibility complex (MHC) class I molecule, A20, was derived from parainfluenza type-3 (PI-3) virus-infected muscle-derived fibroblast cells and peripheral blood leukocytes by extraction of the naturally processed peptides from MHC class I molecules by treatment with TFA and peptide sequencing of the complex mixture. The results showed that the majority of peptides were 9 amino acids long with position 2 occupied by lysine and position 9 occupied by arginine. The arginine at position 9 suggests that cattle, like humans, but unlike the mouse have permissive TAP transporter molecules accepting peptides with positively charged amino acids at their C-terminus. This is the first report of a MHC ligand motif in cattle.

Impact of community neonatal services: a multicentre survey.

OBJECTIVES: To explore the impact of a community neonatal service on high risk infant survivors in the first year of life. DESIGN: Retrospective multicentre survey. Postal questionnaires were sent to selected parents. SETTING: Thirty two neonatal units in England and Wales. INCLUSION CRITERIA: infants over 12 months of age with birth weight < or =1500 g, or who received level I intensive care for at least 48 hours. EXCLUSION CRITERIA: multiple births, infants who had died or had severe congenital abnormalities. A total of 3367 eligible infants were selected, and their parents were sent a questionnaire; 65% responded. MAIN OUTCOME MEASURES: Length of stay on the neonatal unit from birth to initial discharge. Readmission to hospital during the first year of life. RESULTS: The median length of stay in units with a community neonatal service was 35 days compared with 37 days in units without. When adjusted for infant and parent characteristics, the median length of stay was reduced by 12.6% where a community neonatal service was provided (95% confidence interval 5.3% to 19.3%). The readmission rates were 44.6% in units with a community neonatal service and 43.5% in units without. There was no significant reduction in the adjusted odds of readmission. CONCLUSIONS: The retrospective nature of this study means that these findings cannot be definitely attributed to the presence of a community neonatal service. However, the results suggest that community neonatal services may reduce the length of stay without any subsequent increase in readmission.

Modeling the recovery from depressive illness by an exponential model with mixed effects.

In clinical trials of antidepressant treatments, a depression rating score is usually measured at several points of time for each patient. We propose an approach to fit data from this type of clinical trial using an exponential mixed-effects model. Compared to previous proposals, this approach has the advantage that individual recovery curves are fitted rather than curves of means. Furthermore, no artificial fixing of model parameters is needed as in other approaches. The flexibility of the proposed model is shown for various situations. The approach is illustrated by an example from a placebo-controlled study for the treatment of depression with St. John's Wort (Hypericum perforatum).

[Multifocal ERG with confocal scanning laser ophthalmoscope. Comparison with monitor simulation]. / Multifokales ERG mittels konfokalem Scanning Laser Ophthalmoskop. Vergleich mit Monitorsimulation.

BACKGROUND: Multifocal electroretinograms (mfERG) were recorded using a confocal scanning laser ophthalmoscope (cSLO) and compared to the results from conventional monitor stimulation. METHODS: Single and repeated measurements were recorded from 23 normal subjects using the cSLO (Heidelberg Retina Angiograph, Heidelberg Engineering, Heidelberg) as well as a conventional monitor as stimulation devices. Laser power output was modified by various optical filters. The reliability of the method and agreement with the conventional monitor stimulation were determined. RESULTS: CSLO recordings showed a high degree of variability. Reduction of laser power output improved the retinal response topography and characteristically modified response variations with each filter. Differences in amplitude size between cSLO and monitor recordings decreased with increasing amplitude levels. The results of repeated measurements showed considerable variation. CONCLUSION: It is possible to use a cSLO as a stimulator for mfERG recordings. However, a relatively high degree of variability represents a significant limitation of this method. Appropriate reduction of laser power decreases variations and serves to obtain photopic response topographies.

Assess, compare and enhance the status of Persons with Multiple Sclerosis (MS) in Europe: a European Register for MS.

OBJECTIVES: Persons with multiple sclerosis (PwMS) experience health-related quality of life (HRQoL) problems greatly differing across Europe, and the European Union (EU) faces deep inequalities in MS management from country to country. Through the establishment of a European MS Register (EUReMS), an effective action is proposed to improve the overall knowledge on MS and support effective intervention programmes at EU and national political level. EUReMS aims to achieve consensus on its mission and vision, to define existing data providers, to develop models driving future MS health policies and research, to develop an information technology (IT) infrastructure for a data set, to develop a European shared governance and to secure providers' data provision into EUReMS. MATERIALS AND METHODS: EUReMS is meant to build on a minimum set of core data from existing national and regional population-based MS registries and from PwMS' perspectives. EUReMS' main partner is the European MS Platform (EMSP) acting in collaboration with associated and collaborating European partners. RESULTS: EUReMS was launched in July 2011. A Consensus Statement on purposes, vision, mission and strategies was produced in December 2011, and a comprehensive survey on existing MS data collections in Europe has been performed, and the EUReMS data mask is currently being discussed. CONCLUSIONS: EUReMS will represent a tool to provide up to date, comparable and sustainable MS data through an effective and credible register, which will encourage extensive knowledge building of MS, more equitable policies and higher standards in MS treatment and services.