Systematic Evaluation of the Patient-Reported Outcome (PRO) Content of Clinical Trial Protocols

Background

Qualitative evidence suggests patient-reported outcome (PRO) information is frequently absent from clinical trial protocols, potentially leading to inconsistent PRO data collection and risking bias. Direct evidence regarding PRO trial protocol content is lacking. The aim of this study was to systematically evaluate the PRO-specific content of UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme trial protocols.

Methods and Findings

We conducted an electronic search of the NIHR HTA programme database (inception to August 2013) for protocols describing a randomised controlled trial including a primary/secondary PRO. Two investigators independently reviewed the content of each protocol, using a specially constructed PRO-specific protocol checklist, alongside the ‘Standard Protocol Items: Recommendations for Interventional Trials’ (SPIRIT) checklist. Disagreements were resolved through discussion with a third investigator. 75 trial protocols were included in the analysis. Protocols included a mean of 32/51 (63%) SPIRIT recommendations (range 16–41, SD 5.62) and 11/33 (33%) PRO-specific items (range 4–18, SD 3.56). Over half (61%) of the PRO items were incomplete. Protocols containing a primary PRO included slightly more PRO checklist items (mean 14/33 (43%)). PRO protocol content was not associated with general protocol completeness; thus, protocols judged as relatively ‘complete’ using SPIRIT were still likely to have omitted a large proportion of PRO checklist items.

Conclusions

The PRO components of HTA clinical trial protocols require improvement. Information on the PRO rationale/hypothesis, data collection methods, training and management was often absent. This low compliance is unsurprising; evidence shows existing PRO guidance for protocol developers remains difficult to access and lacks consistency. Study findings suggest there are a number of PRO protocol checklist items that are not fully addressed by the current SPIRIT statement. We therefore advocate the development of consensus-based supplementary guidelines, aimed at improving the completeness and quality of PRO content in clinical trial protocols.     

Methods for detecting early warnings of critical transitions in time series illustrated using simulated ecological data

Many dynamical systems, including lakes, organisms, ocean circulation patterns, or financial markets, are now thought to have tipping points where critical transitions to a contrasting state can happen. Because critical transitions can occur unexpectedly and are difficult to manage, there is a need for methods that can be used to identify when a critical transition is approaching. Recent theory shows that we can identify the proximity of a system to a critical transition using a variety of so-called 'early warning signals', and successful empirical examples suggest a potential for practical applicability. However, while the range of proposed methods for predicting critical transitions is rapidly expanding, opinions on their practical use differ widely, and there is no comparative study that tests the limitations of the different methods to identify approaching critical transitions using time-series data. Here, we summarize a range of currently available early warning methods and apply them to two simulated time series that are typical of systems undergoing a critical transition. In addition to a methodological guide, our work offers a practical toolbox that may be used in a wide range of fields to help detect early warning signals of critical transitions in time series data.     

Clinical and Analytical Toxicology of Dietary Supplements: A Case Study and a Review of the Literature

The use of dietary supplements has grown dramatically in the last decade. A large number of dietary and herbal supplements escape regulatory and quality control; components of these preparations are poisonous and may contain, among other toxins, heavy metals. Uncontrolled use of dietary and herbal supplements by special populations, such as the military, may therefore pose a health risk. Clinical symptoms are not always properly attributed to dietary supplements; patients often do not mention supplement use to their health care provider. Therefore, a health risk estimate is hard to make on either the individual or the population level. The literature on this issue was reviewed and discussed in the light of a representative clinical-chemical case study. This case study was performed on a host of preparations that were used by one single individual in the military. Both essential (chromium, copper, zinc, and iron) and poisonous (arsenic, lead, and nickel) trace elements were determined using inductively coupled plasma combined with optical emission spectrometry (ICP-OES) or with mass spectrometry (ICP-MS). Arsenic and lead were detected at exposure levels associated with health risks. These health risks were detected predominantly in hormone-containing supplements and the herbs and botanicals used for performance enhancement. To the extent that this is a representative sample, there is an underestimation of supplement use and supplement risk in the US military, if not in the general population. Since clinical symptoms may be attributed to other causes and, unless patients are specifically asked, health care providers may not be aware of their patients' use of dietary supplements, a strong support of laboratory diagnostics, such as a toxicological screening of blood or urine, is required. In addition, screening of the preparations themselves may be advised.     

Single-Leaf Resolution of the Temporal Population Dynamics of Aureobasidium pullulans on Apple Leaves

The abundance of phylloplane microorganisms typically varies over several orders of magnitude among leaves sampled concurrently. Because the methods traditionally used to sample leaves are destructive, it has remained unclear whether this high variability is due to fixed differences in habitat quality among leaves or to asynchronous temporal variation in the microbial population density on individual leaves. We developed a novel semidestructive assay to repeatedly sample the same apple leaves from orchard trees over time by removing progressively more proximal ~1-cm-wide transverse segments. Aureobasidium pullulans densities were determined by standard leaf homogenization and plating procedures and were expressed as CFU per square centimeter of segment. The A. pullulans population densities among leaves were lognormally distributed. The variability in A. pullulans population densities among subsections of a given leaf was one-third to one-ninth the variability among whole leaves harvested concurrently. Sequential harvesting of leaf segments did not result in detectable changes in A. pullulans density on residual leaf surfaces. These findings implied that we could infer whole-leaf A. pullulans densities over time by using partial leaves. When this successive sampling regimen was applied over the course of multiple 7- to 8-day experiments, the among-leaf effects were virtually always the predominant source of variance in A. pullulans density estimates. Changes in A. pullulans density tended to be synchronous among leaves, such that the rank order of leaves arrayed with respect to A. pullulans density was largely maintained through time. Occasional periods of asynchrony were observed, but idiosyncratic changes in A. pullulans density did not contribute appreciably to variation in the distribution of populations among leaves. This suggests that persistent differences in habitat (leaf) quality are primarily responsible for the variation in A. pullulans density among leaves in nature.     

A limited number of Bacillus subtilis strains carry a tetracycline-resistance determinant at a site close to the origin of replication

Several strains of Bacillus subtilis, e.g., 168 derivatives and R, were found to carry a single copy of a tetracycline-resistance (TcR) determinant (named tetBS908) at a site close to the origin of replication on the chromosome. This gene is highly homologous (80% identical) to the TcR determinant of plasmids widely dispersed among aerobic spore-forming bacilli. B. subtilis RM125 (168 strain) transformants which carry a varying number of tetBS908 sequences in a tandem array on the chromosome were constructed and examined for their TcR level. A nearly proportional relationship between the TcR level and copy number of tetBS908 existed.     

Should We Reject Donated Organs on Moral Grounds or Permit Allocation Using Non‐Medical Criteria?: A Qualitative Study

Conditional and directed deceased organ donations occur when donors (or often their next of kin) attempt to influence the allocation of their donated organs. This can include asking that the organs are given to or withheld from certain types of people, or that they are given to specified individuals. Donations of these types have raised ethical concerns, and have been prohibited in many countries, including the UK. In this article we report the findings from a qualitative study involving interviews with potential donors (n = 20), potential recipients (n = 9) and transplant staff (n = 11), and use these results as a springboard for further ethical commentary. We argue that although participants favoured unconditional donation, this preference was grounded in a false distinction between ‘medical’ and ‘non‐medical’ allocation criteria. Although there are good reasons to maintain organ allocation based primarily upon the existing ‘medical’ criteria, it may be premature to reject all other potential criteria as being unacceptable. Part of participants' justification for allocating organs using ‘medical’ criteria was to make the best use of available organs and avoid wasting their potential benefit, but this can also justify accepting conditional donations in some circumstances. We draw a distinction between two types of waste – absolute and relative – and argue that accepting conditional donations may offer a balance between these forms of waste.     

Effects of experimental shifts in flowering phenology on plant-pollinator interactions

Climate change has led to phenological shifts in flowering plants and insect pollinators, causing concern that these shifts will disrupt plant-pollinator mutualisms. We experimentally investigated how shifts in flowering onset affect pollinator visitation for 14 native perennial plant species, six of which have exhibited shifts to earlier flowering over the last 70 years and eight of which have not. We manipulated flowering onset in greenhouses and then observed pollinator visitation in the field. Five of six species with historically advanced flowering received more visits when flowering was experimentally advanced, whereas seven of eight species with historically unchanged flowering received fewer visits when flowering earlier. This pattern suggests that species unconstrained by pollinators have advanced their flowering, whereas species constrained by pollinators have not. In contrast to current concern about phenological mismatches disrupting plant-pollinator mutualisms, mismatches at the onset of flowering are not occurring for most of our study species.     

CONTINUING STUDIES ON THE SOUTH AMHERST DROSOPHILA MELANOGASTER NATURAL POPULATION DURING THE 1970'S AND 1980'S

Continuing investigations on the South Amherst Drosophila melanogaster natural population following the significant decline and recovery of lethal (le) and semilethal (sle) frequencies in the late 1960's (Ives, 1970) show that the population has been remarkably stable although it contains MR (male recombination) and/or P DNA elements (Kidwell et al., 1977a; Green, 1980). A 13-year study affirms that the lethals present are nonrandomly distributed along the second chromosome and deficient on the right; they differ significantly in distribution from spontaneous (Ives, 1973) and δ-induced lethals (Minamori and Ito, 1971). Between 1970 and 1977, a total of 4,083 second chromosomes from the Markert subpopulation were analyzed; 28.9% of the chromosomes were lethal and 7.25% were semilethal in homozygous condition. Frequencies are similar for early summer and late fall collections although the rate of allelism among lethals is significantly higher in early summer than in late fall. For the large fall (1970–1979) Porch site population, 2,519 second chromosomes were analyzed; 29.5% were lethal and 8.0% were sublethal as homozygotes; the rate of allelism among lethals was 1.50%. At Hockanum, 1977–1983, lethal and semilethal frequencies were lower; the rate of allelism among lethals was 1.43%. The chromosome map distribution of lethals does not change between summer and late fall at Markert. The overall distributions of lethals at the Markert and Hockanum sites are similar. In tests for male recombination (MR) activity in the population over a 6-year period, a total of 0.47% recombinants were observed; these were uniformly distributed along the second chromosome. Comparisons are made with other long studied D. melanogaster populations.