Why Even More Clinical Research Studies May Be False: Effect of Asymmetrical Handling of Clinically Unexpected Values

Background

In medical practice, clinically unexpected measurements might be quite properly handled by the remeasurement, removal, or reclassification of patients. If these habits are not prevented during clinical research, how much of each is needed to sway an entire study?

Methods and Results

Believing there is a difference between groups, a well-intentioned clinician researcher addresses unexpected values. We tested how much removal, remeasurement, or reclassification of patients would be needed in most cases to turn an otherwise-neutral study positive. Remeasurement of 19 patients out of 200 per group was required to make most studies positive. Removal was more powerful: just 9 out of 200 was enough. Reclassification was most powerful, with 5 out of 200 enough. The larger the study, the smaller the proportion of patients needing to be manipulated to make the study positive: the percentages needed to be remeasured, removed, or reclassified fell from 45%, 20%, and 10% respectively for a 20 patient-per-group study, to 4%, 2%, and 1% for an 800 patient-per-group study. Dot-plots, but not bar-charts, make the perhaps-inadvertent manipulations visible. Detection is possible using statistical methods such as the Tadpole test.

Conclusions

Behaviours necessary for clinical practice are destructive to clinical research. Even small amounts of selective remeasurement, removal, or reclassification can produce false positive results. Size matters: larger studies are proportionately more vulnerable. If observational studies permit selective unblinded enrolment, malleable classification, or selective remeasurement, then results are not credible. Clinical research is very vulnerable to “remeasurement, removal, and reclassification”, the 3 evil R''s.     

Modeling Lanthanide Complexes: Towards the Theoretical Design of Light Conversion Molecular Devices

Theoretical techniques have been developed and/or improved to predict the molecular structure of lanthanide complexes which were used to calculate their electronic properties, in particular, their electronic spectra and energy levels necessary to calculate the rates of energy transfer from the ligands to the metal ion. The molecular structure has been obtained by the SMLC/AM1 (Sparkle Model for the Calculation of Lanthanide Complexes – Austin Model 1) model where the lanthanide ion is simulated by a sparkle implemented into the AM1 Hamiltonian used to perform a HF-SCF (Hartree-Fock Self-Consistent Field) calculation. The previous implementation of the SMLC/AM1 model (sparkle/1) involving only two parameters has been generalized to be consistent with the AM1 Hamiltonian and the new model (sparkle/2) significantly improved the prediction of molecular structures of Eu(III) complexes. For the electronic spectra and energy level calculations of the lanthanide complexes the model replaces the metal ion by a point charge with the ligands held in their positions as determined by the SMLC/AM1 model, and uses a INDO/S-CI (intermediate neglect of differential overlap/spectroscopic-configuration interaction) model. A preliminary study of the solvent effects on the absorption spectra of the free ligand is also presented. For the ligand-lanthanide ion energy transfer Fermi's golden rule is used with the multipolar and exchange mechanisms being implemented and tested for several complexes. These theoretical techniques have been applied to several complexes yielding very good results when compared to experimental data as well as predictions for the molecular and electronic structures and the relative contributions of the mechanisms for the energy transfer rates. This revised version was published online in June 2006 with corrections to the Cover Date.     

Randomised Controlled Trials May Underestimate Drug Effects: Balanced Placebo Trial Design

Background

It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment.

Objective

To test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects.

Methods

We used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm²) of pain intensity during injections.

Results

There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm² (95% CI, 4936–7622)) and the total treatment effect (mean AUC 5455 mm² (95% CI, 4585–6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006).

Conclusion

Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.     

Anchoring Revisited: The Role of the Comparative Question

When people estimate a numeric value after judging whether it is larger or smaller than a high or low anchor value (comparative question), estimates are biased in the direction of the anchor. One explanation for this anchoring effect is that people selectively access knowledge consistent with the anchor value as part of a positive test strategy. Two studies (total N = 184) supported the alternative explanation that people access knowledge consistent with their own answer to the comparative question. Specifically, anchoring effects emerged when the answer to the comparative question was unexpected (lower than the low anchor or higher than the high anchor). For expected answers (lower than the high anchor or higher than the low anchor), however, anchoring effects were attenuated or reversed. The anchor value itself was almost never reported as an absolute estimate.     

A Procedure for the Design of Novel Assisting Devices for the Sit-to-Stand

The Sit-to-Stand （STS） is an activity most people perform numerous times daily. Standing up deals with the transition from two stabilized postures, namely seated to standing, with movement of all body segments except the feet. During the STS the body＇s Center of Gravity （COG） is moved upward from a sitting position to a standing position without losing balance and requiring a good coordination of many muscles. Three main phases of the STS movement can be recognized. One begins to stand up by inclining the upper body forward, which moves body mass toward the feet in order to maintain balance after lift-off. Prior to leaving the chair, hip and knee extensor muscles are activated to provide antigravity support for these joints, this action is commonly referred to as ＂weight shift＂. Finally; after leaving the chair, the leg and trunk joints are straightened to achieve upright stance. The STS task can be considered of major importance for impaired and elderly people to achieve minimal mo- bility and independence. In this paper we detail a procedure for the design of assisting devices to be used for the STS. In par- ticular, an experimental procedure is described firstly to track and record point trajectories and the orientation of the trunk during the STS. This analysis is then used to get information for the design of assisting devices. A proposal and simulation results are presented for a novel mechatronic system. In particular, for the case under study experimental tests are used to drive the actua- tion system for the reported simulation. A functional mechatronic scheme is then proposed to control the device during its operation.     

Split earlobes: a method of repair preserving the hole

A method of repairing split earlobes preserving the hole is presented. It is simple, sound, has a good cosmetic appearance, and is more resistant to recurrence of the split than other methods.     

Split sex ratios in the social Hymenoptera: a meta-analysis

The study of sex allocation in social Hymenoptera (ants, bees,and wasps) provides an excellent opportunity for testing kin-selectiontheory and studying conflict resolution. A queen–workerconflict over sex allocation is expected because workers aremore related to sisters than to brothers, whereas queens areequally related to daughters and sons. If workers fully controlsex allocation, split sex ratio theory predicts that colonieswith relatively high or low relatedness asymmetry (the relatednessof workers to females divided by the relatedness of workersto males) should specialize in females or males, respectively.We performed a meta-analysis to assess the magnitude of adaptivesex allocation biasing by workers and degree of support forsplit sex ratio theory in the social Hymenoptera. Overall, variationin relatedness asymmetry (due to mate number or queen replacement)and variation in queen number (which also affects relatednessasymmetry in some conditions) explained 20.9% and 5% of thevariance in sex allocation among colonies, respectively. Theseresults show that workers often bias colony sex allocation intheir favor as predicted by split sex ratio theory, even iftheir control is incomplete and a large part of the variationamong colonies has other causes. The explanatory power of splitsex ratio theory was close to that of local mate competitionand local resource competition in the few species of socialHymenoptera where these factors apply. Hence, three of the mostsuccessful theories explaining quantitative variation in sexallocation are based on kin selection.     

On the Structural Plasticity of the Human Genome: Chromosomal Inversions Revisited

With the aid of novel and powerful molecular biology techniques, recent years have witnessed a dramatic increase in the number of studies reporting the involvement of complex structural variants in several genomic disorders. In fact, with the discovery of Copy Number Variants (CNVs) and other forms of unbalanced structural variation, much attention has been directed to the detection and characterization of such rearrangements, as well as the identification of the mechanisms involved in their formation. However, it has long been appreciated that chromosomes can undergo other forms of structural changes - balanced rearrangements - that do not involve quantitative variation of genetic material. Indeed, a particular subtype of balanced rearrangement – inversions – was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome.     

Improving the Measurement of Maternal Mortality: The Sisterhood Method Revisited

Background

Over the past several decades the efforts to improve maternal survival and the consequent demand for accurate estimates of maternal mortality have increased. However, measuring maternal mortality remains a difficult task especially in developing countries with weak information systems. Sibling histories included in household surveys (most notably the Demographic and Health Surveys (DHS)) have emerged as an important source of maternal mortality data. Data have been mainly collected from women and have not been widely collected from men due to concerns about data quality. We assess data quality of histories obtained from men and the potential to improve the efficiency of surveys measuring maternal mortality by collecting such data.

Methods and Findings

We used data from 10 Demographic and Health Surveys (DHS) that have included a full sibling history in both their women’s and men’s questionnaires. We estimated adult and maternal mortality indicators from histories obtained from men and women. We assessed the completeness and accuracy of these histories using several indicators of data quality. Our study finds that mortality estimates based on sibling histories obtained from men do not systematically or significantly differ from those obtained from women. Quality indicators were similar when comparing data from men and women. Pooling data obtained from men and women produced narrower confidence intervals.

Conclusion

From experience across nine developing countries, sibling history data obtained from men appear to be a reliable source of information on adult and maternal mortality. Given that there are no significant differences between mortality estimates based on data obtained from men and women, data can be pooled to increase efficiency. This finding improves the feasibility for countries to generate robust empirical estimates of adult and maternal mortality from surveys. Further we recommend that male sibling histories be collected from all sample households rather than from a subsample.     

Languages Support Efficient Communication about the Environment: Words for Snow Revisited

The claim that Eskimo languages have words for different types of snow is well-known among the public, but has been greatly exaggerated through popularization and is therefore viewed with skepticism by many scholars of language. Despite the prominence of this claim, to our knowledge the line of reasoning behind it has not been tested broadly across languages. Here, we note that this reasoning is a special case of the more general view that language is shaped by the need for efficient communication, and we empirically test a variant of it against multiple sources of data, including library reference works, Twitter, and large digital collections of linguistic and meteorological data. Consistent with the hypothesis of efficient communication, we find that languages that use the same linguistic form for snow and ice tend to be spoken in warmer climates, and that this association appears to be mediated by lower communicative need to talk about snow and ice. Our results confirm that variation in semantic categories across languages may be traceable in part to local communicative needs. They suggest moreover that despite its awkward history, the topic of “words for snow” may play a useful role as an accessible instance of the principle that language supports efficient communication.     

Culture-Independent Analysis of Gut Bacteria: the Pig Gastrointestinal Tract Microbiota Revisited

The phylogenetic diversity of the intestinal bacterial community in pigs was studied by comparative 16S ribosomal DNA (rDNA) sequence analysis. Samples were collected from a total of 24 pigs representing a variety of diets, ages, and herd health status. A library comprising 4,270 cloned 16S rDNA sequences obtained directly by PCR from 52 samples of either the ileum, the cecum, or the colon was constructed. In total, 375 phylotypes were identified using a 97% similarity criterion. Three hundred nine of the phylotypes (83%) had a <97% sequence similarity to any sequences in the database and may represent yet-uncharacterized bacterial genera or species. The phylotypes were affiliated with 13 major phylogenetic lineages. Three hundred four phylotypes (81%) belonged to the low-G+C gram-positive division, and 42 phylotypes (11.2%) were affiliated with the Bacteroides and Prevotella group. Four clusters of phylotypes branching off deeply within the low-G+C gram-positive bacteria and one in the Mycoplasma without any cultured representatives were found. The coverage of all the samples was 97.2%. The relative abundance of the clones approximated a lognormal distribution; however, the phylotypes detected and their abundance varied between two libraries from the same sample. The results document that the intestinal microbial community is very complex and that the majority of the bacterial species colonizing the gastrointestinal tract in pigs have not been characterized.