Experiments take place in a physical environment but also a social environment. Generalizability from experimental manipulations to more typical contexts may be limited by violations of ecological validity with respect to either the physical or the social environment. A replication and extension of a recent study (a blood glucose manipulation) was conducted to investigate the effects of experimental demand (a social artifact) on participant behaviors judging the geographical slant of a large-scale outdoor hill. Three different assessments of experimental demand indicate that even when the physical environment is naturalistic, and the goal of the main experimental manipulation was primarily concealed, artificial aspects of the social environment (such as an explicit requirement to wear a heavy backpack while estimating the slant of a hill) may still be primarily responsible for altered judgments of hill orientation.

ObjectiveFriedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.MethodsEight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9‐Hole Peg Test, Timed 25‐Foot Walk, visual acuity tests, self‐reported surveys and disability scales. Cross‐sectional outcomes were assessed from recent visits, and longitudinal changes were gaged over 5 years from baseline.ResultsCross‐sectional outcomes correlated with measures of disease severity. Age, genetic severity (guanine‐adenine‐adenine [GAA] repeat length), and testing site predicted performance. Serial progression was relatively linear using FARS and composite measures of performance, while individual performance outcomes were nonlinear over time. Age strongly predicted change from baseline until removing the effects of baseline FARS scores, when GAA becomes a more important factor. Progression is fastest in younger subjects and subjects with longer GAA repeats. Improved coefficients of variation show that progression results are more reproducible over longer assessment durations.InterpretationWhile age predicted progression speed in simple analyses and may provide an effective way to stratify cohorts, separating the effects of age and genetic severity is difficult. Controlling for baseline severity, GAA is the major determinant of progression rate in FRDA. Clinical trials will benefit from enrollment of younger subjects, and sample size requirements will shrink with longer assessment periods. These findings should prove useful in devising gene therapy trials in the near future.

Friedreich's ataxia (FA) is an autosomal recessive disease caused by an intronic GAA triplet expansion in the FXN gene, leading to reduced expression of the mitochondrial protein frataxin. FA is estimated to affect 1 in 50 000 with a mean age of death in the fourth decade of life. There are no approved treatments for FA, although experimental approaches, which involve up-regulation or replacement of frataxin protein, are being tested. Frataxin is undetectable in serum or plasma, and whole blood cannot be used because it is present in long-lived erythrocytes. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of 10 days. The assay is based on stable isotope dilution immunopurification two-dimensional nano-ultra high performance liquid chromatography/parallel reaction monitoring/mass spectrometry. The lower limit of quantification was 0.078 pg frataxin/μg protein, and the assay had 100% sensitivity and specificity for discriminating between controls and FA cases. The mean levels of control and FA platelet frataxin were 9.4 ± 2.6 and 2.4 ± 0.6 pg/μg protein, respectively. The assay should make it possible to rigorously monitor the effects of therapeutic interventions on frataxin expression in this devastating disease.