How to assess the external validity of therapeutic trials: a conceptual approach

Background External validity of study results is an important issue from a clinical point of view. From a methodological point of view, however, the concept of external validity is more complex than it seems to be at first glance. Methods Methodological review to address the concept of external validity. Results External validity refers to the question whether results are generalizable to persons other than the population in the original study. The only formal way to establish the external validity would be to repeat the study for that specific target population. We propose a three-way approach for assessing the external validity for specified target populations. (i) The study population might not be representative for the eligibility criteria that were intended. It should be addressed whether the study population differs from the intended source population with respect to characteristics that influence outcome. (ii) The target population will, by definition, differ from the study population with respect to geographical, temporal and ethnical conditions. Pondering external validity means asking the question whether these differences may influence study results. (iii) It should be assessed whether the study's conclusions can be generalized to target populations that do not meet all the eligibility criteria. Conclusion Judging the external validity of study results cannot be done by applying given eligibility criteria to a single target population. Rather, it is a complex reflection in which prior knowledge, statistical considerations, biological plausibility and eligibility criteria all have plac

The importance of parental knowledge in the association between ADHD symptomatology and related domains of impairment

Parents of children with ADHD experience several difficulties while raising their children and report lower levels of knowledge about their children’s life and behaviors. A recent study found that low levels of parental knowledge mediated the association between ADHD symptoms and risk-taking behavior (RTB) in adolescents. The current study aimed to investigate this previous finding further by replicating it, by taking peer influence into account as additional social factor of importance and by extending it and also investigate the role of parental knowledge in the association between ADHD symptoms and homework problems. Three studies were performed: study 1 (N=234) replicated previous work on parental knowledge mediating the association between ADHD symptoms and RTB, study 2 (pre-registered, N=313) added peer influence, and study 3 (pre-registered, N=315) assessed whether parental knowledge mediated the association between ADHD symptoms and homework behavior. Parental knowledge consistently mediated the association between ADHD symptoms on one hand and RTB and homework problems on the other, and also predicted stronger resistance to peer influence. Because parental knowledge was repeatedly linked to ADHD-related problems, it seems promising to include parental knowledge in treatment of ADHD-related problems in adolescents, by improving the parent-child relationship. Future studies should test more directly how improvement of the parent-child relationship can be used to optimize parental knowledge, which in its turn reduces ADHD-related problems

Effect of immune system stimulation and divergent selection for residual feed intake on digestive capacity of the small intestine in growing pigs

Residual feed intake (RFI) is a measure of feed efficiency that reflects differences in the efficiency of the use of feed for maintenance and growth. The consequences of genetic selection for RFI on intestinal nutrient digestion capacity, particularly during immune system stimulation (ISS), are poorly documented. Our objective was to evaluate the impact of ISS and genetic selection for RFI on apparent ileal digestibility (AID) of nutrients, and intestinal nutrient transport and barrier function

Impact of Mycoplasma hyopneumoniae and Lawsonia intracellularis on the performance of pigs divergently selected for feed efficiency

Feed efficiency (FE) is a valuable trait, yet how genetic selection for enhanced FE affects other processes such as response to disease is unknown. Disease from endemic respiratory and enteric pathogens such as Mycoplasma hyopneumoniae (Mh) and Lawsonia intracellularis (LI) are common in swine production. Therefore, the aim of this study was to examine if pigs selected for high versus low FE based on residual feed intake (RFI) respond differently to a dual respiratory and enteric challenge. Pigs selected for low RFI (LRFI, high feed efficiency) pigs are considered more FE compared to their high RFI (HRFI, low feed efficiency) selected counterparts. Using a 2 x 2 factorial design, 25 littermate pairs from the HRFI and 25 littermate pairs from the LRFI line (barrows, 50 ± 7 kg BW) were selected, with one pig from each pair assigned to individual pens in either the challenge or the non-challenge (control) rooms (n = 25 barrows per line/challenge). On days post inoculation (dpi) 0, the challenged pigs were inoculated with LI and Mh (MhLI). Feed intake, body weight, fecal swabs, and serum samples were collected and recorded weekly for 42 days. On dpi -2 and 47, 14 littermate pairs (n=7 barrows per line/challenge) were utilized for initial and final body composition scans using dual X-ray absorptiometry to calculate longitudinal whole body tissue accretion rates for lean, protein, fat, and bone mineral content. Serum antibody levels and fecal shedding of LI were used to confirm infection. Control pigs remained negative by all measures during the 6 week trial and MhLI inoculated pigs were confirmed positive via serological antibody responses by dpi 14 for LI and Mh. There were no interactions between RFI line and challenge status for any overall performance parameter (P \u3e 0.05). The six week MhLI challenge resulted in a 17% reduction in ADG, a 12% reduction in ADFI, and a 7% reduction in G:F versus controls (P \u3c 0.05). In addition, compared to the control pigs, MhLI challenge reduced lean, protein, and lipid accretion rates by 16% (P \u3c 0.05). Genetic selection for high FE resulted in decreased ADFI and increased G:F (P \u3c 0.01), but did not impact ADG or tissue accretion versus low FE pigs. Collectively, these results demonstrate that a dual enteric and respiratory pathogen challenge reduced ADG, ADFI, G:F and tissue accretion in growing pigs. Further, there was no evidence that selection for enhanced FE based on RFI index affects response to disease

Characterisation of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction