Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis

The SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.This research has been conducted using the UK Biobank Resource.

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an "inflammatory status" during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs. Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status. Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients. After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082). Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. Figure 1 Figure 1. Disclosures Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

The case for formal methodology in scientific reform

Current attempts at methodological reform in sciences come in response to an overall lack of rigor in methodological and scientific practices in experimental sciences. However, most methodological reform attempts suffer from similar mistakes and over-generalizations to the ones they aim to address. We argue that this can be attributed in part to lack of formalism and first principles. Considering the costs of allowing false claims to become canonized, we argue for formal statistical rigor and scientific nuance in methodological reform. To attain this rigor and nuance, we propose a five-step formal approach for solving methodological problems. To illustrate the use and benefits of such formalism, we present a formal statistical analysis of three popular claims in the metascientific literature: (i) that reproducibility is the cornerstone of science; (ii) that data must not be used twice in any analysis; and (iii) that exploratory projects imply poor statistical practice. We show how our formal approach can inform and shape debates about such methodological claims.

On the authenticity of COVID-19 case figures

In this article, we study the applicability of Benford’s law and Zipf’s law to national COVID-19 case figures with the aim of establishing guidelines upon which methods of fraud detection in epidemiology, based on formal statistical analysis, can be developed. Moreover, these approaches may also be used in evaluating the performance of public health surveillance systems. We provide theoretical arguments for why the empirical laws should hold in the early stages of an epidemic, along with preliminary empirical evidence in support of these claims. Based on data published by the World Health Organization and various national governments, we find empirical evidence that suggests that both Benford’s law and Zipf’s law largely hold across countries, and deviations can be readily explained. To the best of our knowledge, this paper is among the first to present a practical application of Zipf’s law to fraud detection.

The 100 top-cited meta-analyses of diagnostic accuracy in radiology journals: a bibliometric analysis

Purpose To identify the 100 top-cited meta-analyses of diagnostic accuracy studies published in radiology, medical imaging and nuclear medicine journals. Methods A PubMed search with pre-defined criteria was performed. The 100 top-cited articles meta-analyses were retrieved, using a custom Python script and the Scopus Application Programming Interface (Elsevier). Publication, citation and affiliation details were extracted from each meta-analysis. No formal statistical analysis was performed. Results The top meta-analysis was cited 394 times, the 100th meta-analysis 38 times. The USA was the top country represented in the papers (33 meta-analyses) followed by The Netherlands, China and Germany. The journal Radiology published 24 studies. The most common modality reported was positron emission tomography (PET) or PET computed tomography (36 instances), followed by magnetic resonance imaging (30 instances) and computed tomography (27 instances). Cardiac (19 meta-analyses), abdominal (18 meta-analyses), followed by neurological (12 meta-analyses) investigations were the most frequently encountered in the top 100 cited meta-analyses. Conclusions The 100 top-cited meta-analyses encompass a broad range of imaging modalities and body regions. This may comprise a useful resource for identifying influential evidence-based diagnostic accuracy information in radiology.

Publishing and Promotion in Economics: The Tyranny of the Top Five

This paper examines the relationship between placement of publications in top five (T5) journals and receipt of tenure in academic economics departments. Analyzing the job histories of tenure–track economists hired by the top 35 US economics departments, we find that T5 publications have a powerful influence on tenure decisions and rates of transition to tenure. A survey of the perceptions of young economists supports the formal statistical analysis. Pursuit of T5 publications has become the obsession of the next generation of economists. However, the T5 screen is far from reliable. A substantial share of influential publications appear in non-T5 outlets. Reliance on the T5 to screen talent incentivizes careerism over creativity.( JEL A14, I23, J44, J62)

The case for formal methodology in scientific reform

Current attempts at methodological reform in sciences come in response to an overall lack of rigor in methodological and scientific practices in experimental sciences. However, most methodological reform attempts suffer from similar mistakes and over-generalizations to the ones they aim to address. We argue that this can be attributed in part to lack of formalism and first principles. Considering the costs of allowing false claims to become canonized, we argue for formal statistical rigor and scientific nuance in methodological reform. To attain this rigor and nuance, we propose a five-step formal approach for solving methodological problems. To illustrate the use and benefits of such formalism, we present a formal statistical analysis of three popular claims in the metascientific literature: (a) that reproducibility is the cornerstone of science; (b) that data must not be used twice in any analysis; and (c) that exploratory projects imply poor statistical practice. We show how our formal approach can inform and shape debates about such methodological claims.

Determinants of successful revenue management

Purpose The aim of this paper is to define which characteristics of a hotel and staff organization determine successful revenue management (RM) implementation in urban hotels. Design/methodology/approach Multiple linear regression analysis was used to determine whether the characteristics of the hotel and the staff member in charge of RM are explanatory variables for the degree of RM implementation. Findings The findings show that hotel category, chain affiliation and the existence of qualified full-time staff are the determinants for successful RM implementation. The creation of the revenue manager position alone is not determinant in the degree of RM implementation, but his/her qualification and dedication are fundamental variables. Research limitations/implications Given that this survey was confined to the region of Madrid, it would be interesting to carry out similar research nationwide. Practical implications This study provides researchers and professionals guidance for the satisfactory implementation and use of RM, tailored to the characteristics of any given establishment. Therefore, this paper states that the creation of a qualified, on-site, full-time revenue manager position is crucial. Originality/value To the best of the authors’ knowledge, this is the first paper to conduct a formal statistical analysis of the relationship between hotel characteristics, staff organization and the degree of RM implementation. The greatest contribution of this research is the empirical demonstration that having a qualified full-time staff in charge of RM leads to better results in terms of RM implementation as opposed to not having one, having one part-time or having one at the corporate level. Therefore, this paper states that the creation of the professional revenue manager position within hotels is fundamental. Thus, the reported results provide a significant contribution to the literature related to the characteristics and organization of RM in hotels.