Clusterization of Behavioral and Psychological Symptoms of Dementia as Assessed by Neuropsychiatric Inventory: A Case Against the Use of Principal Component Analysis.

Background: The term Behavioral and Psychological Symptoms of Dementia (BPSD) covers a group of phenomenologically and medically distinct symptoms that rarely occur in isolation. Their therapy represents a major unmet medical need across dementias of different types, including Alzheimer's disease. Understanding of the symptom occurrence and their clusterization can inform clinical drug development and use of existing and future BPSD treatments. Objective: The primary aim of the present study was to investigate the ability of a commonly used principal component analysis to identify BPSD patterns as assessed by Neuropsychiatric Inventory (NPI). Methods: NPI scores from the Aging, Demographics, and Memory Study (ADAMS) were used to characterize reported occurrence of individual symptoms and their combinations. Based on this information, we have designed and conducted a simulation experiment to compare Principal Component analysis (PCA) and zero-inflated PCA (ZI PCA) by their ability to reveal true symptom associations. Results: Exploratory analysis of the ADAMS database revealed overlapping multivariate distributions of NPI symptom scores. Simulation experiments have indicated that PCA and ZI PCA cannot handle data with multiple overlapping patterns. Although the principal component analysis approach is commonly applied to NPI scores, it is at risk to reveal BPSD clusters that are a statistical phenomenon rather than symptom associations occurring in clinical practice. Conclusions: We recommend the thorough characterization of multivariate distributions before subjecting any dataset to Principal Component Analysis.

The EQIPD quality system - Assessment and certification procedures.

The EQIPD Quality System was designed with the ultimate mission to provide a framework to ensure the quality and integrity of non-regulated preclinical biomedical research. For research quality to be sustained over time, it is crucial to have continuous improvement mechanisms that routinely monitor the research-related processes and enable solutions for identified issues. The present article is focused on these monitoring and assessment procedures that make the EQIPD Quality System a fully functional 'system' (as opposed to a mere collection of guidelines, work instructions and policies). In this context, a critical instrument are the internal and external assessments of the EQIPD Quality System performance described in detail. The assessment procedures emphasize the unique nature of the EQIPD Quality System being user-friendly, flexible and fit-for-purpose. By undergoing the (voluntary) external EQIPD assessment (leading to the EQIPD certification after all EQIPD core requirements have been implemented), a research unit: (i) secures confidence in the quality of data generated, (ii) ensures continuous improvement of research processes, and (iii) obtains an independent seal of quality communicating commitment to best research practices to the research community.

Practical solutions for including sex as a biological variable (SABV) in preclinical neuropsychopharmacological research.

Recently, many funding agencies have released guidelines on the importance of considering sex as a biological variable (SABV) as an experimental factor, aiming to address sex differences and avoid possible sex biases to enhance the reproducibility and translational relevance of preclinical research. In neuroscience and pharmacology, the female sex is often omitted from experimental designs, with researchers generalizing male-driven outcomes to both sexes, risking a biased or limited understanding of disease mechanisms and thus potentially ineffective therapeutics. Herein, we describe key methodological aspects that should be considered when sex is factored into in vitro and in vivo experiments and provide practical knowledge for researchers to incorporate SABV into preclinical research. Both age and sex significantly influence biological and behavioral processes due to critical changes at different timepoints of development for males and females and due to hormonal fluctuations across the rodent lifespan. We show that including both sexes does not require larger sample sizes, and even if sex is included as an independent variable in the study design, a moderate increase in sample size is sufficient. Moreover, the importance of tracking hormone levels in both sexes and the differentiation between sex differences and sex-related strategy in behaviors are explained. Finally, the lack of robust data on how biological sex influences the pharmacokinetic (PK), pharmacodynamic (PD), or toxicological effects of various preclinically administered drugs to animals due to the exclusion of female animals is discussed, and methodological strategies to enhance the rigor and translational relevance of preclinical research are proposed.

Back to the Future of Neuropsychopharmacology.

Disappointments in translating preclinical findings into clinical efficacy have triggered a number of changes in neuroscience drug discovery ranging from investments diverted to other therapeutic areas to reduced reliance on efficacy claims derived from preclinical models. In this chapter, we argue that there are several existing examples that teach us on what needs to be done to improve the success rate. We advocate the reverse engineering approach that shifts the focus from preclinical efforts to "model" human disease states to pharmacodynamic activity as a common denominator in the journey to translate clinically validated phenomena to preclinical level and then back to humans. Combined with the research rigor, openness, and transparency, this reverse engineering approach is well set to bring new effective and safe medications to patients in need.

A call for better understanding of target engagement in Tau antibody development.

Significant efforts have been channeled into developing antibodies for the treatment of CNS indications. Disappointment with the first generation of clinical Tau antibodies in Alzheimer's disease has highlighted the challenges in understanding whether an antibody can reach or affect the target in the compartment where it is involved in pathological processes. Here, we highlight different aspects essential for improving translatability of Tau-based immunotherapy.

PEERS - An Open Science "Platform for the Exchange of Experimental Research Standards" in Biomedicine.

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should have been considered a priori. To address this problem, we developed "PEERS" (Platform for the Exchange of Experimental Research Standards), an open-access online platform that is built to aid scientists in determining which experimental factors and variables are most likely to affect the outcome of a specific test, model or assay and therefore ought to be considered during the design, execution and reporting stages. The PEERS database is categorized into in vivo and in vitro experiments and provides lists of factors derived from scientific literature that have been deemed critical for experimentation. The platform is based on a structured and transparent system for rating the strength of evidence related to each identified factor and its relevance for a specific method/model. In this context, the rating procedure will not solely be limited to the PEERS working group but will also allow for a community-based grading of evidence. We here describe a working prototype using the Open Field paradigm in rodents and present the selection of factors specific to each experimental setup and the rating system. PEERS not only offers users the possibility to search for information to facilitate experimental rigor, but also draws on the engagement of the scientific community to actively expand the information contained within the platform. Collectively, by helping scientists search for specific factors relevant to their experiments, and to share experimental knowledge in a standardized manner, PEERS will serve as a collaborative exchange and analysis tool to enhance data validity and robustness as well as the reproducibility of preclinical research. PEERS offers a vetted, independent tool by which to judge the quality of information available on a certain test or model, identifies knowledge gaps and provides guidance on the key methodological considerations that should be prioritized to ensure that preclinical research is conducted to the highest standards and best practice.

Towards best practices in research: Role of academic core facilities.

Academic Core Facilities are optimally situated to improve the quality of preclinical research by implementing quality control measures and offering these to their users.

Introduction to the EQIPD quality system.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

Improving target assessment in biomedical research: the GOT-IT recommendations.

Academic research plays a key role in identifying new drug targets, including understanding target biology and links between targets and disease states. To lead to new drugs, however, research must progress from purely academic exploration to the initiation of efforts to identify and test a drug candidate in clinical trials, which are typically conducted by the biopharma industry. This transition can be facilitated by a timely focus on target assessment aspects such as target-related safety issues, druggability and assayability, as well as the potential for target modulation to achieve differentiation from established therapies. Here, we present recommendations from the GOT-IT working group, which have been designed to support academic scientists and funders of translational research in identifying and prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical development programmes. Based on sets of guiding questions for different areas of target assessment, the GOT-IT framework is intended to stimulate academic scientists' awareness of factors that make translational research more robust and efficient, and to facilitate academia-industry collaboration.

A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model?

INTRODUCTION: Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients. AREAS COVERED: We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent R&D challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns. EXPERT OPINION: Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Systematic review of guidelines for internal validity in the design, conduct and analysis of preclinical biomedical experiments involving laboratory animals.

Over the last two decades, awareness of the negative repercussions of flaws in the planning, conduct and reporting of preclinical research involving experimental animals has been growing. Several initiatives have set out to increase transparency and internal validity of preclinical studies, mostly publishing expert consensus and experience. While many of the points raised in these various guidelines are identical or similar, they differ in detail and rigour. Most of them focus on reporting, only few of them cover the planning and conduct of studies. The aim of this systematic review is to identify existing experimental design, conduct, analysis and reporting guidelines relating to preclinical animal research. A systematic search in PubMed, Embase and Web of Science retrieved 13 863 unique results. After screening these on title and abstract, 613 papers entered the full-text assessment stage, from which 60 papers were retained. From these, we extracted unique 58 recommendations on the planning, conduct and reporting of preclinical animal studies. Sample size calculations, adequate statistical methods, concealed and randomised allocation of animals to treatment, blinded outcome assessment and recording of animal flow through the experiment were recommended in more than half of the publications. While we consider these recommendations to be valuable, there is a striking lack of experimental evidence on their importance and relative effect on experiments and effect sizes.

Blinding and Randomization.

Most, if not all, guidelines, recommendations, and other texts on Good Research Practice emphasize the importance of blinding and randomization. There is, however, very limited specific guidance on when and how to apply blinding and randomization. This chapter aims to disambiguate these two terms by discussing what they mean, why they are applied, and how to conduct the acts of randomization and blinding. We discuss the use of blinding and randomization as the means against existing and potential risks of bias rather than a mandatory practice that is to be followed under all circumstances and at any cost. We argue that, in general, experiments should be blinded and randomized if (a) this is a confirmatory research that has a major impact on decision-making and that cannot be readily repeated (for ethical or resource-related reasons) and/or (b) no other measures can be applied to protect against existing and potential risks of bias.

Be positive about negatives-recommendations for the publication of negative (or null) results.

Both positive and negative (null or neutral) results are essential for the progress of science and its self-correcting nature. However, there is general reluctance to publish negative results, and this may be due a range of factors (e.g., the widely held perception that negative results are more difficult to publish, the preference to publish positive findings that are more likely to generate citations and funding for additional research). It is particularly challenging to disclose negative results that are not consistent with previously published positive data, especially if the initial publication appeared in a high impact journal. Ideally, there should be both incentives and support to reduce the costs associated with investing efforts into preparing publications with negative results. We describe here a set of criteria that can help scientists, reviewers and editors to publish technically sound, scientifically high-impact negative (or null) results originating from rigorously designed and executed studies. Proposed criteria emphasize the importance of collaborative efforts and communication among scientists (also including the authors of original publications with positive results).

Improving transparency and scientific rigor in academic publishing.

Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories. SIGNIFICANCE: Failure to replicate research findings often arises from errors in the experimental design and statistical approaches. By providing a full account of the experimental design, procedures, and statistical approaches, researchers can address the reproducibility crisis and improve the sustainability of research outcomes. In this piece, we discuss the key issues leading to irreproducibility and provide general approaches to improving transparency and rigor in reporting, which could assist in making research more reproducible.

Activation of trace amine-associated receptor 1 attenuates schedule-induced polydipsia in rats.

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.

Improving transparency and scientific rigor in academic publishing.

Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories.

Improving transparency and scientific rigor in academic publishing.

Progress in basic and clinical research is slowed when researchers fail to provide a complete and accurate report of how a study was designed, executed, and the results analyzed. Publishing rigorous scientific research involves a full description of the methods, materials, procedures, and outcomes. Investigators may fail to provide a complete description of how their study was designed and executed because they may not know how to accurately report the information or the mechanisms are not in place to facilitate transparent reporting. Here, we provide an overview of how authors can write manuscripts in a transparent and thorough manner. We introduce a set of reporting criteria that can be used for publishing, including recommendations on reporting the experimental design and statistical approaches. We also discuss how to accurately visualize the results and provide recommendations for peer reviewers to enhance rigor and transparency. Incorporating transparency practices into research manuscripts will significantly improve the reproducibility of the results by independent laboratories.