Engineering for a science-centric experimentation platform

Netflix is an internet entertainment service that routinely employs experimentation to guide strategy around product innovations. As Netflix grew, it had the opportunity to explore increasingly specialized improvements to its service, which generated demand for deeper analyses supported by richer metrics and powered by more diverse statistical methodologies. To facilitate this, and more fully harness the skill sets of both engineering and data science, Netflix engineers created a science-centric experimentation platform that leverages the expertise of scientists from a wide range of backgrounds working on data science tasks by allowing them to make direct code contributions in the languages used by them (Python and R). Moreover, the same code that runs in production is able to be run locally, making it straightforward to explore and graduate both metrics and causal inference methodologies directly into production services. In this paper, we provide two main contributions. Firstly, we report on the architecture of this platform, with a special emphasis on its novel aspects: how it supports science-centric end-to-end workflows without compromising engineering requirements. Secondly, we describe its approach to causal inference, which leverages the potential outcomes conceptual framework to provide a unified abstarction layer for arbitrary statistical models and methodologies

Engineering for a Science-Centric Experimentation Platform

Netflix is an internet entertainment service that routinely employs experimentation to guide strategy around product innovations. As Netflix grew, it had the opportunity to explore increasingly specialized improvements to its service, which generated demand for deeper analyses supported by richer metrics and powered by more diverse statistical methodologies. To facilitate this, and more fully harness the skill sets of both engineering and data science, Netflix engineers created a science-centric experimentation platform that leverages the expertise of data scientists from a wide range of backgrounds by allowing them to make direct code contributions in the languages used by scientists (Python and R). Moreover, the same code that runs in production is able to be run locally, making it straightforward to explore and graduate both metrics and causal inference methodologies directly into production services. In this paper, we utilize a case-study research method to provide two main contributions. Firstly, we report on the architecture of this platform, with a special emphasis on its novel aspects: how it supports science-centric end-to-end workflows without compromising engineering requirements. Secondly, we describe its approach to causal inference, which leverages the potential outcomes conceptual framework to provide a unified abstraction layer for arbitrary statistical models and methodologies.Comment: 10 page

It takes three to tango: The length of the oligothiophene chain determines the nature of the long‐lived excited state and the resulting photocytotoxicity of a ruthenium(II) Photodrug

Abstract TLD1433 is the first Ru(II) complex to be tested as a photodynamic therapy agent in a clinical trial. In this contribution we study TLD1433 in the context of structurally‐related Ru(II)‐imidozo[4,5‐f][1,10]phenanthroline (ip) complexes appended with thiophene rings to decipher the unique photophysical properties which are associated with increasing oligothiophene chain length. Substitution of the ip ligand with ter‐ or quaterthiophene changes the nature of the long‐lived triplet state from metal‐to‐ligand charge‐transfer to 3 ππ* character. The addition of the third thiophene thus presents a critical juncture which not only determines the photophysics of the complex but most importantly its capacity for 1 O 2 generation and hence the potential of the complex to be used as a photocytotoxic agent

Systems maps and analytical framework. Mapping food waste drivers across the food supply chain

This report generated 17 systems maps for five contrasting product types that were investigated along their supply chains. The system maps identify: (1) Product specific drivers: drivers specific to the selected food products at a specific stage of the supply chain); (2) Generic drivers: drivers which concern two or more selected products (e.g. labelling errors, limited shelf life etc.); (3) Systemic drivers: drivers that are interlinked with more than one step of the supply chain (e.g. minimum orders, last minute cancellation, lack of data and communication, minimum life on receipt criteria etc.). The cross cutting systemic drivers emphasized supply chain issues, e.g. regarding notably the interactions between the different businesses and unfair trading practices. The systems map approach also shed light on two key factors that impact drivers according to the product specificity: (1) Impacts of food waste drivers highly depend on the level of perishability and microbiological risk of food products. For example, less perishable food products such as frozen and canned products are more likely to be wasted because of product damage, labelling errors and/or equipment breakdown. More perishable and higher risk food products are more likely to be wasted when approaching the \u201cbest before\u201d date or because of supply and demand imbalances and poor information sharing along the supply chain. (2) Lack of communication and cooperation is a central drivers of food waste. The impacts of these are higher in more complex products/supply chains where trouble with one ingredient affects the whole product (e.g. prepared meals). Finally, the systems mapping shed light on drivers which were \u201chiding\u201d behind other drivers. For example, the question of date labelling is a well-known cause of waste for perishable products, but very often there are further drivers behind it (e.g. overstocking in the retail sector)

Intracellular Photophysics of an Osmium Complex bearing an Oligothiophene Extended Ligand

This contribution describes the excited-state properties of an Osmium-complex when taken up into human cells. The complex 1 [Os(bpy)2(IP-4T)](PF6)2 with bpy=2,2′-bipyridine and IP-4T=2-{5′-[3′,4′-diethyl-(2,2′-bithien-5-yl)]-3,4-diethyl-2,2′-bithiophene}imidazo[4,5-f][1,10]phenanthroline) can be discussed as a candidate for photodynamic therapy in the biological red/NIR window. The complex is taken up by MCF7 cells and localizes rather homogeneously within in the cytoplasm. To detail the sub-ns photophysics of 1, comparative transient absorption measurements were carried out in different solvents to derive a model of the photoinduced processes. Key to rationalize the excited-state relaxation is a long-lived 3ILCT state associated with the oligothiophene chain. This model was then tested with the complex internalized into MCF7 cells, since the intracellular environment has long been suspected to take big influence on the excited state properties. In our study of 1 in cells, we were able to show that, though the overall model remained the same, the excited-state dynamics are affected strongly by the intracellular environment. Our study represents the first in depth correlation towards ex-vivo and in vivo ultrafast spectroscopy for a possible photodrug. © 2020 The Authors. Published by Wiley-VCH Gmb

The cost of mapping trachoma: Data from the Global Trachoma Mapping Project.

BACKGROUND: The Global Trachoma Mapping Project (GTMP) was implemented with the aim of completing the baseline map of trachoma globally. Over 2.6 million people were examined in 1,546 districts across 29 countries between December 2012 and January 2016. The aim of the analysis was to estimate the unit cost and to identify the key cost drivers of trachoma prevalence surveys conducted as part of GTMP. METHODOLOGY AND PRINCIPAL FINDINGS: In-country and global support costs were obtained using GTMP financial records. In-country expenditure was analysed for 1,164 districts across 17 countries. The mean survey cost was $13,113 per district [median:$11,675; IQR = $8,365-$14,618], $17,566 per evaluation unit [median:$15,839; IQR = $10,773-$19,915], $692 per cluster [median:$625; IQR = $452-$847] and $6.0 per person screened [median:$4.9; IQR = $3.7-$7.9]. Survey unit costs varied substantially across settings, and were driven by parameters such as geographic location, demographic characteristics, seasonal effects, and local operational constraints. Analysis by activities showed that fieldwork constituted the largest share of in-country survey costs (74%), followed by training of survey teams (11%). The main drivers of in-country survey costs were personnel (49%) and transportation (44%). Global support expenditure for all surveyed districts amounted to $5.1m, which included grant management, epidemiological support, and data stewardship. CONCLUSION: This study provides the most extensive analysis of the cost of conducting trachoma prevalence surveys to date. The findings can aid planning and budgeting for future trachoma surveys required to measure the impact of trachoma elimination activities. Furthermore, the results of this study can also be used as a cost basis for other disease mapping programmes, where disease or context-specific survey cost data are not available

The genotypic and phenotypic spectrum of MTO1 deficiency.

BACKGROUND: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). MATERIAL AND METHODS: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. RESULTS: For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. CONCLUSION: MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists

Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2

We have used whole exome sequencing to identify biallelic missense mutations in the nuclearencoded mitochondrial inorganic pyrophosphatase (PPA2) in ten individuals from four unrelated pedigrees that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis and cardiac arrhythmia and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutated PPA2 containing mitochondria from fibroblasts showed the activity of inorganic pyrophosphatase significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations, and suggest that PPA2 is a new cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice.

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive