Linkage Strategies Research Articles

Abstract 2514: Towards homogenous adcs: A new site-specific antibody conjugation using bacterial transglutaminase (btg-adc)

Abstract Purpose : Bacterial Transglutaminase (BTG) allows coupling on endogenous Q295 from an aglycosylated antibody. Here, the work relates to ADCs synthesis through BTG approach on mAbs with single point mutations and the study of stability, pharmacokinetics, as well as in vitro and in vivo efficacy of resulting BTG-ADCs. AdcetriS®, brentuximab vedotin, has been used as comparator, hence for consistency BTG-ADCs have been conjugated with the different linkage strategies (one step and two step) containing distally the same protease sensitive moiety compared to ADCETRIS®, i.e. valine-citrulline-PAB-MMAE. Methods : . For synthesis, a two-step process has been designed consisting of coupling first a linker and coming back with a toxin, and affording versatility and efficiency. The DAR stability was monitored over one week in human and cynomolgus plasma by affinity capture/LC/MS. The pharmacokinetic profile was studied in rat and monitored by affinity capture/LC/MS for conjugated antibody and ELISA for total antibody. In vitro efficacy of ADCs conjugated using BTG was compared side-by-side with ADCETRIS® on Karpas 299 cells. In vivo efficacy was studied in xenogenic nude mice engrafted with Karpas 299 in SC with BTG ADCs or ADCETRIS at doses of 0.6mg/kg. Results: BTG two-step process leads to ADCs with DAR of exactly 2.0 or 4.0 for antibodies with N297S or N297Q single point mutation respectively. The BTG ADCs were stable in human and cynomolgus plasma, with no degradation observed over 15 days in rats and furthermore with favorable total antibody clearance. In vitro efficacy for BTG ADCs DAR=4.0 was comparable to ADCETRIS (mean DAR=4) with respect to EC50 and plateau. In vivo efficacy for BTG ADC was demonstrated to be at least equivalent to ADCETRIS®. Conclusions: Pre-clinical proof of concept is demonstrated for BTG coupling. When considering versatility, speed and efficiency of the process, BTG-ADC coupling should provide a promising technology for the next generation of homogeneous ADCs. Citation Format: Florence Lhospice, Delphine Bregeon, Christian Belmant, Agnes Represa, Angelique Boedec, Yannis Morel, Patrick Dennler, Roger Schibli, François Romagne. Towards homogenous adcs: A new site-specific antibody conjugation using bacterial transglutaminase (btg-adc). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2514. doi:10.1158/1538-7445.AM2014-2514

Optimal strategy for linkage of datasets containing a statistical linkage key and datasets with full personal identifiers.

BackgroundLinkage of aged care and hospitalisation data provides valuable information on patterns of health service utilisation among aged care service recipients. Many aged care datasets in Australia contain a Statistical Linkage Key (SLK-581) instead of full personal identifiers. We linked hospital and death records using a full probabilistic strategy, the SLK-581, and three combined strategies; and compared results for each strategy.MethodsLinkage of Admitted Patient Data for 2000–01 to 2008–09 and Registry of Births, Deaths and Marriages death registration data for 2008–09 for New South Wales, Australia, was carried out using probabilistic methods and compared to links created using four strategies incorporating a SLK-581. The Basic SLK-581 strategy used the SLK-581 alone. The Most Recent SLK-581, Most Frequent SLK-581, and Any Match SLK-581 strategies leveraged probabilistic links between hospital records drawn from the Centre for Health Record Linkage Master Linkage Key. Rates of hospitalisations among people who died were calculated for each strategy and a range of health conditions.ResultsCompared to full probabilistic linkage, the basic SLK-581 strategy produced substantial rates of missed links that increased over the study period and produced underestimates of hospitalisation rates that varied by health condition. The Most Recent SLK-581, Most Frequent SLK-581, and Any Match SLK-581 strategies resulted in substantially lower rates of underestimation than the Basic SLK-581. The Any Match SLK-581 strategy gave results closest to full probabilistic linkage.ConclusionsHospitalisation rates prior to death are substantially underestimated by linkage using a SLK-581 alone. Linkage rates can be increased by combining deterministic methods with probabilistically created links across hospital records.

Big data in medicine is driving big changes.

To summarise current research that takes advantage of "Big Data" in health and biomedical informatics applications. Survey of trends in this work, and exploration of literature describing how large-scale structured and unstructured data sources are being used to support applications from clinical decision making and health policy, to drug design and pharmacovigilance, and further to systems biology and genetics. The survey highlights ongoing development of powerful new methods for turning that large-scale, and often complex, data into information that provides new insights into human health, in a range of different areas. Consideration of this body of work identifies several important paradigm shifts that are facilitated by Big Data resources and methods: in clinical and translational research, from hypothesis-driven research to data-driven research, and in medicine, from evidence-based practice to practice-based evidence. The increasing scale and availability of large quantities of health data require strategies for data management, data linkage, and data integration beyond the limits of many existing information systems, and substantial effort is underway to meet those needs. As our ability to make sense of that data improves, the value of the data will continue to increase. Health systems, genetics and genomics, population and public health; all areas of biomedicine stand to benefit from Big Data and the associated technologies.

Controlling Urban Sprawl with Integrated Approach of Space-transport Development Strategies

Urban sprawl phenomenon has been a huge issue since 20th century characterized by a rapid and unbalanced settlement development with transportation network particularly in a suburban area. The improvement of public transport system is a major requirement to minimize urban sprawl. Academic researchers have explained the linkage strategy between transportation network and urban planning. However, insufficient empirical verification has been made to control this phenomenon by using the integrated approach of space-transport development. This paper focuses on analyzing the improvement of public transport supply incorporated with settlement development. The improvement of public transport (PT) is designed by planning Mass Rapid Transit (MRT), Light Rapid Transit (LRT), and Bus Rapid Transit (BRT) systems. The impact of PT improvement has affected on the settlement development. Setting balance between employment and population density is designed as alternative of urban spatial strategy. These approaches are necessary in order to analyze and evaluate the many alternatives to overcome this situation. The result reveals that the requirement to integrate the space-transport development strategy in order to control the settlement development in the suburb has to be done to reduce 10% of travel time and to increase double the usage possibility to public transport mode. The strategies should be done in the further research with considering on impact assessment and the residents preferences intended to determine the preferred and strategic option for them.

Diethanolamine-modified magnetic fluorescent Fe3O4@ZnS nanoparticles for ultrasensitive detection and removal of Cu2+.

Currently, growing attention has been paid to the sensitive determination and removal of Cu2+ because excessive levels of Cu2+ could do harm to organisms. Herein, a novel diethanolamine-modified magnetic fluorescent Fe3O4@ZnS nanoparticle (MFNP) for simultaneous detection and removal of Cu2+ was designed and synthesized through dithiocarbamate linkage strategy. The characterization of MFNP was confirmed by transmission electron microscope (TEM), infrared (IR) and emission spectra. The results showed that MFNP could quantificationally detect Cu2+ with high sensitivity and selectivity under a broad pH range (pH 4.5-9). The removal of Cu2+ was achieved by the aggregation-induced sedimentation (AIS) strategy and by external magnetic field.

Retention of antiretroviral naïve patients registered in HIV care in a program clinic in Pune, India

Background:Retention in HIV care ensures delivery of services like secondary prevention, timely initiation of treatment, support, and care on a regular basis. The data on retention in pre antiretroviral therapy (ART) care in India is scanty.Materials and Methods:Antiretroviral naïve HIV-infected adult patients registered between January 2011 and March 2012 in HIV care (pre-ART) were included in the study. The follow-up procedures were done as per the national guidelines. Patients who did not report to the clinic for 1 year were considered as pre-ART lost to follow-up (pre-ART LFU). They were contacted either telephonically or by home visits. Logistic regression analysis was done to find out factors associated with pre-ART loss to follow-up.Results:A total of 689 antiretroviral naïve adult patients were registered in the HIV care. Fourteen (2%) patients died and 76 (11%) were LFU till March 2013. The multivariate analysis showed that baseline CD4 count >350 cells/mm3 (P < 0.01) and illiteracy (P = 0.044) were significantly associated with LFU. Of the total pre-ART LFUs, 35 (46.1%) informed that they would visit the clinic at their convenient time. NGOs that referred 16 female sex workers (FSWs) who were LFU (21.1%) informed that they would make efforts to refer them to the clinic.Conclusion:Higher CD4 count and illiteracy were significantly associated with lower retention in pre-ART care. Developing effective “retention package” for patients and strengthening linkage strategies between key sub-population such as FSWs and ART programming will help to plug the leaky cascade in HIV care.

Retention of antiretroviral naïve patients registered in HIV care in a program clinic in Pune, India.

Retention in HIV care ensures delivery of services like secondary prevention, timely initiation of treatment, support, and care on a regular basis. The data on retention in pre antiretroviral therapy (ART) care in India is scanty. Antiretroviral naïve HIV-infected adult patients registered between January 2011 and March 2012 in HIV care (pre-ART) were included in the study. The follow-up procedures were done as per the national guidelines. Patients who did not report to the clinic for 1 year were considered as pre-ART lost to follow-up (pre-ART LFU). They were contacted either telephonically or by home visits. Logistic regression analysis was done to find out factors associated with pre-ART loss to follow-up. A total of 689 antiretroviral naïve adult patients were registered in the HIV care. Fourteen (2%) patients died and 76 (11%) were LFU till March 2013. The multivariate analysis showed that baseline CD4 count >350 cells/mm(3) (P < 0.01) and illiteracy (P = 0.044) were significantly associated with LFU. Of the total pre-ART LFUs, 35 (46.1%) informed that they would visit the clinic at their convenient time. NGOs that referred 16 female sex workers (FSWs) who were LFU (21.1%) informed that they would make efforts to refer them to the clinic. Higher CD4 count and illiteracy were significantly associated with lower retention in pre-ART care. Developing effective "retention package" for patients and strengthening linkage strategies between key sub-population such as FSWs and ART programming will help to plug the leaky cascade in HIV care.

Development of a novel water-soluble magnetic fluorescent nanoparticle for the selective detection and removal of Cu2+

Recently, much attention has been paid to the selective detection and removal of Cu2+ because an excess of Cu2+ can harm the environment and living systems. Herein, we developed a novel water-soluble di-2-picolylamine/proline co-modified Fe3O4@ZnS magnetic fluorescent nanoparticle (MFNP-Cu) for the selective detection and removal of Cu2+ through a dithiocarbamate linkage strategy. The characterization of MFNP-Cu was confirmed by x-ray diffraction (XRD), transmission electron microscope (TEM), magnetization hysteresis loops, infrared (IR) and emission spectra. The results showed that MFNP-Cu could quantifiably detect Cu2+ with high sensitivity and selectivity over a broad pH range (pH 4.1–9). The maximum adsorption capacity of MFNP-Cu was calculated to be about 517.9 mg g−1, which is higher than previously reported. This excellent property was investigated by kinetics equilibrium and thermodynamic studies. Moreover, the removal properties of MFNP-Cu toward Cu2+ from contaminated water samples was achieved by an external magnetic field.

Enter the Matrix: Building Creative Industry through Delivering Insights in Comics

Comic is a media which delivers its content through visual sequence. This media has negative preference in Indonesia’s community because viewed as mild entertainment for children. Yet in modern society, comics observed and researched as one of media which could penetrate deep within its reader’s mind. In re-create cultural insight through comic, the content must encrypt into visual and sequential mode which form a matrix of insight. This matrix will encompasses the effective transformation of cultural content in comic and also other visual media through media linkage strategy. The media linkage strategy is to surround the children’s access of information and visual entertainment in order to build certain knowledge and understanding. It’s a system that crystallized from global marketing practices of visual media industry over decades. This paper urges to highlight the visual communication design study in creating a matrix of cultural insight in translating cultures of Archipelago and media linkage strategy in order to strengthen cultural understanding among children.

Consistency in crime site selection: An investigation of crime sites used by serial sex offenders across crime series

PurposeKnowing sites used by serial sex offenders to commit their crimes is highly beneficial for criminal investigations. However, environmental choices of serial sex offenders remain unclear to this date. Considering the challenges these offenders pose to law enforcement, the study aims to identify sites serial sex offenders use to encounter and release their victims and investigate their stability across crime series. MethodsThe study uses latent class analysis (LCA) to identify victim encounter and release sites used by 72 serial sex offenders having committed 361 sex offenses. Additional LCA are performed to investigate the stability of these offense environments across offenders' crimes series. ResultsDistinct profiles of crime sites that are recurrent across crime series are found, suggesting that serial sex offenders present a limited diversity of victim encounter and victim release sites. Encounter sites representative of longer crime series are also identified. Specifically, the use of sites known to "attract" potential victims decreases over series and offenders become more risk-taking in regard of sites used to encounter their victims. ConclusionsThe study identifies patterns of site- selection for the victim encounter and release in cases of serial crimes. Implications for crime linkage and police investigations strategies are discussed.

Taiwan schizophrenia linkage study: Lessons learned from endophenotype‐based genome‐wide linkage scans and perspective

Taiwan Schizophrenia Linkage Study (TSLS) was initiated with a linkage strategy for locating multiple genes, each of small to moderate effect, and aimed to recruit a large enough sample of pairs of affected siblings and their families ascertained from a multisite study. With a sample of 607 families successfully recruited, a total of 2,242 individuals (1,207 affected and 1,035 unaffected) from 557 families were genotyped using 386 microsatellite markers spaced at an average of 9-cM intervals. Here the author reviews the establishment of TSLS and initial signal derived from linkage scan using the diagnosis of schizophrenia. Based on the limited success of the initial linkage analysis, a sufficient-component causal model is proposed to incorporate endophenotypes and genes for schizophrenia. Four types of candidate endophenotype measured in TSLS, including schizotypal personality, Continuous Performance Test, Wisconsin Card Sorting Test, and niacin skin flush test, are briefly described. The author discusses different strategies of linkage analysis incorporating these endophenotypes, including quantitative trait loci (QTL) linkage analysis, clustering-derived subgroups, ordered subset analysis (OSA), and latent classes for linkage scan. Then the author summarizes the linkage signals generated from seven studies of endophenotype-based linkage analysis using TSLS, including QTL scan of neurocognitive performance, QTL scan of niacin skin flush, the family cluster of attention deficit and execution deficit, OSA by schizophrenia-schizotypy factors, nested OSA by age at onset and neurocognitive performance, and the latent class of deficit schizophrenia for linkage analysis. The perspective of combining next-generation sequencing with linkage analysis of families is also discussed.

TPM, PAC 활동에서 생산성지표와 재무회계 지표의 연계방안 전략

This paper proposes a strategic model of linkage between productivity metrics and financial accounting metrics to properly evaluate the financial effect of TPM activities and the business performance. This linkage strategy provides a connection tool for clear communication between factory-level and headquarters that the metrics proposed by this paper ultimately improves a quality of support from the management by receiving the factors required for productivity activities in the practical field. This factor includes such as equipment, raw materials and labors. Here, we propose that chain reaction models using break down structure of productivity metrics and financial metrics enhance the knowledge sharing of KPI (Key Performance Indicator) which generally tend to create oversimplified communication between management in headquarters and employees in the practical fields. The productivity metrics include OEE(Overall Equipment Effectiveness) of TPM (Total Productive Maintenance), OLE (Overall Labor Effectiveness) of PAC(Performance and Analysis and Control) activities, and OYE (Overall Yield Effectiveness) of TMM(Total Material Management) activities. The financial accounting metrics include ROE(Return on Equity), ROA(Return on Asset), and AVR(Added-Value Rate). The suggested chain reaction model selects the financial metrics as initial stage and branch down until final stage of productivity metrics. When demand exceeds supply, an ideal speed rate, the lean OEE strategy can be initially applied to reduce the gap between the demand and supply, then apply variable costing to estimate correct amount of operating profit. In addition, the paper presents a new type of model for linkage between financial accounting metrics including CAPEX(Capital Expenditure), OPEX(Operating Expenditure), EVA(Economic Added Value), DCL(Degree of Combined Leverage), and TPM productivity activities including AM(Autonomous Maintenance), PM(Preventive Maintenance), MP(Maintenance Prevention) and QM(Quality Maintenance). In order to support the evidence of proposed linkage strategy, a case analysis on 52 projects from national TPM contest from 2011 to 2012 is analyzed. The case presents the classification of CAPEX and OPEX activities from TPM, and proposes the correct implementation of financial effect for TPM projects.

Characterizing the relationship between in‐hospital measures and workers' compensation outcomes among severely injured construction workers using a data linkage strategy

To characterize the relationship between acute measures of severity and three important workers' compensation outcomes associated with a worker's ability to return to work and the cost of a work-related injury. Probabilistic data linkage of workers' compensation claims made by injured construction workers from 2000 to 2005 with two Illinois medical record registries. Multivariable robust regression models were built to assess the relationship between three in-hospital measures and three outcomes captured in the Workers' Compensation data. In the final multivariable models, a categorical increase in injury severity was associated with an extra $7,830 (95% CI: $4,729-$10,930) of monetary compensation awarded, though not with temporary total disability (TTD) or permanent partial disability (PPD). Our models also predicted that every extra day spent in the hospital results in an increase of 0.51 (95% CI: 0.23-0.80) weeks of TTD and an extra $1,248 (95% CI: $810-$1,686) in monetary compensation. Discharge to an intermediate care facility following the initial hospitalization was associated with an increase of 8.15 (95% CI: 4.03-12.28) weeks of TTD and an increase of $23,440 (95% CI: $17,033-$29,847) in monetary compensation. We were able to link data from the initial hospitalization for an injured worker with the final workers' compensation claims decision or settlement. The in-hospital measures of injury severity were associated with total monetary compensation as captured in the workers' compensation process.

Study design elements for rigorous quasi-experimental comparative effectiveness research

Quasi-experiments are likely to be the workhorse study design used to generate evidence about the comparative effectiveness of alternative treatments, because of their feasibility, timeliness, affordability and external validity compared with randomized trials. In this review, we outline potential sources of discordance in results between quasi-experiments and experiments, review study design choices that can improve the internal validity of quasi-experiments, and outline innovative data linkage strategies that may be particularly useful in quasi-experimental comparative effectiveness research. There is an urgent need to resolve the debate about the evidentiary value of quasi-experiments since equal consideration of rigorous quasi-experiments will broaden the base of evidence that can be brought to bear in clinical decision-making and governmental policy-making.

The Radical Left's Turn towards Civil Society in Greece: One Strategy, Two Paths

The Communist Party of Greece (KKE) and the Coalition of the Radical Left (SYRIZA) made remarkable ‘turns towards civil society’ over the last decade. It is argued that this was primarily a response aimed at strengthening their social legitimacy, which had reached its lowest point in the early 1990s. Differences in the way the two parties attempted to stabilise and engage their membership and re-establish links to trade unions and new social movements can be attributed to their distinct ideological and organisational legacies. Despite those differences, their respective linkage strategies were both successful until the game-changing 2012 Greek national elections, which brought about the remarkable rise of SYRIZA and the electoral demise of the KKE.

Rediscovering Civil Society? Renewal and Continuity in the Portuguese Radical Left

The importance of party organisational models to party-civil-society relations has been substantially overlooked in the scholarly literature. Drawing on the Portuguese case, this study examines to what extent radical left parties have established different links with civil society, namely by allying with social movements and trade unions. Our findings confirm that party organisational models significantly shape the relationship between the radical left and civil society. However, external challenges and internal pressures increase the influence of party leadership in determining linkage strategies. Finally, the impact of the recent economic and financial crisis has been limited, especially in terms of programmatic and organisational renewal.

‘Zippin’ up My Boots, Goin’ Back to My Roots': Radical Left Parties in Southern Europe

Radical left parties actively encourage the participation of their members in internal decision-making and insist on promoting organised links to trade unions and social movements. As a party family, they deviate from what is considered to be the trend in which Western political parties have turned their backs on their social roots. Drawing on the experience of South European radical left parties from the fall of the Berlin Wall until the recent financial crisis, we argue that ideology, electoral incentives, party competition and external events explain the radical left's pronounced emphasis on linkage, while organisational trajectory explains variation within the party family in terms of the linkage strategies pursued.

Perron vector optimization applied to search engines

In the last years, Googleʼs PageRank optimization problems have been extensively studied. In that case, the ranking is given by the invariant measure of a stochastic matrix. In this paper, we consider the more general situation in which the ranking is determined by the Perron eigenvector of a nonnegative, but not necessarily stochastic, matrix, in order to cover Kleinbergʼs HITS algorithm. We also give some results for Tomlinʼs HOTS algorithm. The problem consists then in finding an optimal outlink strategy subject to design constraints and for a given search engine.We study the relaxed versions of these problems, which means that we should accept weighted hyperlinks. We provide an efficient algorithm for the computation of the matrix of partial derivatives of the criterion, that uses the low rank property of this matrix. We give a scalable algorithm that couples gradient and power iterations and gives a local minimum of the Perron vector optimization problem. We prove convergence by considering it as an approximate gradient method.We then show that optimal linkage strategies of HITS and HOTS optimization problems satisfy a threshold property. We report numerical results on fragments of the real web graph for these search engine optimization problems.

Overweight condition and waist circumference and a candidate gene within the 12q24 locus

AimsObesity and obesity-associated phenotypes are linked to the chromosome12q24 locus, the non-insulin-dependent-diabetes 2 (NIDDM2) locus. The gene of proteasome modulator 9 (PSMD9) lies in the NIDDM2 region and is linked to type 2 diabetes (T2D), microvascular and macrovascular complications of T2D.We aimed at studying whether the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3+nt460, IVS3+nt437, and 197G are linked to obesity, overweight status and waist circumference in Italian T2D families.Methods and resultsWe screened 200 Italians T2D siblings/families for PSMD9 variants. Using Merlin software, we performed non-parametric linkage analysis to test for linkage with obesity and overweight condition and variance component analysis to test for linkage with waist circumference in our T2D siblings/families dataset.Our study shows that the PSMD9 SNPs IVS3+nt460, IVS3+nt437, and 197G are in linkage with overweight condition and waist circumference in Italians. The statistical power tests performed via simulations on real data confirm that the results are not due to random chance.ConclusionsIn summary, the linkage strategy using a homogeneous family/subject dataset can identify a gene contributing to a complex trait. PMSD9 may be at least one of the genes responsible for the linkage to obesity and obesity-associated phenotypes at the locus 12q24 in other populations.

Analysis of Agglomerative Clustering

The diameter $k$-clustering problem is the problem of partitioning a finite subset of $\mathbb{R}^d$ into $k$ subsets called clusters such that the maximum diameter of the clusters is minimized. One early clustering algorithm that computes a hierarchy of approximate solutions to this problem (for all values of $k$) is the agglomerative clustering algorithm with the complete linkage strategy. For decades, this algorithm has been widely used by practitioners. However, it is not well studied theoretically. In this paper, we analyze the agglomerative complete linkage clustering algorithm. Assuming that the dimension $d$ is a constant, we show that for any $k$ the solution computed by this algorithm is an $O(\log k)$-approximation to the diameter $k$-clustering problem. Our analysis does not only hold for the Euclidean distance but for any metric that is based on a norm. Furthermore, we analyze the closely related $k$-center and discrete $k$-center problem. For the corresponding agglomerative algorithms, we deduce an approximation factor of $O(\log k)$ as well.