Automatic extraction of biomolecular interactions: an empirical approach Background: We describe a method for extracting data about how biomolecule pairs interact from texts. This method relies on empirically determined characteristics of sentences. The characteristics are efficient to compute, making this approach to extraction of biomolecular interactions scalable. The results of such interaction mining can support interaction network annotation, question answering, database construction, and other applications. Results: We constructed a software system to search MEDLINE for sentences likely to describe interactions between given biomolecules. The system extracts a list of the interaction-indicating terms appearing in those sentences, then ranks those terms based on their likelihood of correctly characterizing how the biomolecules interact. The ranking process uses a tf-idf (term frequency-inverse document frequency) based technique using empirically derived knowledge about sentences, and was applied to the MEDLINE literature collection. Software was developed as part of the MetNet toolkit (http://www.metnetdb.org). Conclusions: Specific, efficiently computable characteristics of sentences about biomolecular interactions were analyzed to better understand how to use these characteristics to extract how biomolecules interact. The text empirics method that was investigated, though arising from a classical tradition, has yet to be fully explored for the task of extracting biomolecular interactions from the literature. The conclusions we reach about the sentence characteristics investigated in this work, as well as the technique itself, could be used by other systems to provide evidence about putative interactions, thus supporting efforts to maximize the ability of hybrid systems to support such tasks as annotating and constructing interaction networks. We have described a text empirics approach to mining the biomedical literature for interactionindicating terms that describe how biomolecule pairs interact. This approach relies on statistical evidence provided by efficiently computable text passage characteristics.. IIT stems that tri-occurred with a given biomolecule pair in a sentence were ranked based on their calculated likelihoods of correctly describing how the biomolecules interact. The precisions of the ranked IIT stem lists returned by the system were at a useful level when the returned lists contained at least one correct IIT. Importantly, while the text empirics approach, like various other techniques, can be applied alone it also has the potential to complement other techniques by being used in conjunction with them. This can improve performance compared to a single technique used alone [28, 58] , in turn highlighting the importance to the field of investigating the wide space of possible techniques rather than focusing overwhelmingly on finding a single best technique, a task made more challenging in any case because of the difficulty of reliably comparing different PPI extraction methods [26] .. As one of many possible ways to combine techniques, template matching and text empirics could be merged in a single system by using empirically derived statistics on the semantics of passages that match a given template compared to the semantics of passages that do not match. Another possibility is to use evidence provided by text empirics to adjust quantitative conclusions about the meanings of passages returned by SVMs on parsed graphs. Alternatively, as in Liu et al. [22] , a useful kernel matching function could be defined and then used as a feature, the effectiveness of which would be determined empirically, analogously to the empirical attributes we have discussed in depth in the present work.. The general approach of text empirics we have described could be readily applied in other domains. For example we are currently applying it to extracting neurodevelopmental and ocular development event times from texts. Also the specific empirically determined statistical results described above could be directly applied by others working on protein-protein interaction (PPI) or other biomolecular interaction extraction problems. Figure 6 Interaction between a chemical and a process. It is instructive to compare the text empirics approach used here with template matching. Existing work focusing on IIT extraction has often used template matching to return a conclusion like "A activates B." Templates however are inherently restrictive in that some passages will not match any template in a template set. This "falling through the cracks" phenomenon tends to reduce recall.. To help compare template matching and text empirics, it is useful to note the close connection between the two techniques. Whether a passage matches a template is a passage characteristic, and thus can be used as evidence in eq. (4) like other passage characteristics investigated in this report. Thus template sets are well suited to be used as text passage attributes within a text empirics framework. Viewed this way, it is not surprising that some passage characteristics we have considered are somewhat template-like in character. An example is the pattern "a sentence with two biomolecules for which the intervening words contain an IIT.". Since templates are a subset of the passage characteristics that the text empirics approach can consider, text empirics in general must logically have the potential for higher recall than the template-based approach by itself. Additionally, since an evidence combination strategy like eq. (4) makes incorporating new sources of evidence straightforward, conclusions produced by other techniques can readily be used to improve results. More than 30 million sentences in which at least one biomolecule in our lexicon appeared were extracted from MEDLINE and stored in MetNetDB. More than 8 million of these contained at least one tri-occurrence consisting of a biomolecule pair and an IIT. Earlier analysis showed that most biomolecule name co-occurrences take part in tri-occurrences with IIT(s), but less than 22% of trioccurrences actually describe an interaction. Appendix A in Additional file 1 provides details.. To evaluate our method of ranking the IITs associated with a given biomolecule pair, we randomly chose 200 pairs of biomolecule terms listed in MetNetDB and found by PathBinder to co-occur in sentences of MEDLINE records. Of these, 106 of the biomolecule pairs were both (a) in tri-occurrences, and (b) judged by biologists to actually interact. A test set was then defined, based on: those 106 pairs; all the sentences in MEDLINE in which the pairs co-occurred; and, for each sentence, the different IIT stems it contained, resulting in 1,768 IIT stem occurrences across all the sentences. This test data was used to evaluate how well correct IIT stems could be identified using their rankings. This task was made more challenging by the following factors: (i) numerous sentences typically exist for a given biomolecule pair, (ii)many of these sentences contain other biomolecule names as well as multiple IITs, and (iii)different sentences can describe the same interacting pair using different IIT stems.. For example, one biomolecule pair was 'chlordecone' and 'cytochrome P450.' Pathbinder returned the ranked list of IIT stems shown in Table 5 , of which 'induc-' and 'increas-' are informative and correct. On the other hand 'chang-, ' 'regulat-, ' 'affect-' and 'control-' are correct, but less informative because the type of interaction is left vague.. Vague IITs, though correct, are much less useful for the motivating task of automatically extracting modes of interaction of biomolecule pairs than more specific IITs, because vague affirmations of interaction, like "affect" and "influence," do not specify the type of interaction. Therefore in addition to analyzing the data for the class of correct IITs (which includes vague ones), we also analyzed the data after removing vague IITs from the lists, leaving lists of informative IIT stems for each of the biomolecule pairs in the test set. In both analyses, PathBinder ranked the IIT stems tri-occurring with the pair by tf-idf score. Some tri-occurring IIT stems describe the interaction of a nearby biomolecule pair, while others do not. A good ranking strategy will tend to separate these two categories of IITs. Thus from a data set of ranked lists we can test how well rank predicts correctness of an IIT stem. This was our approach to exploring how to distinguish correct IIT stems from incorrect ones.. Although in some cases a pair had only one informative IIT stem in its list, the pair 'glutathione peroxidase' and 'glutathione' returned 87 correct IIT stems, 74 informative ones and 13 vague ones (Appendix C in Additional file 1). We manually investigated the set of lists of IIT stems and, for each, noted which IIT stem(s) tri-occurring with the associated biomolecule pair correctly characterized the interaction and which did not. Figure 4 (lower curve) indicates that 80% of the pairs tri-occurred in at least one sentence with a correct and non-vague (i.e. informative) IIT stem from our IIT lexicon, making it potentially possible to automatically identify how the pair interacts. On the other hand, the remaining 20% of the pairs did not. Since vague IIT stems are correct (despite minimal informativeness), including them in the analysis gave an improved curve (shown with diamond-shaped plot points).. The shape of the curve indicates how well the rank determined by the tf-idf calculation predicted IIT stem correctness. The curve with square plot points in Figure 4 normalizes the bottom curve, showing the situation for the 80% of the biomolecule pairs for which correct IIT extraction was possible in principle. It shows that in 76% of these a correct IIT stem was ranked first in its associated IIT stem list, in 84% at least one correct IIT stem was ranked first or second, in 88% at least one was in the top-ranked three IIT stems, and in 91% at least one was in the top four. These sub-100% results exemplify an important consequence of applying automatic extraction methods to natural language texts. Since these methods are not at present capable of full understanding of texts, their results cannot be certain, instead providing only some degree of evidence. Highly reliable results thus require a human curation step, until future systems become available that are capable of full NLU, when and if that happens. One possible step in this direction that will be interesting to watch for in the years ahead is the application of IBM's Watson system or an equivalent to the problem.. We next determined the information retrieval metrics of recall and precision as follows. For each pair of biomolecules, let N be the number of IIT stems returned, of which C are correct.. Define the IIT precision p(n) as the fraction of the top-ranked n IIT stems that are in C. Define the IIT recall r(n), n = 1…N, as the fraction of the C correct IIT stems that are present in the top-ranked n IIT stems.. Thus for the various values of n, the top ranked n informative IIT stems in the IIT stem list of each biomolecule pair have associated IIT recall and precision values r(n) and p(n). We computed recall and precision as functions of n for each of the test set biomolecule pairs. Figure 5 shows the average precision for different values of recall, using the standard eleven-point interpolated average precision method ( [54] , p. 146-7). Pairs which tri-occurred only with incorrect IIT stem(s) were Table 5 List of interaction-indicating term (IIT) stems tri-occurring with biomolecule pair chlordecone and cytochrome P450, ranked by tf-idf score, i.e., hypothesized likelihood of correctly describing their interaction excluded since it is impossible to retrieve a correct IIT from a list not containing any.. To place Figure 5 in context, it is based on 231 correct IIT stems out of 1,580 non-vague IIT stems, for a ratio of 0.17 correct IIT stems per incorrect stem, or a precision of just 0.146 for random retrieval. Thus the figure displays significant success in concentrating correct IIT stems into better ranks. Data mining the biomedical literature, sometimes called the biomedical textome, literaturome, or bibliome, has become increasingly important as the vast amount of textual information now available online promises correspondingly great benefits from automatically processing it. A key category of this information is interactions. Comprehensive mining of biomolecular interactions requires determining whether an interaction between entities exists and, if so, what kind of interaction it is. Typically, the interaction is described with an interaction-indicating term (IIT), often a verb.. Automatic extraction from text of information about interactions among biologically relevant entities can target processes such as drug interactions [1, 2] , transcriptomic interactions, protein-protein interactions (PPIs), and others. To support applications, interaction data extracted by text mining can be stored in biomolecular interaction databases. Such databases are an important enabling technology. For example they facilitate human information seeking and conceptual understanding, and support biomolecular network analysis [3] .. A considerable variety of interaction databases have been constructed in recent years. Examples include DIP [4] , BioCyc [5] , MIPS [6] , and MetNet [7] , which is the database and toolbox project associated with the present work. Such databases can be based on laboratory research results, like MIPS and KEGG. Alternatively they can be manually curated from biomedical publications, like DIP and BioCyc. While manual curation of existing publications is a quicker way to populate a database than acquiring wet lab results, automatic methods are much quicker still [8] . Thus, researchers have increasingly pursued automatically extracting interactions described in online biomedical texts such as the 22 million-plus records in PubMed.. Methods for automatically extracting interactions from text passages range across a spectrum of complexity from basic co-occurrence analysis, to rule-based template matching, to natural language processing (NLP), including growing interest in shallow methods such as kernel-based approaches. Corpus-based statistical techniques are often used to help leverage automatic extraction methods.. The most basic methods analyze simple co-occurrence of biomolecules within a text unit (e.g. [9, 10] ). However, much of the information in text is ignored by this approach, implying a tendency to comparatively low precision (but correspondingly higher recall) for detecting interactions compared to more sophisticated approaches that use more of the available information.. Template matching methods may be useful when an interaction template like "A activates B" can be matched to the text [11] [12] [13] . Ontologies can be used to match suitably related words together [14] . Syntactic analysis methods parse each text unit and try to match the parsed result with rules (e.g. [15] ). These methods can have relatively high precision because of the specific requirements a passage must meet before it is considered a match. However recall tends to be correspondingly lowered because a relevant passage can fail to have the precise word placement characteristics required and thus remain undetected.. Thus, new techniques are needed to improve recall relative to template and closely related methods, while improving precision relative to basic co-occurrence detection alone. Such techniques can, for example, consider frequencies and other corpus-wide features of biomolecules [16, 17] . While analysis of individual passages is typically involved, full corpus techniques also use corpus-wide properties, which are inexpressible by methods limited to individual passages. The present work uses this corpus-based strategy.. Ultimately, NLU (computer natural language understanding) will achieve very high levels of both recall and precision to the degree that human language performance levels can be achieved by computers. Thus full natural language understanding (NLU) is the grail of information extraction. NLU is not expected to be feasible for some time, however, syntactically sensitive approaches that do shallow or deep parsing of text can be viewed as steps toward the goal of full NLU, and have gained attention in the PPI literature [18] [19] [20] . These approaches increasingly rely on kernel functions ( [21] [22] [23] [24] [25] [26] ). While kernel approaches reduce to feature vector comparisons in theory, they do so in a way that can use implicit rather than explicit features, including features not strongly localized, in particular syntactic dependency relations [27] . Yet such methods continue to require relatively large amounts of computation, making them cumbersome when applied to large corpora. Such issues help motivate investigating a wide variety of other approaches, such as the one described herein.. Crucially, ensembles of techniques used together can perform better than individual techniques used alone [28] . Consequently, it is useful to explore the rich space of possible techniques because they could be usefully combined in hybrid system designs that work better than individual methods, even if some constituent methods seem to perform better than others when tested in isolation on benchmarks. While our earlier work explored biomolecular pair cooccurrence to extract interactions from single sentences [32] , it gave no indication of the way they interact. Our present work is designed to extract information about how they interact. Here, we apply a text empirics approach to design an algorithm which extracts which IIT(s) in a given sentence describes the way a given pair of biomolecules in the sentence interact. This single-sentence technique is then extended to combining evidence from multiple sentences found throughout MEDLINE to provide evidence from the experimental literature about how two biomolecules interact. The method starts with finding a list of stems of the IITs tri-occurring in sentences with the biomolecule pair of interest. It concludes by ranking the list of IIT stems based on their probabilities of correctly describing the interaction.. The challenge. We consider biomolecular interactions, defined as direct influences (association, regulation, modification, creation, transportation, etc.) between two organic molecules in a living organism. Proteinprotein interactions (PPIs) are a prominent example. We used the individual sentence as a unit of analysis [29] , and investigated extracting the IITs (interaction-indicating terms) that co-occur with and correctly describe the interaction of a biomolecule pair of interest, while filtering out those IITs that also are present but do not pertain. For example, consider sentences S1-S3 that contain the terms ' ATP' and 'myosin' (S1 is a title and titles were treated as sentences). S1. Measurement of the reversibility of ATP binding to myosin in calcium-activated skinned fibers from rabbit skeletal muscle. [48] S2. A parallel pathway model of regulation simulated the effects of Ca(2+) and ATP-free myosin binding on both equilibrium binding of myosin-nucleotide complexes to actin and the general features of ATPase activity [49] .. S3. In rigor (in the absence of ATP, when all the myosin heads are rigidly bound to the thin filament), a slight decay was observed in the first few microseconds, followed by no change in the anisotropy. [50] S1-S3 each contain several IITs. Their canonical forms are: 'bind, ' 'activate, ' 'regulate, ' 'complex, ' and 'change.' 'Bind' appears more frequently than the others. On this basis we might hypothesize 'bind' as the interaction between ATP and myosin, and manual inspection shows this is indeed true.. Note a distinction between the following cases.. An IIT is used to describe an interaction in a particular sentence. An IIT characterizes an interaction as an independent fact.. One refers to what is said by a given single sentence, while the other refers to a general fact about an interaction. These cases need to be distinguished because of examples like S3. S3 contains the terms "bound," "ATP," and "myosin" and, as other sentences establish, binding is in fact an interaction between ATP and myosin. However S3 does not describe that interaction because "bound" is used for a different purpose in that sentence.. The probability that a particular IIT describes an interaction of a given biomolecule pair in a given sentence may be determined by a combination of the evidence contributed by different text characteristics of it. Thus, we manually analyzed sentences from the literature to empirically identify useful characteristics that could assist efforts to automatically extract IITs that correctly describe the interactions of given biomolecule pairs.

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A Method to Evaluate the Suitability of Requirements Specifications for Offshore Projects The success of an offshore application development project based on division of labor on the one hand heavily depends on the quality of the developed requirements specifications. On the other hand, even a poor quality of requirements specifications can possibly be compensated during the course of the offshore project. In this contribution, we present a method to evaluate the suitability of requirements specifications for an offshore project. For this purpose, we consider eight quality criteria and five potentially compensating factors. The application of the method is illustrated by a complex case study that has been conducted with an industry partner. With the growing importance of offshoring as a decision option even for highly complex application development projects, the quality of requirements specifications has evolved to a central determinant. In this contribution we therefore described a method to evaluate the quality of requirements specifications systematically, comprehensively, with regard to several criteria, and in a rational process. In addition, compensating factors were included into the analysis to achieve a better control or even a rectification of specification deficits during the course of the project. The evaluation method does not require a renewed involvement of the user. In the case study, the assessment also accounted for only about four percent of the total expense which the client had estimated for the design and implementation on the basis of a function point analysis.. The presented research results have implications for both science and practice. For practice, the developed approach provides an immediately deployable, efficient way to constitute a better foundation for planning decisions for an offshoring project depending on the quality of available requirements documents. From a scientific point of view, the presented approach closed the research gap concerning decision support approaches for the planning of offshore projects for application development. To achieve a more comprehensive decision support in the planning of offshore projects, we particularly have to research further influencing factors. The method described in this paper presents a first step which was developed in terms of a design science approach and which has been iteratively improved. We focused on the quality of requirements specifications and specific compensating factors with a balancing effect on specification deficits.. The presented method itself is subject to further research to be carried out in further iterations of the design science cycle. On the one hand, focus is on the development of an algorithmic process to systematically derive the weights of the single quality criteria during the assessment based on the preferences of decision makers. The Analytic Hierarchy Process (AHP) serves as the basis for this purpose. On the other hand, we plan to develop so called best practices and guidelines for the application of the presented method through further case studies in collaboration with practice partners. In this way, we intend to further improve the desired offshore decision support. Assigning the development and operation of information processing functions to external partners became a sustainable business model in 1963 at the latest, when the EDS company agreed with the Blue Cross health insurance to completely take over their IT (Dibbern et al. 2004, pp. 7 f) . Contracting out parts of business application development to external service providers has become a standard planning alternative today. For some time, the offshoring approachoutsourcing to low-wage areas that are envisaged to be far away and barely regulated ("off shore") -has been propagated in the course of globalization and has become the focus of considerations (Aspray et al. 2006, p. 6, 15; Kobitzsch et al. 2001, pp. 78 ff; Pryor and Keane 2004, pp. 11 ff) .. On the contracting side, there primarily is the expectation of reducing costs through wage and price differentials between client and contractor areas. Aspray et al. (2006, pp. 6 f) argue that economic theory as well as anecdotal evidence show economic benefits for clients and contractors. On the other hand, additional costs resulting from offshoring parts of the business application development are emphasized (Dibbern et al. 2008) . Overby (2003, p. 65) , for example, estimates that up to ten percent of additional costs incur for the necessary improvement of development processes only.. Today, offshoring is seen as a global mega trend (Boos et al. 2005 , pp. 6 f), and such approaches are now being pursued even for highly complex development projects. With the global allocation of development work to various stakeholders based on division of labor, the development task is directly subject to an interorganizational and cross-cultural context where implicit assumptions can hardly be made (Hofstede 1997; Vlaar et al. 2008, pp. 227 ff; Winkler et al. 2007, p. 96) . Especially in such a context, necessary functions of an application system and required interfaces to other software components can only be explicitly specified through precise, intersubjectively unambiguous requirements specifications (Davis 1993) . Therefore, requirements specifications constitute the substantive basis of the division of labor, become contractually agreed specifications of services (Gsell et al. 2008, pp. 26 ff; Overhage 2006, pp. 122 ff) , and are therefore one of the most important factors for offshore projects (Overby 2003, p. 65; Sakthivel 2007, p. 70) .. Although precise requirements specifications are crucial and their quality has great influence on the results of subcontracted steps of application development (Wehrmann and Gull 2006, p. 407, pp. 413 f) , it is observed in practice that they routinely remain unclear and thus may create significant difference of opinion in regard to the agreed scope of services (Heindl and Biffl 2006, p. 21; Pruß and Skroch 2008; Vlaar et al. 2008, p. 235) . For a decision on the offshoring of development steps, it is therefore essential to assess the suitability of requirements specifications in advance, e.g., based on criteria that have to be met. Despite the central importance of such an assessment, however, so far there have been hardly any efforts described to support this issue systematically and specifically with regard to offshore projects.. In this paper, we present a method to systematically and rationally assess the suitability of requirements specifications for the offshoring of development steps. The approach is characterized by two main features. First, the evaluation can be carried out without reconsulting users from the departments -who represent the requirements as regards content -for further clarification. In practice, such an approach would cause ongoing difficulties because of the users' limited availability and their limited willingness to discuss already given requirements again. Second, the approach's assessment also includes compensation opportunities, which makes it possible to (totally or partially) balance out specification deficiencies in a particular offshore project -these then constitute critical success factors for the offshore project to be carried out. For the preparation of appropriate sourcing activities, the presented approach not only makes it possible to assess a specification in terms of high or low quality. Additionally, it becomes possible to highlight compensating options for the responsible decision makers.. In developing the evaluation method, we followed the design-oriented approach of business and information systems engineering (BISE), specifically the design science method (Hevner et al. 2004) . Apart from the theoretical foundation and iterative improvement, the latter also includes an explicit validation, which was primarily carried out in the context of a large case study. Here, the developed method was used in a large development project for custom software, providing decision support in the planning of the offshore parts of the project. The further presentation of the developed evaluation method is based on the design science cycle which differentiates between the formulation of the problem, the solution concept, the realization of the solution, and its validation as key steps (Takeda et al. 1990, p. 43) .. Section 2 describes the theoretical background and related approaches for the assessment of requirements specifications in order to highlight the existing research gap. Section 3 presents the conceptual basis of the evaluation method before it is presented in detail in Section 4. Section 5 includes a reflection of the performed case study as well as a reception of the results obtained. At the end of the contribution we discuss implications for science and practice as well as remaining research questions.

O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Tradeoff Between Latch and Flop for Min-Period Sequential Circuit Designs With Crosstalk Latches are extensively used in high-performance sequential circuit designs to achieve high frequencies because of their good performance and time-borrowing feature. However, the amount of timing uncertainty due to crosstalk accumulated through latches could be larger than the benefit gained by time borrowing. In this paper, we show that the tradeoff between a latch and a flop can be leveraged in a sequential circuit design with crosstalk, so that the clock period is minimized by selecting a configuration of mixed latches and flops. A circular time representation is proposed to make coupling detection easier and more efficient. Experiments on our heuristic algorithm for finding an optimal configuration of mixed latches and flops showed promising results. I N A sequential circuit, clock signals are usually applied at memory elements to lock correct state values and to filter out unintended transitions. Generally speaking, memory elements can be categorized into two groups according to how they respond to clock signals: 1) edge-triggered flops store the data when the clock switches and 2) level-sensitive latches let the output have the input value during its active duration.. Latches dominate high-performance designs as they have smaller delays and occupy less area than flops. More importantly, since signals can pass through a latch anytime during its active duration, time borrowing between two consecutive latches is possible. As a result, circuits designed with latches can operate at higher frequencies than their edge-triggered counterparts [1] .. For correct operation, the data are required to be stable before the latching edge by an amount of time called the setup time-This is known as the setup condition. The data have to remain stable after the latching edge for an amount of time called the hold time-This is known as the hold condition. A clocking violation refers to a violation of the setup condition or the hold condition.. Clock schedule verification (also known as timing verification) for edge-triggered circuits is straightforward. Since signals cannot pass transparently through flops, the output times Manuscript of the flops are used as the input times of the combinational components, and the setup and hold conditions of the flops are checked against the combinational outputs. However, clock schedule verification involving latches is much harder. Since signals can pass through latches transparently during their active durations, the setup and hold conditions on paths between any two latches need to be considered. These conditions become even more complex in the presence of a multiphase clock schedule.. On the other hand, with increasing clock frequencies and shrinking process geometries in deep-submicrometer technology, both capacitive and inductive couplings (also known as crosstalks) become big concerns in designs. For present-day processes, the coupling capacitances can be as high as the sum of the area capacitances and the fringing capacitances. Trends indicate that the role of crosstalk will be even more dominant in the future as feature sizes shrink [2] . Besides introducing noises on quiet wires, crosstalk may greatly change the wire delays and, hence, affect the timing analysis. If an aggressor and a victim switch simultaneously in the same direction, the victim will speed up, which is called assistive coupling. Likewise, if an aggressor and a victim switch simultaneously in opposite directions, the victim will slow down, which is called opposing coupling. Assuming that coupling capacitances and inductances dominate all other capacitances and inductances of wires, failure to take crosstalk effects into timing analysis may produce wrong results. Our work in this paper equally applies to crosstalk induced by capacitive and inductive couplings. However, to simplify the presentation, we only talk about capacitive couplings in the rest of this paper.. Since latches allow signals to pass transparently, crosstalk effects on switching windows may accumulate on a long path and cause a clocking violation in the end. These phenomena will be explained in more detail in Section II. It is interesting to observe that the switching window at the output of a flop is just a single point or a switching window with width zero (for the ease of the presentation, we assume no clock skew uncertainty). A natural thought is to select a set of latches such that when they are replaced with flops, the crosstalk effects contributed by their original output switching windows are greatly reduced, and the previous clocking violations are removed.. Our contribution in this paper is twofold. First, we propose a circular time representation for coupling detection. We show that detecting coupling under the circular time representation is easier than state-of-the-art approaches used in [3] and [4] . Furthermore, since complicated phase translations are avoided, clock schedule verification under the circular time representation is more efficient. Second, we formulate the tradeoff between a latch and a flop in sequential circuits with crosstalk as a problem of seeking a configuration of mixed latches and flops to minimize the clock period. We present an effective and efficient heuristic algorithm to solve this problem. Experiments showed promising results.. The rest of this paper is organized as follows: Section II presents the motivation and problem formulation. Section III describes the models we will use in this paper. Section IV recaps the previous work. The circular time representation is proposed in Section V. Our algorithm is presented in Section VI, followed by experimental results in Section VII. Conclusions are given in Section VIII.

O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Open- vs. Restricted-Domain QA Systems in the Biomedical Field Question answering systems (QA systems) stand as a new alternative for information retrieval systems. We conducted a study to evaluate the efficiency of QA systems as terminological sources for physicians, specialized translators and users in general. To this end we analysed the performance of two open-domain and two restricted-domain QA systems. The research entailed a collection of 150 definitional questions from WebMed. We studied the sources that QA systems used to retrieve the answers, and later applied a range of evaluation measures to mark the quality of answers. Through analysing the results obtained by asking the 150 questions in the QA systems MedQA, START, QuALiM and HONqa, it was possible to evaluate the systems' operation through applying specific metrics (MRR, FHS, TRR, Precision, Recall). Despite the limitations demonstrated by these systems, it has been confirmed that these four QA systems are valid and useful for obtaining definitional medical information in that they offer coherent and precise answers. Information retrieval (IR) is a discipline focused on the problems of information items' selection from a storage system in order to facilitate retrieval for the users' needs [1] [2] [3] [4] [5] . Traditionally, IR is understood as a fully automatic process that responds to a user query by examining a collection of documents and returning a sorted document list that should be relevant to the user requirements as expressed in the query [1] . Simply stated, it could be said that retrieval implies finding certain requested information in a storage system or database of information [6] . An optimal IR system recovers all the relevant documents (implying an exhaustive search, i.e. a high recall) and only the relevant documents (implying perfect accuracy, that is to say, a high precision). This traditional model involves many implied restrictions: the assumption that users want full-text documents, rather than answers, and that the query will be satisfied with these documents; that the process is direct and unidirectional rather than interactive; and finally, that the query and document share the same language.. Information overload is felt more strongly on the web than elsewhere. All too often a query made with a web search tool (search engine or meta-search engine) results in the retrieval of too many pages -many of which are useless or irrelevant to the user. Question answering systems (QA systems) are an evolutionary improvement in IR systems. As alternative traditional IR systems, they give correct and understandable answers to factual questions [7] -rather than just offering a list of documents related to the search. The benefit is that users do not have to read whole documents to find the desired information. Therefore, professionals from various areas are beginning to recognize the usefulness of these systems, for quickly and effectively finding specialized information [8] [9] [10] .. We conducted a study to evaluate the efficiency of QA systems as terminological sources for physicians, specialized translators and users in general. To this end we analysed the performance of two open-domain QA systems, START and QuALiM, and two restricted-domain QA systems, MedQA and HONqa. The research entailed a collection of 150 definitional questions (What is…?), either general or specialized, from WebMed. We studied and analysed the performance of each QA system through to the answers retrieved by them in order to assess their efficacy in the biomedical field, using multiple evaluation measures. Today, users are more demanding of the retrieved information, as much with regard to the quality as with regard to the quantity, just as in response time. QA systems could therefore be one of the future systems of IR on the internet as they intend to meet the needs and demands of the current users. Nonetheless, despite an increase in QA system research, the open-domain systems are scarce and not all of them function adequately. In as much, it is necessary to continue analysing and evaluating such systems and their characteristics, in order to promote their development and commercialization. Through analysing the results obtained by asking the 150 questions in the QA systems MedQA, START, QuALiM and HONqa, it was possible to evaluate the systems' operation through applying specific metrics. Despite the limitations demonstrated by these systems, as they are not accessible to everyone and they are not always completely developed, it has been confirmed that these four systems are valid and useful for obtaining definitional medical information in that they offer coherent and precise answers.. Another interesting aspect concerns the sources of information used by each of these QA systems. In previous work [15] , we compared the sources used by the restricted-domain QA systems with those used by the general-domain systems to ascertain if we could see significant differences in the typology and specialization. A comparison of the sources used by START and QuALiM confirms the absence of significant differences, as both systems use Wikipedia as their main source, although START recurs to more sources for its retrieval. Nonetheless, we see big differences in the sources used by the two restricted-domain QA systems. While MedQA uses dictionaries, encyclopaedias and databases specializing in the biomedical field, HONqa opts for websites specializing in this area.. The results are encouraging because they present this type of tool as a new possibility for gathering precise, reliable and specific information in a short period of time. In this sense, some authors [33] have explored various possibilities for improvements, such as the use of ontologies, which will increase the quality of the answers obtained by formalizing the relevant information from the domain in question. In addition, these approaches together with others are slowly attracting more researchers who are experienced in handling the results they produce. These data suggest that we may see unexpected changes in the future and this area deserves to be studied and evaluated in future research.. QA systems have been extended in recent years to explore critical new scientific and practical dimensions [34] . Additional aspects, such as interactivity (often required for clarification of questions or answers), answer reuse, and knowledge representation and reasoning to support question answering, have been explored. Future research may explore what kinds of questions can be asked and answered about social media, including sentiment analysis. Another key aspect of these systems is that the system-user relationship is two-way. Establishing an interaction helps QA systems find better answers and, in turn, the QA system helps users find answers more quickly. However, it is still necessary to deepen the interactive design of these systems and enable true feedback between questions and answers so that users communicate with the system in a conversational manner. Finally, retrieval has shown that the QA systems are a useful tool to retrieve information quickly and accurately. In total, a sample of 150 definitional questions about different medical issues formed the basis of this study (Figure 1) . We decided to use definitional questions because they do not demand specific data (such as a date, name or place) as the QA system builds an answer. So, these systems have to identify and obtain relevant information in their sources used, and have to summarize and develop the best answer possible as a definition. The questions were obtained from the webpage WebMD (http://www.webmd.com/), a US health portal providing valuable health information and support, tools for managing health problems and specialized background on a number of illnesses. It was created by health specialists who aspire to explain, briefly yet credibly, in-depth medical information, reference material, and online community programmes. The set of questions used passed the internal consistency test with a Cronbach's alpha coefficient of 0.997.. We used START and QuALiM as open-domain QA systems -although allowing users to pose questions about various health issues, they can respond to even very specialized questions within the area of healthcare [30] -and, as restricteddomain QA systems, MedQA and HONqa.. After asking questions in the four systems, a group of two medical professionals and three medical students evaluated the answers as incorrect, inexact or correct. Correct answers were those that answered the question adequately, were expressed in fewer than 100 words and did not contain information that was irrelevant to the question. Responses that answered the question correctly but that did not meet the rest of the criteria were evaluated as inexact. The evaluations performed on each answer created a base for the application of the evaluation measures on the system's operation [31] , measures which are described next.. Mean Reciprocal Rank (MRR) is a statistical tool for evaluating any process that produces a list of possible answers to a query. The reciprocal rank of a query response is the multiplicative inverse of the rank of the first correct answer (for example, if a question gets the correct answer in first place, it will receive a score of 1, it will be 1/2 if it is in the second place, 1/3 in the third place, and so on). If the answer is not found, a score of 0 is assigned. MRR can be used with several correct answers, but it only takes into account the first correct answer found. Total Reciprocal Rank (TRR) is useful when there is more than one correct answer to a question. In these cases, it is not sufficient to consider the first correct answer in evaluations; instead, TRR takes into consideration all the correct answers and assigns a weight to each according to its ranking in the list provided by the system. For example, if the QA system provides two correct answers (the first and the third ones), the TRR will be 1/1 + 1/3.. First Hit Success (FHS) assigns 1 if the first answer returned by the system is correct and 0 if it is not. This measure, then, only accepts the first questions in the list of results.. We have also used the classic measures of evaluation in IR: precision and recall [4] . Precision is understood as the capacity of a system to retrieve documents, or answers (in the case of QA systems), relevant to the query.

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A framework for filtering web accessibility guidelines This paper first presents a framework for filtering the Web Accessibility Guidelines according to contexts of use. It then presents a prototype that implements the framework and explains an evaluation of the prototype. The World Wide Web Consortium (W3C), governments and special interest groups have developed Web accessibility guidelines that provide guidance on how to develop or procure IT products and services that can be used by people with disabilities (PWDs). But many web based systems are still not accessible to PWDs [1, 2, 3, 4, 5, 6] . Presently, the most comprehensive, recognized and widely adopted Web accessibility guidelines is the Web Content Accessibility Guidelines (WCAG) by W3C [7, 8] . The WCAG have formed the basis of Web accessibility policy of many organizations across the world, are referred to in court cases concerning accessibility and are used as evaluation criteria by most automated evaluation tools [9, 10] .. However many members of the target audience still find WCAG difficult to use [8, 11] . One of the challenges faced is difficulty in getting the advice needed [12] . WCAG 1.0 has been criticized for being difficult in this respect for much of its potential audience. WCAG 2.0 which was developed to address limitations of WCAG 1.0 has also been criticized for being 'overlong', unreadable and impossible to understand [13, 14] . Some critics have recommended continuing with WCAG 1.0 [14] . This paper discusses a framework for filtering Web accessibility guidelines according to a context of use. The context of use is important for the usability of accessibility guidelines since they are used by different groups of people with different interests and skill base [8] .. A prototype that implements the framework was developed and tested alongside the WCAG 1.0 guidelines. The results suggest that the framework is an improvement to the one view for all. Other than accessibility guidelines, the framework is also useful to any static online content if intended for various groups of users. The testing involved tasks on the 'raw' (WCAG 1.0) guidelines and the 'framework' guidelines. The tasks required participants to identify and document advice for addressing accessibility issues specified in the tasks. The tasks for each group were related to their roles in the Web development process. The task descriptions covered typical scenarios in which Developers and IT Managers might need to use the guidelines. For each task, participants were asked to rate the ease of completion. In addition participants documented their experience about the usability of the two sets of guidelines. Instead of using the same task for each set of guidelines, different tasks were given, but each testing the same aspect e.g. advice for different disabilities. The background color of the framework guidelines was changed to differentiate it from the 'raw' guidelines.

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Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces Abstract Microelectrode arrays (MEAs) are designed to monitor and/or stimulate extracellularly neuronal activity. However, the biomechanical and structural mismatch between current MEAs and neural tissues remains a challenge for neural interfaces. This article describes a material strategy to prepare neural electrodes with improved mechanical compliance that relies on thin metal film electrodes embedded in polymeric substrates. The electrode impedance of micro-electrodes on polymer is comparable to that of MEA on glass substrates. Furthermore, MEAs on plastic can be flexed and rolled offering improved structural interface with brain and nerves in vivo.MEAs on elastomer can be stretched reversibly and provide in vitro unique platforms to simultaneously investigate the electrophysiological of neural cells and tissues to mechanical stimulation. Adding mechanical compliance to MEAs is a promising vehicle for robust and reliable neural interfaces. Electrode arrays designed for recording and stimulation of neural activity are widely used in neurological research as well as clinical therapy. Most of these arrays are microfabricated using MEMS technology and stiff materials including silicon, glass and metals. Dense arrays of up to 256 electrodes are used in vitro to monitor/stimulate individual neurons or acute tissue slices [14, 27] and in vivo to treat or repair damaged brain tissues or peripheral nerves [16, 31] . These 2D arrays interface very well with neurons' population cultured in vitro or 2D-organized neural networks in vivo such as ganglionic neurons in the retina. However, rigid microelectrode arrays (MEAs) do not provide long-term and robust interfaces when interfaced with 3D neural tissues such as a nerve, or when mechanical stimulation is applied to the probed tissue.. In this article, we describe the technology and design of mechanically compliant neural MEAs, and current prototypes for in vitro and in vivo applications. The focus of these soft neural interfaces is on extracellular recording of action or field potentials but extracellular stimulation can also be implemented.. The mechanical mismatch between man-made device materials for MEAs and biological tissues and cells is clearly illustrated Fig. 1 . Cells are soft and visco-elastic with well-defined mechanical properties characterized by elastic modulus in the range of 100s to 1,000s Pa. In vivo, they are surrounded by other cells and extracellular matrix. In vitro or when interfaced in vivo with man-made implants, cells are in contact with materials that are many orders of magnitude stiffer. For example, silicon and glass are brittle materials with Young's modulus of hundreds of GPa. An increasing number of studies focused on cells' biomechanics highlight that cells can be extremely sensitive to changes in the mechanical properties of their surroundings, occurring independently of the biochemical environment [4, 18, 29, 35] . In vivo, implanted electrodes trigger a foreign body reaction leading to chronic inflammation and scar formation [34] . Fibrotic tissue encapsulates the recording and stimulating sites of the electrodes, and prevents reliable and long-term electrophysiology.. Furthermore, in vivo biological tissues withstand moderate and repeated mechanical deformations to accommodate movements around joints. During traumatic injuries, neural tissues may experience violent mechanical stretch with strains of tens of percent.. The design of electrode arrays falls into one of following categories: planar, penetrating, cuff, and regenerating electrodes.. Planar electrodes are metallic patterns on glass, silicon and more recently polyimide substrates designed for extracellular stimulation and recordings in vitro on various types of tissues or cells, e.g., acute hippocampal slices, primary neurons or organotypic preparations [7] . Electrodes are typically patterned in 8 9 8 or 6 9 10 grids over a few mm 2 surface area, but 16 9 16 arrays are also available [30] . Whilst planar MEAs provide spatial as well as temporal information about neural networks, they are rigid MEAs and thus, cannot monitor neuronal activity from tissues or cells subject to mechanical deformation or injury.. Penetrating MEAs are based on needle-like structures, which are pushed into the brain or the nerve in vivo [15, 19] . They are fabricated with silicon or titanium. They may comprise a single needle bearing multiple contacts on its shaft [20, 39] or a 10 9 10 matrix of single contact electrodes [19, 36] . Successful penetrating electrodes are already available to humans, e.g., cochlear implants [40] and deep brain stimulator [10, 17] . However, stable and long-term recording and stimulation remain a challenge. One of the recurrent hurdles is the cellular reactive response and increased tissue-electrode impedance due to insertion trauma, tethering and micro-motion of the stiff needle-like electrodes.. Cuff electrodes are insulating polymeric sleeves, which wrap around a nerve and carry electrical contacts on their inner surface [5, 41] . Because they do not penetrate or cut the nerve, cuff electrodes only interface with outer axons; distinguishing between signals from different axons in the same fascicle is then nearly impossible.. Regenerative electrodes are devices inserted to the proximal stump of a sectioned nerve. They provide a structure that allows for nerve fibers outgrowth, and an array of electrodes distributed across the nerve's cross-section, often referred to as sieve electrodes [6, 41] . The sieve is prepared as ''transparent'' as possible to guarantee robust axon regeneration. However, sieve MEAs usually have a modest number of electrodes (up to 12) given the conflict between hole space and lead-out space [31] . Furthermore, long-term ([12 month post-implantation) reliability of regenerative implants has not been reported.. Therefore, the challenge lies in finding technological routes to produce electrode arrays, which disrupt minimally the cells' environment so that (i) they behave in vitro like in the body, (ii) they induce in vivo minimal inflammatory response, (iii) they provide long-term communication between neural fibers and electronic hardware, and (iv) when needed, they conform and deform along with the 3D neural tissue.. In this article, we propose to use thick polymer microtechnology to design and fabricate improved MEAs. We report on the fabrication and electromechanical characterization of flexible (polyimide-based) and stretchable (silicone-based) MEAs. We further illustrate the potential of compliant micro-electrodes for neuronal electrical interfaces. Neural electrodes rely on an accurate and reliable interface between the neuronal cell(s) and the electrode recording sites. Advanced microtechnologies using polymers offer new opportunities for the development of active neural interfaces that go beyond the design of rigid and planar MEAs. We have optimized a set of fabrication processes for highly compliant interfaces without compromising on electrode performance, and demonstrated promising in vitro and in vivo extracellular recordings using flexible and stretchable micro-electrodes.

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