In Nigeria, as in other developing countries, access to training in research ethics is limited, due to weak social, economic, and health infrastructure. The project described in this article was designed to develop the capacity of academic staff of the College of Medicine, University of Ibadan, Nigeria to conduct ethically acceptable research involving human participants.Three in-depth interviews and one focus group discussion were conducted to assess the training needs of participants. A research ethics training workshop was then conducted with College of Medicine faculty. A 23-item questionnaire that assessed knowledge of research ethics, application of principles of ethics, operations of the Institutional Review Board (IRB) and ethics reasoning was developed to be a pre-post test evaluation of the training workshop. Ninety-seven workshop participants completed the questionnaire before and after the workshop; 59 of them completed a second post-test questionnaire one month after the workshop.The trainees came from a multi-disciplinary background including medicine, nursing, pharmacy, social science and laboratory science. The mean scores for knowledge of the principles of research ethics rose from 0.67 out of 3 points at pre-test to 2.25 at post-test (p < 0.05). Also, 42% correctly mentioned one international guideline or regulation at pretest, with most of those knowing of the Declaration of Helsinki. Trainees' knowledge of the operations of an IRB increased from 6.05 at pre-test to 6.29 at post test out of 7 points. Overall, participants retained much of the knowledge acquired from the workshop one month after its completion.The training improved participants' knowledge of principles of research ethics, international guidelines and regulations and operations of IRBs. It thus provided an opportunity for research ethics capacity development among academic staff in a developing country institution. Research ethics in its broadest definition encompasses the principles, standards, norms and guidelines that regulate scientific inquiry . The priTrovan in Nigeria and Tenofovir in Cameroon that have again highlighted the need for African professionals to have sophistication in research ethics in order to be able to participate in the debates locally  eyes to the role of the IRB."There was consensus of opinion among interviewees and FGD participants that the proposed training on research ethics was both timely and appropriate. As one interviewee pointed out, "FGD participants ranked principles of research ethics as the most appropriate content, followed by international guidelines, informed consent, ethics of research design, justice and obligation, scientific misconduct, and IRBs, in that order. None of the participants considered standard of care, obligations of researchers to study participants and conflict of interest to be relevant content for training.To ensure the success of the training, it was suggested that there was a need to invite those who have genuine interest in learning about research ethics, that adequate publicity should be provided for the training, and that resident doctors and other post-graduate students should be invited to participate. There was also a suggestion that case studies and proposal writing should be included in the workshop.These findings were considered in the planning and implementing of the training program.In order to ensure wide participation of staff in the training, a letter was written to the Heads of all the 32 departments/units in the institution to solicit nominations from each. The number of staff was limited to four per department or unit due to funding constraints. The letter of invitation stressed the fact that participation in the program was voluntary. Of the 32 departments/units invited to nominate staff, 29 (91%) responded and 3 (9%) did not. In addition, two Non-Governmental Organizations that routinely conduct behavioral and biomedical researchers in Ibadan were invited to nominate staff to participate in the training. Upon receiving names of nominees, a formal letter of invitation was sent to each person providing details about the logistic arrangements for the training.Three rounds of training workshops were conducted between December 2003 and February 2004. Each round, which lasted 21 hours spread over three days, was organized in ways that ensured that the composition of the trainees was multi-disciplinary. The objectives of the workshop were to expose participants to existing international guidelines and regulations on research involving human participants, increase knowledge and application of the principles of research ethics, deepen understanding of the role of investigators and IRBs in ensuring the protection of study participants, and equip participants with knowledge and skills to deal with the ethical challenges they may face in their future research activities. The workshops were facilitated by seven resource persons who had previous training and experience in research ethics. The resource persons used multiple training techniques including lecture, question and answer sessions, and group discussion of case studies. The training had both plenary and group sessions. Participants were divided into small groups to discuss the case studies and feedbacks were provided during plenary sessions thus ensuring in-depth discussions of the issues. The workshops were conducted in English, the official language in Nigeria. The training emphasized the importance and universality of the principles of research ethics as described in the Belmont Report; however, the resource persons provided several examples of the local application of these principles. The contents covered during the workshop were history of research ethics, principles of research ethics, ethics in research design, ethical issues in drug/vaccine trials, confidentiality\obligation, informed consent, conflicts of interest and scientific misconduct. Twenty reference materials were distributed and certificates of attendance were presented.Only research funded by an external agency should be submitted to the Ethical Review Committee for consideration," and, "approvals from an Ethical Review Committee are for the duration of the research." Trainees were also requested to identify the principle of research ethics that matched each of a different set of seven statements. A sample statement read, "The special needs of vulnerable populations such as prisoners and children must be protected at all times"  are presented both in percentages and mean scores. The first process in analyzing the answers to this question was to enumerate all the responses mentioned by trainees. Codes were then assigned to each answer indicating whether the response corresponded with any of the three principles. In computing the mean score, one point was assigned for each correct answer such that three possible points could be achieved for this knowledge score.We also developed a seven-point knowledge score in assessing trainees' knowledge of the application of principles of research ethics (questions 8–14). Similar procedures were adopted for knowledge about operations of an IRB (question 7). Using a chi-square test, we compared mean values of the trainees on each component of knowledge variable at three points in time, before, after and follow-up.Of the 133 persons who attended the workshops, 97 (73%) completed the pre-test and post-test questionnaire. Of the 97 trainees contacted at one-month follow-up, only 59 (61%) returned their questionnaire. Thirty-six trainees did not complete the pre-test because they either arrived late (i.e. after the pre-test had been conducted) or did not provide informed consent. There is no data on the demographic characteristics of persons who did not complete the pre-test. Those who did not complete the pre-test were told they were not eligible for the post-test or follow-up survey.The 97 trainees came from multi-disciplinary backgrounds including medicine, nursing, pharmacy, social science and laboratory science Table . Their aTrainees were requested to list the three most important considerations that should guide the conduct of research involving human participants. At baseline (pre-test), 35.1% of trainees provided answers relating to beneficence, 22.7% mentioned justice, but no one provided answers relating to respect for persons. Examples of answers that were not directly related to the three principles of ethics include, "conduct ethically sound research," "non-personalizing issues" "non-exploitation," and "notification of side effects." By post-test, 97% provided answers relating to beneficence, 68% mentioned justice, and 68% invoked the concept of respect for persons. The mean scores for knowledge of the principles of research ethics rose from 0.67 out of 3 points to 2.25 at post-test; this dropped to 2.19 at follow-up (p < 0.05).On the topic of awareness of international guidelines or regulations, 42% correctly mentioned at least one known guideline at pre-test; 58% could not list any. Of those who knew of a guideline, 71% listed the Declaration of Helsinki, 20% mentioned the Nuremberg Code and 9% identified the Belmont Report. None of the participants mentioned CIOMS at pre-test. The proportion that mentioned these guidelines at post-test were 67.0%, 42.3%, 33.0%, 37.1% respectively.the capacity and rights of all potential Nigerian research participants to make their own decision must be respected by all investigators." This figure rose to 87% at post-test, but dropped slightly to 81% at follow-up. Similarly, at pre-test, 43% of trainees knew that the principle of justice was applicable to the statement, "the use of poor Nigerians for the exclusive benefit of more privileged Nigerians should be discouraged." This figure rose to 60% at post-test, and was 59% at follow-up. When the scores for the seven items were summarized, the mean rose from 2.64 at pre-test to 3.05 and 3.24 at post-test and follow-up respectively (p < 0.05).The proportion of trainees who provided correct answers before, after, and at 1-month follow-up to the seven statements that measured application of research ethics is shown in Table "IRB approvals of a research project are for the duration of the project." Only 27% of trainees answered correctly that this is not true, indicating that they appeared to recognize the concept of "expiration" and/or the process of "renewal." This proportion rose to 57% at post-test, but dipped to 40.7% at follow-up. Additional details are provided in Table Table Tables Participants' knowledge of the five statements posed in the case study on researchers' obligations is shown in Table Although the number of formal and online training programs in research ethics has increased during the last five years due largely to the efforts of many regional and international organizations, many professionals in African countries still have limited access to formal training in research ethics. At the same time, more and more African scientists are involved in research, as greater numbers of clinical trials are being carried out in developing countries . Even paThe training program described in this paper was developed to contribute to fulfilling this goal. Sixty-five percent of workshop attendees had their first opportunity of formal training in research ethics as a result of their participation in this project, thus addressing an important unmet need of scientists and clinicians in this institution. The fact that trainees were drawn from a large majority (91%) of the departments/units in the institution helped to ensure that many staff were reached with this intervention. It is also encouraging that ten of the fifteen members of the local IRB participated in the training. The expectation is that the participation of these IRB members would improve their capacity to perform their oversight functions.It is noteworthy that, during the needs assessment phase of this project none of the FGD participants considered "standard of care," "obligations of researchers to study participants," and "conflict of interest" to be relevant topics for training. It may be that the topics to which they gave higher priority were topics they have encountered more frequently through their work. These other topics, while clearly animating much of the existing research ethics scholarly literature, may be confronting these individuals less often. As knowledge of the more basic concepts becomes more sophisticated, it is likely that subsequent training covering these additional topics would be appropriate. Indeed, members of the IRB and researchers likely should have the opportunity for additional continuing education programs in research ethics to enable them to continue to develop their thinking around all of these issues as well as those that will emerge in the future.Post-training improvements were found in participants' knowledge of the principles of research, the application of these principles, the international regulations, and the operations of an IRB. This improvement is similar to findings in previous studies ,12 and mOverall, trainees retained much of the knowledge acquired from the workshop one month after its completion. Knowledge about the operations of IRBs and application of the principles of research improved significantly one month after completion. This may mean that trainees had greater opportunity to reflect on these issues over other topics covered. It may also imply that trainees were able to apply, or otherwise internalize, their knowledge of certain standard operating procedures of IRBs. There was only a marginal increase in trainees' knowledge relating to requirements for durational IRB protocol approvals. Perhaps this aspect of the operation of an IRB was not emphasized enough during the training. This suggests the need for the local IRB to improve its efforts at educating scientists of the fact that approvals for protocols must be renewed every year.There were limitations to this study. First, the time for the follow-up was too short to determine the extent to which trainees retained the information long-term. Second, it was not designed to determine the degree to which trainees actually applied what they learned from the training. Knowledge on quizzes may or may not predict how researchers or IRBs apply these principles to their own work, and that clearly is the outcome we all strive for in conducting research ethics education. Third, lack of a comparison group limits confidence to draw firm conclusions about the outcome of the training, although it is hard to see why or how changes in responses, particularly after the one month of the workshop would be due to factors other than the training. Fourth, case studies provided only limited information to trainees and there may have been misunderstandings of what the case was describing. For example, some of the trainees who incorrectly "disagreed" that the mock study was not reviewed by an ethics committee may have done so because this information was not provided in the case study. Finally, these problems reflect the inherent limitations in using a questionnaire to test effectiveness of research ethics training. Several of the items in the questionnaire may well have assessed participants' recall of factual information about codes or definitions rather than determining whether their ability to identify or help reason through an ethics dilemma in research actually changed. Admittedly, it is more straightforward to measure knowledge. Further research identifying tools to measure sophistication of moral reasoning skills would be an important contribution to evaluation of future training efforts. One alternative may be interviews with members of the IRB and with various health researchers throughout the institution at 12 months to determine if researchers approach their research any differently in terms of ethics considerations, and if the protocols submitted by trainees have changed accordingly.Although capacity development in research ethics for researchers, members of IRB, and sponsors of research is not, alone, a guarantee of safety for research participants, it is an important component of the interventions that can contribute to that goal. Capacity development for the conduct of ethical research is required across the globe, and it is especially necessary in resource constrained settings where the risk of exploitation in research may be higher. The training program reported in this article was developed to help fulfill this goal. The training met a previously unmet need for capacity development in research ethics among academic staff in a major Nigerian university. The training improved participants' knowledge of principles of research ethics, international guidelines and regulations, and operations of IRBs, but there is an ongoing need to develop an effective mechanism for assessing the application of knowledge trainees derived from this and similar interventions.The author(s) declare that they have no competing interests.AJA conceived the project, developed draft instruments, supervised data collection and wrote drafts of findings. NK reviewed and edited draft instruments, supervised data collection process, reviewed and edited draft manuscripts. Both authors read and approved of final manuscript.The pre-publication history for this paper can be accessed here:Pre and Post Test Questionnaire. The questionnaire is the instrument used to collect data on demographic information, knowledge about international guidelines, principles of research ethics, their application and ethics reasoning from workshop trainees.Click here for file


Community-acquired (CAP) and nosocomial pneumonias contribute substantially to morbidity and hospital resource utilization. Hyponatremia, occurring in >1/4 of patients with CAP, is associated with greater disease severity and worsened outcomes.+] < 135 mEq/L within 24 hours of admission value.To explore how hyponatremia is associated with outcomes in hospitalized patients with pneumonia, we analyzed a large administrative database with laboratory component from January 2004 to December 2005. Hyponatremia was defined as at least two  may impact these outcomes.Hyponatremia is common among hospitalized patients with pneumonia and is associated with worsened clinical and economic outcomes. Studies in this large population are needed to explore whether prompt correction of [Na Community-acquired (CAP) and nosocomial pneumonias represent a substantial burden to the US healthcare system. CAP alone is responsible for over 1 million hospital admissions annually . In addiHyponatremia is the most common electrolyte imbalance seen in clinical practice . It alsoTo extend our understanding of the epidemiology and outcomes of hyponatremia at the time of hospitalization among subjects with pneumonia, and to clarify the association of hyponatremia with the measures of hospital resource utilization, such as the need for mechanical ventilation (MV) and the need for and LOS in the ICU, we conducted a large retrospective cohort study. We hypothesized that hyponatremia at admission is associated with an increased risk of hospital death among patients with pneumonia and that this condition additionally adds significantly to HLOS and costs.No human subjects were prospectively enrolled in the study, and therefore an independent Institutional Review Board  granted an exemption and waived the informed consent requirement.® database, a sample of hospitals that contribute general discharge-level information, in addition to specific drug and laboratory information. Approximately 27 hospitals contribute data at any point in time, with 39 unique hospitals represented over the two-year study period from January 2004 through December 2005. The data source is de-identified in compliance with HIPPA regulations.Data were obtained from Solucient's ACTracker+] available during their hospital admission. For those patients who did not meet the laboratory definition for hyponatremia (see below), we further required that s/he have no primary or secondary diagnosis of hyponatremia (ICD-9-CM code 276.1).We identified persons with pneumonia based on the presence of the International Classification of Disease version 9, Clinical Modification (ICD-9-CM) 3-digit disease code for the principal discharge diagnosis of pneumonia (ICD-9-CM code 486) . We requ+] below 135 mEq/L on the first or second day of admission. To improve specificity for the diagnosis, we defined hyponatremia to be present if there was at least one additional [Na+] below 135 mEq/L within 24 hours of the admission value. We did not specifically seek to exclude pseudohyponatremia.Hyponatremia discharges were required to have an admission  measurement, patients with hyponatremia at admission who died prior to having a second [Na+] drawn are by definition not included in our mortality analysis. Additionally, to the best of our knowledge, ours is the first study to show an association of hyponatremia with such important components of the hospitalization as the need for MV and the need for and LOS in the ICU, as well as to derive hospital costs attributable to hyponatremia.Our study, although finding a lower prevalence of hyponatremia, adds to this earlier work. First, by employing a more restrictive definition, we confirm the general impact of hyponatremia on multiple outcomes and help clarify the importance of this factor. We further extend the earlier work in that our data derive from a larger and more generalizable multi-center cohort of patients with pneumonia. Simply put, with a sample size more than ten-fold greater we were able to explore more precisely the impact of hyponatremia on economic outcomes and measures of resource use. The lack of effect of hyponatremia on mortality likely reflects the overall low rate of mortality in our cohort. Reliance on a more stringent definition of hyponatremia may have also contributed to this discordant finding regarding mortality. Since we required a second [Na+] < 130 mEq/L) has been found to be better than CURB or CURB-65 at identifying low-risk CAP patients, and thus more helpful at avoiding potentially costly and unnecessary hospitalizations [+] value without compromising its simplicity.Pneumonia is an important driver of healthcare costs. The full burden of hospitalization with pneumonia in the US approaches 1.5 million cases annually and its economic impact may be close to $8 billion ,4-6 in hizations . HoweverAlong similar lines, and once the decision to admit to the hospital has been made, attention to modifiable determinants of hospital outcomes becomes a critical component of care in patients with pneumonia. As an illustration, a randomized controlled trial showed that a simple intervention consisting of making sure that a CAP patient is sitting out of bed or ambulating for at least 20 minutes during the first 24 hours of hospitalization cut the average HLOS fully by 1 day without an increase in adverse events . Approac+] and hospital mortality [+] < 135 mEq/L) of 20% and noted that there is a 20% increase in the risk of hospital death for each 3 mEq/L decrease in [Na+] below 140 mEq/L; admission hyponatremia was also independently associated with increased HLOS [+] < 135 mEq/L) and a similar association between hyponatremia and outcomes  value we may have eliminated a substantial number of patients with hyponatremia who died prior to having the opportunity to have had the second [Na+] checked. As far as the diagnosis of pneumonia, misclassification remains a potential concern, though, if present, it is most likely non-differential leading the estimated associations to appear less strong. Along the same lines, it is also possible that at least some of the included patients were actually misclassified cases of congestive heart failure. Though our dataset precludes us from confirming or refuting its presence, this misclassification is not unusual in clinical practice, and thus should not detract from the relevance of our estimates. Finally, we have not attempted to separate our cohort by the origins of pneumonia . Although of importance for future investigations, our aim for the current analysis was to answer a more general question of what role hyponatremia may play in any patient with an infection of the lower respiratory tract, regardless of its etiology.Our study has several important limitations that should be acknowledged. Firstly, because of its observational nature, the crude associations between hyponatremia and outcomes are likely confounded. Notably, we have attempted to address this limitation by performing multivariable analyses. However, the possibility of residual confounding remains. Secondly, by virtue of its retrospective design, the study is prone to several forms of bias. Thirdly, the fact that the data source is not clinical but administrative in nature makes our case definition prone to misclassification. Although the presence of laboratory data and our stringent definition of hyponatremia eliminated that as a limitation of exposure classification, the definition of pneumonia was somewhat less precise, as it relied on the presence of the corresponding ICD-9-CM code. Conversely, our stringent definition of hyponatremia may have itself resulted in an immortal time bias, such that our current estimate of mortality rate among hyponatremic patients is an underestimate of the actual risk of death. That is, by excluding cases without a confirmatory [NaIn summary, we have shown that hyponatremia is common among hospitalized patients with pneumonia and independently associated with worsened clinical outcomes, as well as with an increase in the utilization of MV, ICU and hospital resources. Future research needs to focus not only on how hyponatremia may affect subpopulations of patients with pneumonia, but also how severity of hyponatremia impacts hospital outcomes. Most importantly, studies are needed to evaluate the role of currently available therapies aimed at correction of hyponatremia in improving the outcomes of patients with pneumonia.This project was supported by a grant from Astellas Pharma US, Inc. Drs. Zilberberg and Shorr are consultants to Astellas Pharma US, Inc., who markets an arginine vasopressin antagonist. Drs. Exuzides and Colby, Ms. Foreman and Ms. Graves Jones are employees of ICON Clinical Research, which has received research funding from Astellas Pharma US, Inc. Dr. Spalding is an employee and a stock holder of Astellas Pharma US, Inc. The sponsor contributed to analysis planning but had no veto power over their performance or reporting of the data. All analyses were performed by ICON Clinical Research. No external medical writer was engaged to develop this manuscript.MDZ participated in the design of the study, data interpretation, drafting and revision of the manuscript for important intellectual content. AE participated in the design of the study, data acquisition and analysis, and drafting of the manuscript. JS participated in the design of the study, data interpretation and revision of the manuscript for important intellectual content. AF participated in the design of the study, data acquisition and analysis, and drafting of the manuscript. AGJ participated in the design of the study, data acquisition and analysis, and drafting of the manuscript. CC participated in data acquisition and analysis, and drafting of the manuscript. AFS participated in the design of the study, data interpretation and revision of the manuscript for important intellectual content.The pre-publication history for this paper can be accessed here:


Information extraction (IE) efforts are widely acknowledged to be important in harnessing the rapid advance of biomedical knowledge, particularly in areas where important factual information is published in a diverse literature. Here we report on the design, implementation and several evaluations of OpenDMAP, an ontology-driven, integrated concept analysis system. It significantly advances the state of the art in information extraction by leveraging knowledge in ontological resources, integrating diverse text processing applications, and using an expanded pattern language that allows the mixing of syntactic and semantic elements and variable ordering.OpenDMAP information extraction systems were produced for extracting protein transport assertions (transport), protein-protein interaction assertions (interaction) and assertions that a gene is expressed in a cell type (expression). Evaluations were performed on each system, resulting in F-scores ranging from .26 – .72 . Additionally, each of these systems was run over all abstracts in MEDLINE, producing a total of 72,460 transport instances, 265,795 interaction instances and 176,153 expression instances. OpenDMAP advances the performance standards for extracting protein-protein interaction predications from the full texts of biomedical research articles. Furthermore, this level of performance appears to generalize to other information extraction tasks, including extracting information about predicates of more than two arguments. The output of the information extraction system is always constructed from elements of an ontology, ensuring that the knowledge representation is grounded with respect to a carefully constructed model of reality. The results of these efforts can be used to increase the efficiency of manual curation efforts and to provide additional features in systems that integrate multiple sources for information extraction. The open source OpenDMAP code library is freely available at  Conceptual analysis is the process of mapping from natural language texts to a formal representation of the objects and predicates  meant by the text. The history of attempts to build programs to do conceptual analysis dates back to at least 1967 46]. ThreThe intimate connection between the ontology and the natural language processing system provides two significant advantages over prior information extraction systems generally. First, the output of the information extraction system is always constructed from elements of the ontology, ensuring that the knowledge representation is grounded with respect to a carefully constructed model of reality. In contrast, the outputs of most natural language processing systems are grounded only in substrings of text, not normalized to any model at all. Progress in normalizing biological entities recognized in text to specific database identifiers -54 has mThe second advantage of the OpenDMAP approach is that all of the knowledge used by the system to recognize concepts is structured by the ontology. In contrast, the nearly universal alternative approach is to embody knowledge of language into a lexicon, which associates individual lexical items with their possible semantic interpretations. In the OpenDMAP approach, information about which concepts are potentially relevant to the analysis of a particular text passage straightforwardly places limits on the linguistic knowledge relevant to analyzing that passage. This approach finesses many difficult ambiguity resolution problems faced by lexicon-driven systems, since these limits on the knowledge applied to conceptual analysis prevent many multiple interpretation problems from arising at all. For example, the string "hunk" refers to a cell type , a gene , and the general English word meaning a large piece of something without definite shape. A traditional, lexicon-driven system would have an explicit method for assigning the correct word sense to any occurrence of the string "hunk." However, OpenDMAP patterns specify expectations of semantic classes ; if it is possible to construe a string as an instance of an expected class, the pattern matches. The fact that there might be possible alternative interpretations of the matching string has no consequence, and no explicit ambiguity resolution step is necessary. Ambiguity is a leading cause of errors in text processing systems, and this approach is one of the contributing factors to OpenDMAP's superior performance. Our top-down approach to restricting possible interpretations does not address all problems due to ambiguity in language; for example, errors in preprocessing systems  are not effected.The use of UIMA greatly facilitates the incorporation of various applications as input to OpenDMAP. The outputs of NLP tools integrated into the system are described by the extensible UIMA type system. In the case that a new type of information is produced by a preprocessor, OpenDMAP patterns would have to be modified to take advantage of the new type of information available. For example, the first time an external cell type tagging system is added, the UIMA type of the result of that processor must be linked to a cell-type concept in an OpenDMAP ontology in order for it to be used in patterns. However, if a new NLP tool produces a UIMA output type that has been used by OpenDMAP previously, then no changes in the ontology or patterns are needed.We believe that the outputs of information extraction systems are not likely to useful until the F-score (or at least the precision) is greater than about 0.85 , so the Error analysis of the false positives in the transport data set indicates that more than 80% are due to errors in the syntactic analysis. For example, in the sentence "Rho protein regulates the tyrosine phosphorylation of FAK through translocation from the nucleus to the membrane," the subject of the translocation was incorrectly identified as FAK (rather than Rho) by the Stanford parser. That parser was developed for general English rather than biomedical text, so using specialized syntactic analysis systems may improve the precision of OpenDMAP. Remaining problems in false positives are due to problematic tokenization, failures to properly resolve anaphoric reference, and, rarely, negation. False negatives are due to gaps in concept recognition patterns, more than half of which arise from a failure to properly handle coordinated clauses and conjunctions. Addressing these issues remains an open area of research.Another issue was that the Stanford parser was too slow to use in the application of the transport system to all of Medline, so it wasn't run. OpenDMAP ignores aspects of patterns that require inputs that aren't present, so the patterns that contained syntactic dependencies did not have to be altered. These syntactic constraints are important for accuracy, however. Tested on the gold standard set for the system without the parser precision drops to 0.62, while strict recall remains largely unchanged, rising to 0.51.Despite OpenDMAP elevating the state of the art for biomedical information extraction significantly beyond previous levels, error rates remain high. In the most challenging BioCreative task, finding curatable assertions in full text documents, only about 29% of the relevant assertions were found, and only about 39% of the extracted assertions were completely correct. Such error rates mean that automatically generated databases cannot replace manual curation efforts. However, the evidence is quite clear that manual curation cannot keep up with the rate of data generation . The surAlthough the outputs produced by large-scale IE systems are not yet suitable for producing factual databases for direct use by biomedical researchers, the current level of performance provides two important facilities to the research community. First, the results of these efforts can be used to significantly increase the efficiency of manual curation efforts. Each extracted assertion is tied to a specific text, which can be used to direct the attention of manual curators both to relevant documents and to specific relevant passages within a document. Effective integration of IE results into curatorial workflows will require the development of new tools. OpenDMAP developers are working with curators at IntAct to address these issues. The open source availability of OpenDMAP will facilitate the work of others addressing this issue as well. The second important use of the sorts of results that IE systems are currently able to generate is in statistical integration with multiple sources of noisy data, such as those described in  and 58]58]. As dOpenDMAP uses Protégé  to proviFor the transport task, patterns were produced for 30 ontology concepts; eight directly related to transport and 22 others for cellular components that are the sources and destinations of transport. A large number of other concepts  do not have explicit patterns associated with them, but are instead tagged as such by UIMA tools during preprocessing. The protein-protein interaction task involved producing patterns for nine concepts, and the cell expression task required patterns for six additional concepts.The UIMA architecture  manages In order to be able to recognize a concept in text, OpenDMAP associates one or more patterns with each concept. A pattern describes the words, phrases, parts of speech, syntactic structures or concepts that should cause an instance of the associated concept to be recognized. A simple pattern, such as the one shown in equation 1, enumerates a disjunction of words that should trigger recognition of a concept.The patterns for all of the CELLULAR-COMPONENT concepts were derived from the GO term names and synonyms, supplemented with derivational variants, such as the adjectival "nuclear" in equation 1. Twenty-two GO cellular component terms were used, along with 19 synonyms associated with the GO terms, and 78 additional derivational variants generated by inspection of the training corpus.More complex patterns can include references to non-terminals, particularly other concepts. Equation 2 is one of the patterns for recognizing instances of the PROTEIN-TRANSPORT concept. This pattern specifies that a reference to PROTEIN-TRANSPORT can appear in text as a reference to a concept that can fill the [TRANSPORTED-ENTITY] slot, followed by the word "translocation" followed optionally by a phrase beginning with the word "from", possibly including a word with the part of speech determiner, and a concept that could fill the [TRANSPORT-ORIGIN] slot, also followed optionally by a similar phrase that regarding the [TRANSPORT-DESTINATION] slot.When a pattern that includes a slot name is matched, the instance created has its slots filled with the concepts that matched the slot names in the pattern. For example, the above pattern matches the GeneRIF that contains "... Bax translocation to mitochondia..." (from Entrez GeneID 27113). Bax, which is recognized as a protein by ABNER, will cause an instance of the protein concept to be created; an instance of a protein matches one of the constraints on filler of the [TRANSPORTED-ENTITY] slot, which causes that slot to match to the Bax protein concept. The word "translocation" matches, and, while the optional "from" clause does not match, the "to" clause does match, since "mitochondria" matches one of the patterns for a subclass of CELLULAR-COMPONENT, the constraint on the filler of the [TRANSPORT-DESTINATION]. Since the entire pattern matches, an instance of PROTEIN-TRANSPORT is created, with the Bax protein concept in its [TRANSPORTED-ENTITY] slot and an instance of the mitochondria concept (from GO's cellular component hierarchy) in its [TRANSPORT-DESTINATION] slot.OpenDMAP patterns can express variability in word and phrase order. Note, for example, that equation 2 would fail to match the phrase "Bax translocation to mitochondria from the cytosol." The special pattern marker @ is used to identify a set of subpatterns that are both optional and can occur before or after a required phrase; multiple @ marked phrases can occur in any order. For example, equation 2 can be modified with this marker to recognize the above text:Many sentences in the literature express multiple concepts, making extraction of even simple assertions problematic. Consider the following GeneRIF from GeneID:29560: "...HIF-1alpha which is present in glomus cells translocates to the nucleus...." The intervening phrase "which is present in glomus cells" prevents the pattern in equation 3 from matching that sentence. OpenDMAP does have a wildcard character (underscore) that could be added to the pattern in equation 3, between the [TRANSPORTED-ENTITY] concept and the word "translocation," allowing this sentence to be matched. However, using such a wild card would make any protein mentioned before the word "translocation" match the pattern, which is too promiscuous. To address this problem, OpenDMAP allows patterns to specify syntactic constraints on potential matches. For example, the [TRANSPORTED-ENTITY] slot can be constrained to have a syntactic dependency on the head of a phrase that contains the translocate action, thereby constraining it both semantically (it must be a protein or molecular complex) and syntactically . Furthermore, the reliance on the exact word "translocation" can be relaxed to be any reference to a transport action word, including both verbal and nominal forms of multiple terms . The PROTEIN-TRANSPORT class is extended to have an [action] slot that specifies the type of transportation action, to keep track of the term that was used. Equation 4 demonstrates the pattern language for specifying syntactic constraints:The use of the variable "x" in the specification identifies a specific syntactic unit, linking the dependency to the head of a phrase. Multiple variables can be used to specify constraints on different syntactic units within a sentence.OpenDMAP patterns are very powerful. Only five such patterns, shown in equations 5–9 were required for the transport extraction system performance noted above. These patterns were devised manually, based on expert knowledge of the domain and on a small training set of sample GeneRIFs.These patterns were augmented with 119 cellular component patterns.The test data used in the transport and expression evaluations were marked up by domain experts trained in conceptual annotation, using the Knowtator annotation tool . under the Mozilla Public License v1.1 (OpenDMAP) and GPL v2.0 license (UIMA wrappers). The results of the information extraction effort are available as RDF format files in the Additional Files The OpenDMAP platform-independent Java 1.5 source code, including UIMA wrappers for the tools used in this work and the patterns for the three tasks, is available from LH conceived of the project, supervised the design and implementation of the system and wrote the manuscript. ZL was responsible for the transport project, including writing the patterns and analyzing the results; he also contributed suggestions for the interaction task. JRF implemented the OpenDMAP pattern recognition engine and its UIMA wrapper. WAB wrote all other infrastructure software, including the other UIMA wrappers, managed the data, applied OpenDMAP to all of MEDLINE, and designed and built other software. HLJ was responsible for the interaction and expression projects, including writing the patterns, analyzing the results, and doing the associated error analyses. PVO managed the creation of the gold standard data for transport and contributed to the design of the pattern language syntax. KBC managed the team, selected the preprocessing tools, coordinated and supervised the interaction and expression task efforts, and provided linguistic and software design contributions during all phases of the project. All authors have read and approved this manuscript.Transport instances from MEDLINE. This file contains the RDF formatted instances of transport, mined from MEDLINE with OpenDMAP.Click here for fileInteraction instances from MEDLINE, part 1. The interaction data set is very large. This file contains the first half of RDF formatted instances of interaction, mined from MEDLINE with OpenDMAP.Click here for fileInteraction instances from MEDLINE, part 2. The interaction data set is very large. This file contains the second half of RDF formatted instances of interaction, mined from MEDLINE with OpenDMAP.Click here for fileExpression instances from MEDLINE. This file contains the RDF formatted instances of expression, mined from MEDLINE with OpenDMAP.Click here for file


Sir,British Journal of Cancer into the variability in housekeeping gene expression under different oxygen tensions.We have read with great interest the study by et al, however, the housekeeper is not used for compensation in differences in RNA quality, as this is much less of an issue in cell lines than in retrospectively analysed stored tumour tissue. Thus, the housekeeping gene suitable for normalisation of cell-line expression levels under different oxygen tensions should be primarily constant between different levels of hypoxia. For this reason, we have selected 18S to compensate for input, RT, and PCR efficiency for in vitro hypoxia experiments (We concur with the authors that the choice of normalising gene can have important consequences on the results obtained, and should therefore be validated for the experimental setup, tissue, or cell line under investigation. Earlier, we have carried out a similar investigation of 13 different housekeeping genes in 80 different tumour and normal tissues, trying to compensate for both differences in tumour grade and RNA quality (et al.We would be interested in learning how 18S expression levels compared to the expression levels of the other genes tested by Caradec


This conference will feature the best of the computer and life sciences through a variety of core sessions running in multiple parallel tracks, along with single-tracked Keynote Presentations, posters on display throughout the duration of the conference, and an extensive commercial exposition. The first day (July 18) of the meeting is reserved for two-day Special Interest Group (SIG) and Satellite meetings, the second day (July 19) runs SIGs for the first time in parallel with Tutorials and the Student Council Symposium, and for the first time two SIGs are running in parallel with the main ISMB meeting (July 20–23).The International Society for Computational Biology (ISCB) presents the Sixteenth International Conference on Intelligent Systems for Molecular Biology (ISMB 2008), to be held in Toronto, Canada, July 19–23, 2008. Now in the final phases of scheduling selected presentations, demonstrations, and posters, the organizers are preparing what will likely be recognized as the premier conference on computational biology in 2008. ISMB 2008 . ISCB has been organizing the ISMB conference series since 1998. While ISCB evolved into the only society representing computational biology globally, its flagship conference has become the largest annual worldwide forum focused on computational biology. In January 2007, the ISCB came to an agreement with the European Conference on Computational Biology (ECCB) to organize a joint meeting in Europe every other year. This led to the ISMB/ECCB in Vienna in 2007 that set the standard for a large-scale integrative forum for all those with interest in subjects related to computational biology.The ISMB conference series began in 1993, the result of the vision of David Searls (GlaxoSmithKline), Jude Shavlik (University of Wisconsin Madison), and Larry Hunter (University of Colorado). A few years later, ISMB had established itself as a primary event for the computational biology community and triggered the founding of ISCB, the International Society for Computational Biology (http://incob.binfo.org.tw/) has already been sponsored by ISCB, and another one in North Asia is going to follow. ISMB itself has also been held in Australia (2003) and Brazil (2006).ISCB is now focusing on expanding participation beyond North America and Europe, which has accounted for the majority of participants during the history of ISMB. One meeting in South Asia , two for presentations from high-profile work published in refereed journals (Highlights Tracks). Further expansion may offer even greater opportunities to include new and relevant areas of research into the scientific program.Accepting this complex challenge already implies the need for at least four parallel tracks: two for presentations from proceedings . Most papers accepted in past ISMB proceedings were by investigators who were already established in the community. Published work with a track record of being a highlight in the field finds a home in the Highlights Track. One of the selection criteria for a Highlights talk is that the designated presenter has strong presentation skills. Thus, most presenters are already well-known in the community. An important body of work is typically the prerequisite for invitation for a Keynote Presentation by an accomplished researcher. Finally, the Special Sessions are ways to expose the field to areas and novelties that are not already integrated into the community. The extension of what was previously a track for software demonstrations to a more inclusive Technology Track now includes investigators from all scientific career stages.One way of drawing the dividing line between the multiple events  is with Keynote Presentations (http://www.iscb.org/ismb2008/keynotes.php) are run in a single track with no other competing session and typically attract most participants. In Toronto we will continue our pursuit of several missions for these talks: to make the marriage between computational and experimental biology more beneficial for biology, to present outstanding, exciting, and thought-provoking jewels of the biological sciences, and to celebrate the marvels uniquely represented in the world by ISCB.The Keynote Presentations feature the winners of the annual ISCB awards—the Overton Prize, in memory of Chris Overton, for outstanding investigators early in their career, and the Accomplishment by a Senior Scientist Award given to those at the zenith of their career who have made major contributions to the field of computational biology through research, education, service, or a combination of the three. This year's Overton prize goes to Aviv Regev , and the Senior Scientist award goes to David Haussler . The awards will be presented along with the accompanying Keynote addresses. In fact, the Senior Scientist will conclude the scientific presentations of ISMB on the afternoon of Wednesday, July 23. Claire M. Fraser-Liggett : David Jaffe , Hanah Margalit , Eugene M. Myers , Bernhard Ø. Palsson , and Morag Park . These lectures will review recent outstanding results in areas such as Oncology, Metabolic modeling and reconstruction, transcriptional regulation, genomics, microbiology, neuronal Imaging, and new sequencing technologies.Two Special Sessions Track  will enable in-depth focus on emerging and important areas. Seven Special Sessions will cover a wide spectrum of topics, including cancer research, virology, proteomics, new generations in technologies including sequencing, mass spectrometry, flow cytometry, and cell imaging. For example, the session on Health and Diseases in our Genomes chaired by ISMB's honorary co-chair Thomas Hudson  will highlight the role of computational biology spanning from analyzing human genome variability to understanding disease. Other Special Sessions will feature the Toronto scientific community's efforts towards aspects of proteomics and disease, e.g., Interaction Networks and Disease chaired by Shoshana Wodak and Gary Bader  and Structural Bioinformatics: Deciphering the Proteome chaired by Igor Jurisica  and Ryan Lilien . Imaging techniques are introduced in Frontiers in Cell Imaging chaired by Robert F. Murphy , the challenges of tackling the interactions between organisms are summarized in Computational Challenges and Opportunities in Host–Pathogen Systems Biology chaired by T. M. Murali and Matthew D. Dyer , and the very large-scale sequencing of the future is previewed in Sequencing Thousands of Human Genomes chaired by Francisco De La Vega  and Gabor Marth .For the second year, a PLoS Computational Biology, present a perspective on the Future of Scientific Publishing chaired by Scott Markel . This is one of the two events highlighting the connection between ISCB and PLoS Computational Biology .Finally, a group of investigators involved with both ISCB and the Society's official journal, Special Sessions will review the current state of a specialized field, and will explore growing opportunities for computational biologists and the need for new tools and methodologies.All ISMB Proceedings as a special issue of the journal Bioinformatics. Common practice for computer science precludes the re-publication of material published in Conference Proceedings in any other peer-reviewed journal or meeting. Thus, the special issue of Bioinformatics increases the value of these Conference Proceedings for the more biology-oriented members in the field. In 2008, we received 287 submissions to this track; Alfonso Valencia  chaired the rigorous review process modeled on the editorial review in scientific journals. He and his team of Area Chairs selected 48 (16.7%) original research papers for presentation in Toronto. This acceptance rate is slightly higher than ISMB/ECCB 2007.Traditionally the major event at the ISMB meetings is the presentation of original papers, which are published in the Proceedings, in contrast, have to be ready by May. For the first time, the mechanism of revision for some of the submissions was used, by Alfonso Valencia and his team of experts, which accounted for the higher acceptance rate.One problem for the reviewers is that submissions have to be accepted or rejected given the submitted material without the conditional acceptance pending major revisions that satisfy the authors. In fact, most papers accepted by journals go through revisions and are published whenever ready; the Bioinformatics under the open-access model, i.e., will be made freely available, and, as in previous years, will be fully indexed in PubMed and by the Institute of Scientific Investigation (ISI).Papers will be presented in two parallel tracks. The paper reviewing process put increased weight on work that opens new directions and is likely to impact molecular and medical biology. All papers selected for oral presentation will be published in the conference proceedings as part of a regular online issue of Highlights Track (http://www.iscb.org/ismb2008/highlights.php) featuring recently published, high impact work. Work from highly ranked journals and from journals traditionally featuring more experimental biology is welcome. As with the other two tracks that were introduced in Vienna , the Highlights Track was very well received by many participants, as it increased diversity and added quality. This year, we received 189 proposals for this track. A diverse team of accomplished and dedicated experts accepted 61 of those for presentation in two Highlights Tracks in Toronto  will run for the second year and is for talks that are more relevant and interesting for participants from industry. Chaired by Reinhard Schneider , this track introduces a new forum for the meeting of academia and industry in a venue that highlights innovative applications and practical impact studies of Life Science Informatics. Each selected talk will describe a scientific problem from a business perspective, including the approach used to address the problem, the current state of the project, an evaluation of the benefits, and plans for future developments. These presentations are tailored to give attendees the opportunity to view scientific approaches through an industrial lens, which may prove especially valuable to young researchers' understanding of the use of Life Science Informatics in the business sector.The Demo sessions have proven to be in high demand, and have consistently added a valuable aspect of the conference for both presenters and attendees alike. These traditional demonstrations are currently being selected by a team of experts chaired by Rodrigo Lopez  and a team of experienced colleagues.Demonstrations of software have also become an integral part of the ISMB and ECCB conference series, and are now also offered at other bioinformatics conferences. Demos allow academic institutions as well as for-profit organizations to showcase their software and/or hardware in a hands-on format to audiences of up to 50 participants. The Demo to Technology Track reflects the following extensions and novelties. Firstly, we will give institutions and research consortia the opportunity to reserve a block of slots and use this to evolve the concept of a demonstration into a series of synchronized demonstrations. The second is another Toronto pilot: in addition to the traditional tutorials, we will introduce interactive, hands-on workshops for freely available software tools and methods. The ones chosen for the pilot reflect the wide range of popular packages and the range of activity in Computational and Systems Biology. These workshops will be more comprehensive than the current “demos” and give attendees an opportunity to bring their own data, laptops, and problems for practical learning.For the Toronto meeting, we decided to extend the concept of demonstrations by integrating other events that had no traditional place in the ISMB framework. The change in the name from Posters (http://www.iscb.org/ismb2008/posters.php) accepted for presentation will be on exhibit for the entire meeting. Over the years, ISMB has grown to a size that has made it impossible to display all accepted posters during the entire conference. Yet, posters bring enormous value to the conference. The Metro Toronto Convention Center hosting ISMB 2008 has the capacity to accommodate more than 1,000 Posters on display at the same time. Therefore, we are especially pleased to ease the viewing of Posters by allowing all attendees the opportunity to view and absorb this abundance of research in a single venue. Two Poster Author Sessions, carved out of the evening program, will provide an opportunity to further explore posters of specific interest to any attendee: one evening for even- and one for odd-numbered Posters will be available. Marco Punta  chairs the selection of Posters in Toronto.For the second time, all SIGs;http://www.iscb.org/ismb2008/sigs.php). For Toronto, the event is coordinated by a group of experts chaired by Hershel Safer . Five meetings will run for two days (July 18–19) and four for one day. The two-day meetings are: 3Dsig: Structural Bioinformatics & Computational Biophysics, the Bioinformatics Open Source Conference (BOSC), BioPathways, Alternative Splicing, and the Joint AFP-Biosapiens SIG. Two of the one-day meetings will precede the main meeting: BioLink (July 18) and Next Generation Sequencing (July 19). Two others will occur during the main meeting: Bio-Ontologies (July 20), and Genome-Scale Pattern Analysis in the Post-ENCODE era (July 21).An increasingly important aspect of ISMB is the series of smaller meetings that accompany the main event, namely the Satellite and Special Interest Group Meetings  that ran the day before the main meeting. Janet Kelso  chairs this event. In the attempt to shorten the overall meeting, the Tutorials will be given in parallel with some of the SIGs on July 19.From the beginning, an integral part of ISMB has been the ISCB Student Council Symposium  on July 18 chaired by Lucia Peixoto  and Amr Abuzeid , will run in parallel with the first day of two-day SIGs preceding ISMB. Each of these pre-conference meetings offers additional opportunities to learn and network with a specific group of peers of similar interests and goals.For the first time, the Exposition that runs through the entire main meeting (July 20–23). The ISMB Expo has consistently proven to be highly successful for the exhibiting companies featuring products and services of specific value to the computational biology community. Similarly, ISMB attendees take full advantage of the opportunity to meet one-on-one with the conference sponsors and exhibitors to catch the latest updates and information on valuable software, hardware, publications, and tools of the trade. Overall, the Expo is another avenue focused on the importance of industry in science, and many of the exhibitors present talks in the Industry Track to detail the problems, applications, benefits, and future plans being addressed within their companies.Another pillar of ISMB is the Attendees traveling with family members and/or children will find this year's event offers a variety of optional tours and activities during the meeting, and extended tours on dates surrounding the conference. Specifically for those traveling with children, we are working on providing childcare options and information that would enable parents to attend the meeting while children are safely entertained.Visual Reflections on Science (http://www.iscb.org/ismb2008/vrs.php) organized by the ISCB Student Council  and chaired by Milana Frenkel-Morgenstern . A space has been set aside for the presentation of ideas that reflect upon science from a very different perspective—perhaps more art than science. Finally, we will celebrate the 16th ISMB with an Off-Site Dinner followed by the high energy Matrix Party; this event will happen in Toronto's Liberty Grand (http://www.libertygrand.com/) entertainment complex.Two other Toronto novelties try to expand into different realms: The first is Many of us may remember our first ISMB and our surprise at how many colleagues we wished to connect with attended the meeting. ISMB connects an interdisciplinary scientific community through a single, international point of contact. ISMB has been growing in terms of its breadth of coverage and the number of presentations .At our current size, it becomes extremely challenging to identify venues that are big enough to host meetings and at the same time small enough to foster informal communication and a more intimate feel. While many countries have venues that would allow meetings of between 1,000 and 5,000 participants, such venues often do not permit the level of full-scale parallelism that ISMB has grown into . The Metro Convention Center in Toronto is one of the few sites that appear to be ideal for the goals of ISMB.ISMB 2008 Registration (http://www.iscb.org/ismb2008/registration.php) discounts, while non-members are offered a complimentary one-year-membership as part of their higher non-member fees. The early bird registration discount period ended June 4 for all registration categories, although registration will remain open through the conference dates.ISMB 2008 is expected to draw more than 1,400 attendees to Toronto to take part in the world's largest and most scientifically comprehensive bioinformatics meeting of the year. ISCB members gain significant We hope to welcome all of you in Toronto.


In South Africa, the severity of the HIV/AIDS epidemic varies according to geographical location; hence, localized monitoring of the epidemic would enable more effective prevention strategies. Our objectives were to assess the core areas of HIV infection in KwaZulu-Natal, South Africa, using epidemiological data among sexually active women from localized communities.A total of 5753 women from urban, peri-rural and rural communities in KwaZulu-Natal were screened from 2002 to 2005. Each participant was geocoded using a global information system, based on residence at time of screening. The Spatial Scan Statistics programme was used to identify areas with disproportionate excesses in HIV prevalence and incidence.This study identified three hotspots with excessively high HIV prevalence rates of 56%, 51% and 39%. A total of 458 sexually active women  were included in these hotspots, and had been exclusively recruited by the Botha's Hill (west of Durban) and Umkomaas (south of Durban) clinic sites. Most of these women were Christian and Zulu-speaking. They were also less likely to be married than women outside these areas  and more likely to have sex more than three times a week  and to have had more than three sexual partners . Diagnosis of genital herpes simplex virus type 2 was also more common in the hotspots. This study also identified areas of high HIV incidence, which were broadly consistent with those with high prevalence rates.Geographic excesses of HIV infections at rates among the highest in the world were detected in certain rural communities of Durban, South Africa. The results reinforce the inference that risk of HIV infection is associated with definable geographical areas. Localized monitoring of the epidemic is therefore essential for more effective prevention strategies - and particularly urgent in a region such as KwaZulu-Natal, where the epidemic is particularly rampant. It is estimated that more than 60% of the world's HIV-infected population lives in sub-Saharan Africa, and South Africa is currently experiencing the heaviest HIV/AIDS load in the world . In SoutUse of current HIV prevention methods, such as condoms, monogamy and abstinence, is not always realistic in practice for many reasons. The need for improved preventative technologies against HIV infection remains urgent. Researchers are trying to develop an effective microbicide that could be used by women to help prevent HIV transmission. However, clinical trials of the efficacy of microbicides have so far proved disappointing -7.As the epidemic continues its devastating impact in this region, geostatistical approaches have received increasing attention as a way of determining possible "hotspots" of HIV infection and prioritizing areas for intervention ,9. If foHowever, investigating the spatial structure of the HIV epidemic can be challenging. Sparsely populated, large geographical areas can mask geographical heterogeneity and may potentially cause misinterpretation of true underlying geographical patterns .The HIV Prevention Research Unit of the Medical Research Council in Durban, KwaZulu-Natal, has been involved in many international research programmes and clinical trials in HIV prevention, playing an important role in the fight against HIV . The role of this unit includes teaching thousands of women about caring for themselves, including using condoms, and encouraging them to test for HIV, as well as helping those already infected.In this study, we investigated the geographical clustering of HIV infection using data from six geographical strata; these came from two of the unit's site-preparedness studies and one HIV prevention phase III clinical trial of vaginal diaphragms. The cohorts of women were drawn from rural, semi-rural and urban communities in KwaZulu-Natal.The geographical data (latitude and longitude) obtained using the geographic information system (GIS) and global positioning system (GPS) technologies were fed into a statistical programme  to charaWe hypothesized that geographical clusters of HIV infection would represent location-specific networks, and could be used as the basis to link socio-demographic data to show that these clusters represent relatively homogenous groups of women, thus allowing a large sexual network to be divided into smaller sub-communities. We also addressed the question of whether or not other demographic or sexual behavioural data could further differentiate the geographically distinct clusters in this region. Such data could provide valuable insight into the spread of HIV infection.We combined data from 5753 sexually active women who consented to screening for three studies from six clinics and 158 census locations included in this study. The studies were as follows: the Methods for Improving Reproductive Health in Africa (MIRA) trial of the diaphragm for HIV prevention, September 2002 to September 2005  ; the MicDetails of participants' places of residence were collected on a locator information form at screening, and residential areas were captured onto a spreadsheet. Field staff visited each participant's place of residence; once an appropriate satellite fix was acquired, the coordinates were recorded on a hand-held GPS device, and a back-up hard copy of the data was also created.Participants' confidentiality was ensured by using identifying numbers linked to the GPS coordinate reading, instead of names and addresses. At the end of each working day, field staff captured the coordinates digitally on a spreadsheet. These data were forwarded to the GIS lab and geographical coordinates for each of 158 census locations were used as a proxy for the location of participants in the study.For the MIRA and HPTN 055 trials, HIV diagnostic testing was achieved using two rapid tests on whole blood sourced from either finger-prick or venepuncture . During the MDP feasibility study, the Abbot IMX ELISA test , in combination with the Vironostika HIV1/2 ELISA for positive and equivocal results, was used on whole blood sourced from venepuncture. Only women who had a test result and geographical data were included in the study.The main eligibility criteria were consistent across the trials and included: being sexually active; being HIV negative at screening at inclusion; willingness to provide written consent and follow study procedure; not being pregnant and with intention to maintain this status; and residing in and around the study area for a minimum of one year. At all visits, all participants received counselling on risk reduction and as many male condoms as desired. Counsellors emphasized that condoms are the only known method to prevent HIV and sexually transmitted infections (STIs), and that condoms should be used for every act of sex.Women who were identified as HIV positive at screening were referred to local health care facilities for care and support. Women who seroconverted during the trial remained in the study and were provided with ongoing counselling and referred to local health care facilities for further care at the end of the study. The protocol and informed consent forms were approved by the respective ethics committees at each site.The geographical data obtained from GIS/GPS techniques were used to determine the potential areas with an excess of HIV infection by using the Spatial Scan Statistics (SaTScan) programme developed by Kulldorf . This haA Poisson-based model was chosen, where the number of HIV counts in an area is Poisson distributed according to a known underlying population at risk. Under the Poisson assumption, the likelihood function for a specific window is proportional to:C is the total number of cases, c is the observed number of cases within the window, and E[c] is the covariate adjusted expected number of cases within the window under the null hypothesis. Since the analysis is conditioned on the total number of cases observed, C- E[c] is the expected number of cases outside the window. I is an indicator function. When SaTScan is set to scan only for clusters with high rates, I is equal to 1 when the window has more cases than expected under the null-hypothesis, and 0 otherwise.where For a given zone (circular window), the methodology calculates the probability of a data point being a case inside or outside the circle under consideration. For each circle, a likelihood ratio is computed for the alternative hypothesis that there is an increased risk of disease inside the circle, against the null hypothesis that the risk inside the circle is the same as that outside. In this context, a cluster or hotspot is said to be detected within a defined geographical area during a specific timeframe if the area has a disproportionate excess of HIV cases when compared with neighbouring areas under study.By meeting the statistical assumptions of a set of statistical models, an unusual rise or reduction in cases in a specific spatial area can be characterized by statistical significance. The sets of potential clusters are then rank-ordered according to the magnitude of their likelihood ratio test statistics.Once the null hypothesis is rejected and clusters are formed, this means that the number of HIV infections detected in this region is significantly different from those in other study areas. Socio-demographic and behavioural characteristics of the women within these hotspots were compared with those of women outside of them. Cluster detection analysis was restricted to the "spatial option" only because the temporal variation in this study was not large enough to detect any temporal clusters.The user-defined maximum radius used by SaTScan was set to its default value of 50%, as recommended by Kulldorf  as optimt test (a nonparametric test) to compare differences in continuous variables.The Chi-square test was used to compare differences in proportions, and Student's http://www.satscan.org, and results were imported into the Stata  software environment to compare the characteristics of cluster (hotspots) and non-cluster areas.Calculations were carried out using SaTScan version 8.0 As described earlier, our study included women who consented to participate in one of three studies from six clinic sites and 158 census locations, from among a total black female population of ~2,400,000. Figure Table Analysis identified three hotspots or clusters of prevalence, and these included 458 cases  recruited at two study sites: a less urbanized clinic in Botha's Hill and a peri-urban clinic in Umkomaas. These three hotspots were determined to be areas of particularly high prevalence when compared with other study sites  Figure .In one cluster, 144 (31%) HIV cases were determined to be centred within a 4.5 km radius in Inchanga and Hammersdale , west of Durban. The second cluster included 168 (37%) HIV cases within a 32 km radius in the south of Durban, from the three residential areas of Umzinto, Molweni and Mtwalume . Like the first, the third cluster was again located west of Durban, with 146 (32%) HIV cases  in residential areas encompassing Hillcrest and Botha's Hill.Distribution of the demographic characteristics and reported sexual behaviour of women who fell within the cluster areas or hotspots were compared with those who did not Table .Trichomonas vaginalis) (p = 0.987) and current contraceptive use (p = 0.835).Women who fell within one of the three hotspots were similar in terms of age (p = 0.548) and education level (p = 0.481) to those who did not. Proportions of women were similar between those in the hotspots and those who were not in terms of those living with a regular sex partner , being diagnosed with an STI . Significantly more women in the geographical hotspots reported being Christian  and speaking Zulu at home  compared with those in non-cluster areas.More women within the hotspots reported having sex an average of three or more times per week  and to having three or more sexual partners in their lifetime  compared with those outside the hotspots. Also, significantly more women within the hotspots were diagnosed with genital herpes simplex virus type 2 (HSV-2) than those not in these areas .A total of 2523 HIV-positive women enrolled in the three studies were eligible, with a median duration of follow up of 12 months. Of these, 211 had seroconverted during the follow-up period (incidence rate 6.6/100 women-years). Using the SaTScan programme, and adjusting for the underlying population at risk and age, a total of 48 of the women who seroconverted  were geographically clustered into four hotspots . The second hotspot included Camperdown and Cato Ridge  and another included Hillcrest and Botha's Hill , both located west of Durban, within 4.3 km and 3.73 km radii, respectively. The fourth hotspot included Umkomaas and Mkomanzi  south of Durban.Our study identified three localized hotspots of high HIV prevalence; two of these were exclusively located west of Durban and included women from two of the clinical sites. In addition, four hotspots of high HIV incidence were found, two of which overlapped with high HIV prevalence areas and also comprised census areas west of Durban.The Spatial Scan Statistics programme was used to investigate geographical patterns and variations in HIV prevalence within the relatively homogeneous population. Strong statistical evidence of clustering of HIV infections in communities of Durban was found. This supports the notion that risk factors for HIV might be associated with certain specific socio-economic characteristics, which could be targeted to improve existing public health prevention measures aimed at the general population.Prevalence of HIV infection in South Africa has always been reported either on a national basis or as a provincial average . While iThe results from this study support the conclusion that risks for HIV infection are associated with definable socio-demographic factors, which may be fundamental ecological units of HIV transmission . A multiThe spatial clustering of HIV cases was found to be related to certain demographic and risk behaviours. Number of male sexual partners was not collected in this study; however, being single, combined with high frequency of sexual acts, gives strong evidence for those women having multiple partners, as well as possibly engaging in transactional sex.These results may be due to fundamental differences between the communities with regard to health care centres, population density and other socio-economic factors. These data provide new evidence to support the need to investigate potential sources of infection and to study transmission patterns in the community in order to apply relevant interventions for prevention of this devastating disease.Our data suggest strategies for targeted control and for prioritization of scarce resources. A community-based prevention programme could be formulated to educate residents in these endemic areas about the risks associated with HIV and other high-risk sexual behaviours.Information on the spatial distribution of populations and services is essential to understand access to health services. There should be specially focused strategies to optimize health care for people living in the high-risk areas. Spatial analysis is an important tool for monitoring the HIV epidemic, predicting future treatment demands, and targeting areas for public health interventions. The mapping of areas of high HIV prevalence will aid community interventions, such as education, prevention, treatment and care, and optimum location of referral health centres.The strength of our study is that we were able to use data from a region that is at the epicentre of the HIV epidemic in South Africa, if not the world, to determine core areas of the epidemic.Our study has some limitations that need to be considered in the interpretation of the results. First, because of the nature of the research conducted in these trials, populations selected were known to be moderate-to-high risk of HIV infection. Although we were able to target women from different communities in different settings , the women in this study may not necessarily be representative of women in the KwaZulu-Natal province. Second, this analysis is that sexual networks may be subject to temporal trends, which we were not able to determine. Third, we were unable to collect any sexual behaviour data from male partners of the women, which can have a substantial impact on the results. Therefore, additional research is required to fully understand the reasons for these spatial variations in HIV infections in this region, and important insights will be gained by further in-depth study of the communities identified in this study.Another limitation of the approach used in the present study is the circular nature of the SaTScan window; SaTScan identifies clusters by imposing circular windows on maps and allowing the size of these to vary between zero and a preset upper limit. Although this may work well on maps that show relatively large geographical units (such as those used in the present study), it may not work as well on a smaller scale, where neighbourhood-level geographical barriers, such as rivers or train tracks, could create non-circular interaction patterns. However, the Spatial Scan Statistics employed in the present study has higher statistical power than other geostatistical methods and has been widely applied to the detection of clustering of diseases -21.We investigated spatial and demographic variations in HIV infection in small communities in KwaZulu-Natal, South Africa, making use of a cohort of women recruited for various trials through population-based clinics. HIV prevalence rates have always been higher in KwaZulu-Natal than in any other province in South Africa, and this trend has been sustained since the early 1990s. Our findings are consistent with previous work in this population ,3,9. HowAn understanding of geographical variation and determination of the core areas of the disease may provide an explanation regarding possible proximal and distal contributors to the HIV/AIDS epidemic. It is more urgent than ever to determine and target the specific communities that are most in need of education, prevention and treatment activities.This study provides a first attempt to visually and quantitatively describe the geographical characteristics of HIV infections in a region where the disease is known to be rampant. The results may inform development of prevention programmes to address the HIV epidemic while considering those groups most affected differentially by geographical area.Investigating the geographical structure of the HIV epidemic in sparsely populated, large geographical areas is challenging, if not impossible. There needs to be urgent public demand for monitoring at localized level, designating the resources carefully to those places where the infection is clustered. We provide evidence of clusters of particularly vulnerable women through research on the prevalence and incidence of HIV in our setting, and would urge the authorities to provide a rapid response by scaling up HIV prevention, treatment and care efforts in all these communities.The authors declare that they have no competing interests.Both authors contributed to the manuscript, and saw and approved the final version. HW carried out the analyses and drafted the manuscript. GT participated in the design of the study and drafted the manuscript. Both authors read and approved the final manuscript.


One of the major environmental challenges of the twenty-first century is the continued rapid deforestation of Amazonia. The 2005 dieback crisis emphasizes the unprecedented challenges facing Brazil. The examination of past and present institutions for ecosystem management, in Amazonia, shows structural barriers across public, private and community arrangements. The adaptive governance concept helps to understand why these institutions are failing to deliver sustainable futures. In looking forward, it is encouraging to see that important networks of knowledge and a number of novel initiatives are emerging in Brazil. These new arrangements are novel in the way that they seem to be adaptive and navigate structures in the hope of overcoming insurmountable drivers of deforestation. The resulting smoke pollution affected more than 400 000 people, and the fire damaged more than 300 000 ha of rainforest; direct costs amounted to more than US$50 million . The Acre government in turn established a ‘situation room’ staffed by two civil defence coordinators, three state employees from INPE and several researchers and students from the LBA-ECO team. Using both satellite imagery and on-the-ground information, the team provided daily briefings by email on the locations of fires to the local authorities and the Brazilian army, helping to coordinate and focus state and national efforts. Following the successful response to the crisis, access to CBERS-2 satellite imagery is now granted to Brazilian institutions and more widely across South America. The Environmental Institute of Acre has also since established a permanent situation room that incorporates the use of multiple satellite sensors to monitor the extent of fire and drought conditions . The governance system that tackled the 2005 crises was unconventional in its rapid response and in the establishment of a situation room, extensive networks and reliance on available information on the internet. One may wonder whether such a ‘flexible’ governance system can be institutionalized, strengthened or replicated to cope with the future climate-related surprises in Amazonia.Still, it is evident that the existing governance and management strategies for Amazonia have largely fallen short of adequately protecting both people and ecosystems. To blame are both global economic demand for raw materials, minerals and agricultural commodities and weak enforcement of policies at the national level. In Brazil, federal command and control structures have failed to deliver conservation , transportation investments and rapidly growing urban areas . The fed2) was located within protected areas (PAs), primarily indigenous lands . Brazil is implementing a major extension of PAs by 2009, with 270 000 km2 of strict PAs, and 500 000 km2 of sustainable production forest , in which public lands are set aside for permanent production forests where loggers can harvest timber . More thWhile the state has an important role to play in promoting this system, public forestry institutions remain under-resourced in Brazil to deal with the many drivers of land-use change .Market–community arrangements have emerged in more recent years with a focus on environmental services, such as non-timber forest products and carbon sequestration under the Clean Development Mechanism of the Kyoto Protocol. These arrangements aim to put an economic value on resources by transferring the externalities and social costs in the price of goods and services to the consumer. In Brazil, these arrangements include forest carbon , non-timOne of the noticeable shortcomings in the management of Amazonia is that each combination of arrangements mentioned is hampered by some kind of structural barrier. Moreover, the relationship between the structures and the biophysical system seem to be overlooked. In searching for ways to better understand the changes that are ongoing, i.e. complex and mega environmental problems, conventional steady-state and linear models of ecological and social change lend insufficient understanding. The adaptive governance framework, although by no means a panacea, seems to capture the importance of adaptive and transformative capacity as a prerequisite for addressing uncertainty and change in systems (Adaptive governance is a lens that can help to identify both positive resilience (strengths) and vulnerability (weaknesses) in the system, i.e. mechanisms that lead to strengthening management or key institutions that sabotage processes. Positive resilience is the ability to buffer, reorganize and learn from crisis. As a framework, adaptive governance explicitly considers social and ecological systems as linked—rather than as separate entities . Adaptivhttp://www.geog.leeds.ac.uk/projects/rainfor/index.html). The LBA, an evident example of ongoing efforts to construct a better understanding of the Amazon's ecosystems, is a 10-year international research collaboration (1995–2005) led by Brazil. The research component of the LBA, LBA-Eco, focuses on synthesizing knowledge on carbon dynamics, sustainability, system functioning, hydrometeorology and future projections for the Amazon. The next step will be to consider how to feed ecological knowledge into adaptive management processes by continuous testing, monitoring and re-evaluation of data. This condition relates to a wider discussion about the need for change from the current preservation-oriented biological approach to a dynamic one that captures ‘nature under change’ (A general constraint for forest management strategies in Amazonia is the lack of knowledge and data on the ecological system (In dealing with ecological surprise with severe consequences, it may also be necessary to move from precautionary governance to a complexity principle (and community initiatives (The governance arrangements presented in tiatives . In Matotiatives . Anothertiatives . AnotherAdaptive governance lends further ideas on how financing mechanisms, such as carbon markets, can contribute more broadly to sustainable development, and there are suggested ways in which the design and implementation of markets could provide benefits to low-income communities (One of the major environmental challenges of the twenty-first century is the continued rapid deforestation of Amazonia. The 2005 events in Amazonia emphasize the unprecedented challenges facing the people and ecosystems of Brazil. The examination of ecosystem management institutions in Amazonia points to structural barriers across all forms of institutional arrangements. In discussing adaptive governance, it appears that Brazil has already established important networks of knowledge and a number of novel initiatives that are emerging in response to past management failures. These new arrangements are novel in the way that they seem to have evolved to navigate structures and insurmountable drivers of deforestation. The federal government will have to think carefully about how to support and enhance these initiatives and knowledge networks. To conclude, saving Amazonia will require a great deal of effort across all scales of administration and decision-making; however, the networks of knowledge and novel use of technology such as satellite imagery are encouraging examples of action. Perhaps adaptive governance can lend insights into how to extend institutions beyond structures to enhance agency of groups and individuals at many different scales.