Nurses and midwives are the key providers of nursing and midwifery services; in many countries, they form the major category of frontline workers who provide both preventive and curative services in the community. When the skills and experience of nursing and midwifery personnel are maximized, they can contribute significantly to positive health outcomes. We conducted a survey among nurses and midwives working at district level in Sudan and Zambia to determine their roles and functions in polio eradication and measles elimination programmes.Nurses and midwives practising in four selected districts in Sudan and in Zambia completed a self-administered questionnaire on their roles and responsibilities, their routine activities and their functions during supplementary immunization campaigns for polio and measles.Nurses and midwives were found to play significant roles in implementing immunization programme activities. The level of responsibilities of nurses and midwives in their routine work related more to existing opportunities than to their job descriptions.In Zambia, where nurses reported constraints in performing their tasks, the reasons cited were an increase in the burden of disease and the shortage of health personnel. Factors identified as key to improving work performance included written job descriptions, opportunities for staff and career development and opportunities to earn extra income through activities associated with their jobs.Other non-monetary incentives mentioned included reliable transport, resources and logistics to support routine work in the district. However, in both countries, during supplementary immunization activities or mass campaigns for polio eradication and measles control, nurses and midwives took on more management responsibilities.This study shows that nurses and midwives play an important role in implementing immunization activities at the district level and that their roles can be maximized by creating opportunities that lead to their having more responsibilities in their work and in particular, their involvement in early phases of planning of priority health activities. This should be accompanied by written job descriptions, tasks and clear lines of authority as well as good supportive supervision. The lessons from supplementary immunization activities, where the roles of nurses and midwives are maximized, can be easily adopted to benefit the rest of the health services provided at district level. Human resources are crucial to effective delivery of health services. Strategies across countries are, however, constrained by patchy evidence, limited planning tools and a scarcity of technical expertise .Nursing and midwifery services are a subsystem of health services that are provided by a wide range of personnel. These services share common attributes such as: prevention of diseases; caring for, supporting and comforting clients; continuously assessing and monitoring health needs and responses to interventions; advocacy and education of clients and communities; and delivering and coordinating health services across the care spectrum . Nurses Barriers to the delivery of primary health care interventions include lack of prescribing authority, lack of support from physicians, reimbursement difficulties and lack of public awareness . Recent These lessons can be used to improve the delivery of other health services in many resource-constrained settings. This paper reports on a survey conducted in Sudan and Zambia in 2007, which looked at the roles of nurses and midwives in the expanded programme on immunization.The objectives of this study were to document the roles, functions and contribution of nurses and midwives in the delivery of routine immunization services and supplementary immunization activities for disease prevention, control or eradication and to identify the best practices that can be adopted for use in other priority health programmes.One of the key strategies for addressing the current human resources crises in many countries is to maximize the roles of existing human resources for health. For nurses and midwives, who are core providers of health care services, changes in how their work is structured and in their perception of themselves can enable them to improve their contribution to the health system. Facilitating nurses to function at this level is necessary for the process of empowerment .Given the pace of change in health systems across the world, the need to develop nurses and midwives who value creativity and innovation and enjoy the challenge of constant change has never been greater. Today's nurses need to be comfortable with reorganization of their roles and work patterns and to regard problem solving rather than problem identification as essentially the norm of operations .Two countries, Sudan and Zambia, participated in the study. These countries were selected because they had programmes for routine immunization for children (Expanded Programme on Immunization); had conducted supplementary immunization campaigns for polio eradication in the previous three years; had conducted supplementary immunization campaigns for measles in the last three to four years; and had an established surveillance system for vaccine-preventable diseases. In each participating country, a purposeful convenient sample of four districts was selected; in each district, four health facilities  were selected to participate in the survey.In each district, two groups of health personnel were invited to participate in the survey. These were (1) the district EPI programme manager  for polio and measles) and (2) all nurses and midwives working on immunization/child health activities at health facilities in the participating district. Participation in the survey was voluntary and the study was conducted in August and September 2007.Structured, self-administered questionnaires were completed by the study participants. Both closed and open-ended questions were used. The information from the two groups of participants of the surveys fell into the following broad categories: (1) general information on EPI and supplementary vaccination activities in the district; (2) overall numbers and categories of health workers in the district; (3) the role of nurses and midwives in EPI and supplementary vaccination activities for polio and measles; (4) perceptions of nurses and midwives on how their role can be maximized or enhanced in EPI, supplementary vaccination activities and other priority health issues at district level; and (5) best practices and lessons learnt from EPI and supplementary immunization activities for disease eradication or control. The findings from the survey were descriptively summarized.The study is descriptive in nature and although comparisons can be made between the two countries that participated, standardized statistical testing and weighting of results could not be applied.Eight district EPI managers, one from each district, participated in the survey. All the selected districts had conducted SIAs for polio eradication and measles in 2006 and 2007. The district managers in Zambia were nurse-midwives, while in Sudan they included nurses, midwives, medical doctors and environmental health officers. In both countries, the managers had been involved in EPI programme activities for an average of five years.All the districts had functioning routine EPI programmes and the vaccine delivery strategies included fixed sites , outreach , mobile delivery  and campaigns. All districts had a DTP3 coverage (an indicator for routine immunization services) in the last two years of more than 75%, and in all the supplementary vaccination activities for both polio and measles, coverage achieved was more than 90% of the target population.In both countries, the district managers were involved in all aspects of immunization programmes, including SIAs. These included planning, implementation, supervision of staff and evaluation of programme activities. In Sudan, the district managers reported that only 50% of the nurses were involved in all the seven functions during SIAs  and the same proportion was involved in AFP surveillance. On the other hand, in Zambia, nurses and midwives were involved in the full range of functions for SIAs and AFP surveillance.Forty-eight nurses and midwives participated in the survey. Twenty-six were from Sudan and 22 from Zambia. The proportion of midwives was 30.1% and 68.2%, respectively. The responses of the participants are presented in Table Whereas 80.8% of the nurses in Sudan reported that the tasks in their routine work were performed in a professional manner and matched their skills, in Zambia this proportion was only 36.4%. The reason most commonly cited by the nurses in Zambia was that they spent more time dealing with diseases related to HIV infection, including HIV counselling - including prevention of mother to child transmission - referral of patients and administrative tasks. Furthermore, there was more delegation of tasks to other personnel in Zambia.Supervision in both countries was reported as regular: Sudan (76.9%), Zambia (72.7%). Whereas all respondents in Sudan had received supervision in the three months prior to the study, the proportion in Zambia was only 31.8%. As regards supplies, logistics and salaries, including benefits, these were considered adequate: 34.6%, 23.1%, 23.1%, respectively, in Sudan, but by a much lower proportion in Zambia . Lastly, in Sudan, 92.3% reported they had regular in-service training and 73.1% said they had career advancement prospects in their jobs. In Zambia, the proportions were lower (63.6% and 31.8%).Factors that were considered important to improving work performance are listed in Table The involvement of the nurses and midwives in activities related to polio and measles SIAs is presented in Table On the other hand, advocacy, social mobilization, training implementation and supervision were reported in much higher proportions by nurses from both countries. Monitoring and evaluation for polio and measles SIAs were much lower in Sudan  compared to 95.5% and 100.0% in Zambia.Table The factors reported to be important barriers hindering good performance during immunization activities are listed in Table The main lessons learnt from supplementary vaccination campaigns for polio and measles control cited by the respondents that can be used to improve the work of a nurse or midwife were: understanding the community needs, including mapping (Sudan 65.4%); the importance of supervision (Sudan 53.8%); importance of good planning (Zambia 31.8%); and social mobilization and community participation (Zambia 22.7%). Salaries were cited by only 26.9% and 18.1% in Sudan and Zambia, respectively, as an important factor for improving work performance.Nurses and midwives reported that they played a leading role in the implementation of supplementary immunization activities at the district level. When they served as district managers, they did all the planning and budgeting for activities. In addition, for the polio programme, nurses and midwives coordinated advocacy meetings at the district level and also organized sensitization meetings and workshops for the community. Other programme activities in which nurses played a significant role included social mobilization, training and serving as supervisors for other health workers in the district.This case study on nurses and midwives working at district level and at health facilities in Sudan and Zambia provides valuable insight into the roles of nursing and midwifery personnel in a priority public health programme area. The finding that nurses and midwives in Zambia have more responsibilities than were observed in Sudan may be related to the organizational structure and nature of personnel in the district. In Zambia, the managers at the district are nurses and midwives.Whatever the situation, however, in both countries nurses and midwives are able to perform all the functions for the programmes. The differences in responsibilities seem to be related more to opportunities available for nurses to take on management functions. This is reflected in the finding that during SIAs, except for management functions, the other functions are performed in similar proportions in both countries.Delegation of responsibilities to others appears to be related to the management structure in place and possibly the level of training. In both countries, the nurses and midwives felt that the tasks they performed were consistent with their job description. However, the finding that only 38.5% in Sudan and 63.6% in Zambia reported being aware of their written job descriptions for their routine work was of concern. Studies show that job descriptions in addition to professional norms and codes of conduct influence personnel performance.World health report of 2006 suggested that there is need for proper matching of skills to the tasks at hand, supported by supervision. It appears, in the case of Zambia, that an increase in the burden of one disease, mainly HIV-related care, takes up much of the nursing personnel's time. Nurses were not performing the tasks related to their job descriptions and only 36.4% indicated that the tasks matched their skills and job descriptions.The Job descriptions that have clear objectives, responsibilities, authority and lines of accountability have been associated with improved attainment of work goals for all categories of health workers. Health worker motivation cannot be expected to be high in a situation where other tasks take up too much time.The SIAs for polio eradication and measles control have provided an opportunity for nurses and midwives to take on more responsibilities. This in itself is a motivator and consequently leads to better job performance, especially when the tasks are clear and opportunities exist for performing management tasks during SIAs . In ordeThe roles and functions of nurses and midwives during SIAs for polio and measles in both countries probably are the best example of how their roles can be maximized in programme implementation. Admittedly, SIAs for polio require the commitment of personnel for defined periods. However, the experience with participation in these activities and the roles played by nurses and midwives could be adopted in their routine work.Important factors identified by the nurses and midwives that were crucial for improvement of performance are all the well-known factors such as good, effective supervision at all levels; planning of activities with community involvement; and proper training of persons involved in programme implementation. For supplementary activities, in contrast to routine activities, the barriers to implementation that were named tended to be non-human resources related (such as community involvement, adequate transport for operations and negative perceptions of the community to interventions related to immunizations.The key lessons learnt from participation in supplementary vaccination activities for polio eradication and measles control include the importance of good planning, understanding community needs, good social mobilization and supervision during implementation. All throughout, good and reliable transport seems to be an important incentive or factor for improving performance.In summary, this study shows that nurses and midwives play an important role in implementation of routine and supplementary immunization activities at the district level. Their roles can be maximized by creating opportunities that lead to giving them more responsibilities, in particular their involvement in early phases of planning of priority health activities. This must, however, be accompanied by written job descriptions, tasks and clear lines of authority as well as good supervision. The lessons from supplementary immunization activities, where the roles of nurses and midwives are maximized, can be easily adopted to benefit the rest of the health services that are provided at district level.The authors declare that they have no competing interests.AMN conceptualized the project and wrote the study proposal, designed the questionnaires and initiated and participated in discussions, data analysis and writing of the article. LB participated in the conceptualization of the project, design of the study proposal, discussions, data analysis and review of the article. SH, ETAES and HM were involved in data collection, discussion and review of article. All authors have read and approved the final manuscript.


Health-related quality of life (QoL) has become a crucial outcome in medical care. However, few studies have assessed physician knowledge of QoL and rate of physicians adopting QoL measures in clinical practice. The present study aimed at assessing the level of knowledge of QoL and the perceived importance of incorporating QoL assessment in clinical practice among physicians of a tertiary level academic hospital in Rome, Italy.A survey study performed through the distribution of a questionnaire assessing knowledge of QoL studies that used the SF-36 scale, participation in studies evaluating QoL as well as knowledge of journals publishing articles on QoL Physicians and residents at the hospital Policlinico Gemelli, Catholic University of Rome.Three-hundred nine physicians completed the questionnaire. Thirty-eight percent % reported knowing studies on QoL and using their results in clinical practice or for research purposes; 29% reported knowing the SF-36 questionnaire; 30% stated that at least one study assessing QoL had been conducted in their department. Fourty-six percent % stated that QoL must influence much or very much diagnostic choices and an even higher percentage reported that QoL must influence much or very much therapeutic and palliative strategies . Reported barriers to the use of QoL measures in clinical practice were related to time constraints (8.7%) but also to doubts on methodological issues of QoL (30.7%). The large majority of physicians (94.3%) would have used more expensive drugs if these could improve QoL.The present study shows that in a tertiary level academic italian hospital one third of the physicians, reported to know QoL measures and that more than 80% of them would like to use QoL in their daily clinical practice. Future studies are needed to identify the best strategies to implement the use of QoL measures in clinical practice. Health-related quality of life (QoL) has become a crucial outcome in medical care ,2. A comThe survey was conducted on physicians and residents at the hospital Policlinico Gemelli, Catholic University of Rome. The Policlinico Gemelli is a 1700-bed academic hospital, located in the North of the town, built in 1964 (with more than 57.000 admissions per year). It is a public hospital and it is classified as hospital of a National relevance with high specialization. The mission of the hospital is to provide the best health care services, to implement a partnership with patients, to implement the best education in medicine and in management of health care services, and to combine technical health care services with a managerial approach. Since 1997 a process of re-engineering is ongoing with the purpose of developing a new vision of patient care, focused on patient centredness, on efficacy, effectiveness, and safety. The Policlinico Gemelli staff includes 999 physicians and 320 residents. Two hundred nine physicians (21.9%) were not included in the survey since they do not have contact with patients  The questionnaire items assessed knowledge of studies that used the SF-36 scale, participation in studies evaluating QoL and knowledge of journals publishing articles on QoL  completed the questionnaire. Their characteristics are shown in Table As shown in Table However, as shown in Table Reported barriers to the use of QoL measures in clinical practice were related to time constraints (8.7%) but also to doubts on methodological issues (30.7%).We did not find any significant difference in the characteristics of the physicians who answered to know or not to know the SF-36 questionnaire. Results are shown in Table The present study shows that the majority of physicians who answered to the questionnaire on QoL are aware of its usefulness in clinical management. More than 80% of participants would like to use QoL in their daily clinical practice but only one third of the physicians who participated to the survey know QoL measures. To our knowledge, this is the first survey that on physicians of different specialities of a tertiary level academic hospital to evaluate their knowledge and perception of QoL.Indeed, little is known about physicians' attitudes towards QoL and rate of physicians adopting QoL measures in clinical practice. An Italian study exploring the knowledge of hospital physicians on QoL assessment revealed that 62% had some knowledge of QoL assessment in oncology but that most tended to rely on a physician-base assessment rather than patient-based instruments . In 1998http://www.nhs.uk/NHSEngland/thenhs/records/proms/Pages/aboutproms.aspx. The gap between the knowledge of QoL and the perception of its importance documented in the present study merits further attention especially in order to find strategies to reduce this gap. Several causes may explain the gap: first, QoL methodology is scarcely taught during education courses [Results from the present survey suggested that the importance of assessment of QoL is highly perceived. Many institutions are implementing programs including the assessment of patient-reported outcomes and, particularly, of QoL. The National Health Service (NHS) in Great Britain, for example, asks all patients who are having hip or knee replacements, varicose vein surgery or groin hernia surgery to fill in a questionnaire on patient-reported outcomes to help improving the quality of care.  courses ; second, courses . MoreoveAnother interesting finding of this study is that, comparing the characteristics of physicians who answered to know or not to know the SF-36, we did not find significant differences. It seems that the knowledge of QoL measures is independent of age, gender, academic role, and medical speciality.Who should measure the quality of life? most answered that physicians should do so. We think that this is a topical issue. Some authors believe that physicians' perceptions of QoL may be at odds with those held by the patients and QoL assessment should be performed by the patients themselves using adequate and valid measures or, in alternative, by someone who acts as a proxy or surrogate, such as a family member or a health professional [Also interesting is the finding that to the question essional . HoweverThis study has several limitations. First, less than one fourth of the physicians answered the questionnaire and we do not know why about 70% of the physicians did not answer. It could be that they were not interested in the target of the study and in this case the conclusion of the study could be different. However, it is useful to underline that the rate of answer in surveys involving a large number of physicians may be low or very low . Second,In summary, the present study shows that, in a tertiary level academic Italian hospital, one third of the physicians who answered to a questionnaire on QoL, reported to know QoL measures and over 80% of them would like to use QoL in their daily clinical practice. Further studies, also in different medical settings, could assess whether increasing the knowledge on health-related QoL could lead to a growing use of QoL measures in daily clinical practice, possibly increasing also the quality of clinical care.The authors declare that they have no competing interests.MB and RM designed and conducted the study as well as participated in the writing of the manuscript and in the statistical analysis. LP, MF, AT and GO contributed to the design of the study and to the statistical analysis. MF contributed to the writing and the revision of the manuscript. All authors read and approved the final manuscript.


An evolutionary classification of genes from sequenced genomes that distinguishes between orthologs and paralogs is indispensable for genome annotation and evolutionary reconstruction. Shortly after multiple genome sequences of bacteria, archaea, and unicellular eukaryotes became available, an attempt on such a classification was implemented in Clusters of Orthologous Groups of proteins (COGs). Rapid accumulation of genome sequences creates opportunities for refining COGs but also represents a challenge because of error amplification. One of the practical strategies involves construction of refined COGs for phylogenetically compact subsets of genomes.New Archaeal Clusters of Orthologous Genes (arCOGs) were constructed for 41 archaeal genomes  using an improved procedure that employs a similarity tree between smaller, group-specific clusters, semi-automatically partitions orthology domains in multidomain proteins, and uses profile searches for identification of remote orthologs. The annotation of arCOGs is a consensus between three assignments based on the COGs, the CDD database, and the annotations of homologs in the NR database. The 7538 arCOGs, on average, cover ~88% of the genes in a genome compared to a ~76% coverage in COGs. The finer granularity of ortholog identification in the arCOGs is apparent from the fact that 4538 arCOGs correspond to 2362 COGs; ~40% of the arCOGs are new. The archaeal gene core  consists of 166 arCOGs. The arCOGs were used to reconstruct gene loss and gene gain events during archaeal evolution and gene sets of ancestral forms. The Last Archaeal Common Ancestor (LACA) is conservatively estimated to possess 996 genes compared to 1245 and 1335 genes for the last common ancestors of Crenarchaeota and Euryarchaeota, respectively. It is inferred that LACA was a chemoautotrophic hyperthermophile that, in addition to the core archaeal functions, encoded more idiosyncratic systems, e.g., the CASS systems of antivirus defense and some toxin-antitoxin systems..The arCOGs provide a convenient, flexible framework for functional annotation of archaeal genomes, comparative genomics and evolutionary reconstructions. Genomic reconstructions suggest that the last common ancestor of archaea might have been (nearly) as advanced as the modern archaeal hyperthermophiles. ArCOGs and related information are available at: This article was reviewed by Peer Bork, Patrick Forterre, and Purificacion Lopez-Garcia. A robust classification of genes based on accurately deciphered evolutionary relationships is the cornerstone of comparative and evolutionary genomics. Such a classification is indispensable both for the functional annotation of sequenced genomes and for any genome-wide evolutionary reconstruction. The construction of an evolutionary classification of genes is a non-trivial task because of the complexity of homologous relationships between genes. The two principal classes of homologs are orthologs and paralogs. Orthologs are homologous genes that evolved via vertical descent from a single ancestral gene in the last common ancestor of the compared species. Paralogs are homologous genes, which, at some stage of evolution, have evolved by duplication of an ancestral gene ,2. OrthoCorrect identification of orthologs and paralogs is of central importance for both the functional and the evolutionary aspects of comparative genomics. Orthologs typically occupy the same functional niche in different organisms; by contrast, paralogs evolve to functional diversification as they diverge after the duplication ,4. ThereIn principle, orthologs, including co-orthologs, should be identified by means of phylogenetic analysis of entire families of homologous proteins in the compared genomes, which is expected to define orthologous protein sets as clades. However, for genome-wide protein sets, such analysis remains extremely labor-intensive, and error-prone as well . AccordiThermus-Deinococcus group [Cyanobacteria [Lactobacillales [The methods for the construction of COGs were developed and originally applied to small sets of genomes; these and other related methods do not guarantee correct identification of the paralogous and orthologous relationships, due to the variability of domain architectures of proteins, differential loss of paralogs in different lineages, extreme divergence of some orthologous and paralogous genes, and other complications ,12,13. Tus group , Cyanobabacteria , and Laccillales . In eachIn the previous comparative-genomic analyses of archaea, we delineated COGs for this domain of life and used them to partition archaeal genes into the evolutionarily stable, conserved core and the "shell" of genes that are often lost during evolution or are characteristic of a narrow group of species ; we furtHere we present the updated set of COGs that includes 41 sequenced archaeal genomes and delineate the core sets of genes that are represented in all archaea or in the major archaeal divisions, Euryarchaeota and Crenarchaeota. We further describe evolutionary reconstructions aimed at inferring the nature of the Last Archaeal Common Ancestor (LACA) and other ancestral forms, and uncovering the trends of gene loss and gain during archaeal evolution.Nanoarchaeum equitans) to ~5.8 Mb (the mesophilic euryarchaeon Methanosarcina acetivorum); there are 20 hyperthermophiles and 21 mesophiles and moderate thermophiles; 27 genomes represent the Euryrchaeota, 13 belong to the Crenarchaeota, and the remaining one is N. equitans whose taxonomic position is considered uncertain [Table ncertain ,31.The archaeal COGs (arCOGs) were constructed using a new computational pipeline Fig.  which isHalobacteria, Pyrobaculi, and Methanosarcina, but a substantial increase was seen across the entire set of genomes, with two notable exceptions, Nanoarchaeum equitans and, particularly, Cenarchaeum symbiosum . The frsum Fig. . In the OGs Fig. . The rea lineage  whereas families , which lfamilies  were splIn an early comparative-genomic study of the archaea, we developed the notion of a conserved core of genes that are shared by all or the substantial majority of the genomes and, by inference, are likely to be essential for the cell function, as opposed to the variable "shell" of genes that show diverse distributions among species and, accordingly, appear to be subject to lineage-specific gene loss and horizontal gene transfer (HGT) . The curN. equitans (50 arCOGs); again, this is hardly unexpected given the small number of genes in N. equitans, suggesting massive gene loss. Although phyletic patterns provide only a crude assessment of the relationship between the compared genomes and caution is due, such that too sweeping conclusions on evolution are not drawn solely from the inspection of these patterns, some conjectures from the trend seen in Figure The notion of a phyletic pattern which is, simply, the pattern of presence-absence of a COG in the analyzed set of a species, has been developed in the original COG study and, indeThe 166 arCOGs that comprise the strictly defined core of the archaeal genomes, as well as the core gene sets of Euryarchaeota and Crenarchaeota, are, for obvious reasons, of special interest. First, it has to be noticed that the euryarchaeal core (282 arCOGs) and the crenarchaeal core (336 arCOGs) are not dramatically larger than the pan-archaeal core, emphasizing the high prevalence of gene loss and gain  during the evolution of archaeal genomes. Along the same lines, but more unexpectedly, the euryarchaeal and crenarchaeal genomic signatures, i.e., the sets of arCOGs that are represented in all species in one group but not found in any species of the other group, consist of only one and three arCOGs, respectively. In agreement with previous observations, a breakdown of the functional assignments  revealsFrom the inception of the COG methodology, it had been realized that COGs have potential for straightforward evolutionary-genomic applications. One of these is the construction of gene-content trees whereby the phyletic patterns of COGs are converted into a distance matrix between the analyzed genomes, with an appropriate normalization for genome size ,38,40, closely followed by Thermoplasmales  and C. symbiosum (a symbiotic archaeon that might have undergone a major life style shift). The lineages with the most gene gain include those with the largest genomes, namely, Halobacteriales and Methanosarcinales, and Sulfolobales-Desulfurococcales. More unexpectedly, substantial gene gain, along with major gene loss, was inferred also for Thermococcales and Thermoplasmales; apparently, these are groups with highly dynamic genomes.We then addressed the reverse problem, namely, reconstruction of the history of gene gain and loss in archaea given a particular phylogenetic tree topology. On the account of the uncertainty of the deep branches in archaeal phylogeny, we chose to use a partially unresolved tree in which the relationship between several clades is presented as a multifurcation Fig. . The recThermoplasma  and those that were assigned to LACA. Because a comprehensive phylogenomic analysis is beyond the scope of this paper , this was done by analyzing the taxonomic breakdown of the proteins that are most similar to the representatives of a given arCOG as detected in BLAST searches. In order to eliminate potential effects of HGT, a special protocol was developed to identify coherent affinities, e.g., a bacterial affinity was assigned only when the proteins from a given arCOG had best hits in multiple bacterial species . We are fully aware of the limitations of such methodology that, at best, gives a crude approximation of the true phylogeny  but we aComparing these observations with those presented in Figs. The arCOGs, which are expected to be updated as genome sequencing progresses, are a resource for genome annotation of the newly sequenced archaeal genomes and the refinement of the existing annotations, as well as evolutionary reconstructions. Crude reconstructions presented here indicate that the ancestral archaeal forms, including LACA, probably, were full-fledged prokaryotes, of approximately the same level of complexity as the simplest of the modern free-living archaea.Caldivirga maquilingensis IC-167, Cenarchaeum symbiosum and Uncultured methanogenic archaeon). Protein sequences of Thermoproteus tenax were kindly provided by Bettina Siebers with permission from the sequencing consortium. The procedure of COG construction involved the following steps.Protein sets for 40 completely sequenced genomes of Archaea were downloaded from the NCBI FTP site  or from 1. All-against-all BLAST  search w2. Multiple alignments of the initial cluster members were constructed using the MUSCLE program ; alignmei-th and the j-th clusters was given weight equal to the lowest rank among the i→j and j→i relationships . Connected components were extracted from the graph; pairs of nodes within a connected component were assigned an edge with a rank of infinity if they were not connected directly. A minimum-linkage clustering procedure was applied to the connected sets of clusters , resulting in a rooted dendrogram of relationships between the clusters. Then each node on on the tree was labeled with the number of species that were present in all descendant clusters. Two rules were used to determine if the descendant clusters should be merged: i) if species-coverage of the node is at least 50% greater than that of any of the descendant nodes and ii) if, among the descendants of a node, one is species-rich and the other one is species-poor  where si and sj stand for the species-coverage of the species-rich and species-poor descendant nodes, respectively).3. Sequences of expanded cluster members were aligned using MUSCLE, and the PSSMs constructed from these alignment were used for a second round of PSI-BLAST search against the database of archaeal proteins. The search results were used to construct a similarity graph for the relationships between the expanded clusters. Formally, all statistically significant (e<0.01) hits in a search with the PSSM for a particular cluster were classified according to the cluster they belong to; clusters in the hit list were ranked according to the mean score across their members (members missing from the hit list were assigned an arbitrary score 2 bits below the significance threshold). An edge between the 4. In parallel to the above procedures, a BLAST search against the COG 2003 database was performed, followed by using a modified COGNITOR program ,13 to asReconstruction of gene gain and loss during the evolution of Archaea was performed using a modified weighted parsimony approach  implemenThe paper describes the construction of orthologous group for archea.Given the success of the COGs and KOGs (a subset for eukaryotes with higher resolution) and the inability of current purely automatic procedures to produce reliable orthologus groups and, very importantly, their reliable functional annotation, I see this as an important resource for various studies. Furthermore, it uses a semi-automatic procedure that includes some clever guiding principles e.g. it takes into account phylogenetic gene presence patterns. The average coverage of 88% at a higher resolution than the current 76% COG coverage of genes in archeal genomes is another noteworthy and useful feature. As far as I can see, the arCOGs are of high quality and I look forward to use them.There is no comparison to more recent orthology-built procedures, but I assume that this semi-automatic procedure presented here provides a more accurate picture than purely automatic methods.The only concerns I have are availability/formate issues and some minimalistic Figure captions. Both should be easy to solve.Taken together, I congratulate the authors for this nice, important and very useful piece of work.Authors' response:The formats of the files on the ftp site were modified to increase transparency, and an extended README file was added. We hope this imporves accessibility which is, indeed, crucial. The figure captions were amended.The «easy to use» COG database has been especially useful for the biological community. It has helped to improve the quality of genome annotation and has been widely adopted by non bioinformatic experts to perform preliminary rounds of comparative genomic analysis. The main problem with such popular database is the delay in their updating, a daunting task considering the current avalanche of completely sequenced genomes. The present paper by Kira Makarova and colleagues reports a much welcome update of the COG database that focus on archaea (arCOGs). The number of completely sequenced archaeal genomes remains quite low (compared to the situation with bacteria) allowing an exhaustive analysis that remains to be done for bacteria and eukarya. The arCOGs database will be for sure an extremely important source of information for the community working on archaea and for all scientists interested in comparative genomics and microbial evolution. The new analysis corresponds to a substantial increase in information compared to previous one, since around 40% of arCOGs are new.In addition to the description of the arCOGs database, the paper by Kira Makarova and co-workers present several analyses that bring new (or update) data and raise several interesting evolutionary questions. In particular, they have built a gene-content tree based on the presence-absence of arCOGs in archaeal genome and estimated the evolution of the archaeal genome content along the evolutionary tree based on a gene loss and gain analysis. They reported several intriguing observations that are worth to be discussed in the framework of current debates on archaeal phylogeny and on the nature of the last universal archaeal ancestor.Makarova and co-workers noticed that the number of strictly specific euryarchaeal and crenarchaeal proteins is very low . This seems to strongly argue in favour of the monophyly of Archaea (against the «eocyte» hypothesis). However, it should be interesting to present a slightly «relaxed» version of these cores, by allowing for the possibility for a protein to be missing in a group of related archaea . More generally, it could be interesting in the future to define a category of conserved arCOGs (carCOGs?) present in all members of at least two archaeal orders in order to discriminate between ORFans arCOGs that are only present in one order  and arCOGs of probable ancient origin that can tell us something about the evolutionary relationships between the diverse archaeal orders. It should be then interesting to determine if the distribution of such carCOGs correlate with the archaeal phylogeny based on various evolutionary markers.Nanoarchaeum equitans lacks the larger number (50) of universal arCOG, confirming that this archaeon probably evolved by «genome reduction». Some authors have suggested that N. equitans is a primitive organism. I suspect that there is a relatively high percentage of these 50 proteins that have homologues in Bacteria or Eukarya. This could be indicated as an argument in favour of the reduction scenario versus the "old nano" hypothesis! Interestingly, the gene content tree based on arCOGs groups N. equitans with Thermococcales among Euryarchaeota. Although gene-content trees can be sometimes highly biased by lateral gene transfer, this observation is in good agreement with a preliminary global analysis based on best BLAST-hits and refined phylogenies based on proteins of the small ribosomal subunits, reverse gyrase, Topo VI and elongation factors . This confirms that N. equitans should not be considered as a member of a new archaeal phylum  but as an odd member of the Euryarchaeota, probably, distantly related to Thermococcales.The parasitic archaeon Cenarchaeum symbiosum with euryarchaea in the gene-content tree. Interestingly, the COG coverage is quite similar for all archaeal genomes (around 88%) except for C. symbiosum and N. equitans. This can be explained by genome reduction in the case of N. equitans, but not in the case of C. symbiosum whose genome has a «normal» size. Significantly, the authors reported that the coverage of C. symbiosum genome with the old COGs was greater than with the new arCOGs! This indicates that this genome contains COGs present in Bacteria or Saccharomyces cerevisiae but not in any other archaeon. The proposed explanation is that C. symbiosum is a symbiotic crenarchaeon that has acquired lots of bacterial genes. An alternative hypothesis is that C. symbiosum is not a crenarchaeon after all, but represents an early branching archaeal phylum that contains bacterial and archaeal homologues that have been lost in other archaea.Another puzzling observation is the grouping of From their reconstruction of gene loss and gain events, Makarova and co-workers suggest that the last Universal archaeal ancestor (LACA) was a hyperthermophile and a chemo-litoautotrophe with a minimal number of genes around 1000. They conclude that LACA might have been (nearly) as advanced as modern archaeal hyperthermophiles and found this conclusion quite «unexpected». I am not so surprised. It's a prejudice to think that ancestors are always simpler than present-day organisms and that ancient evolution always occurred toward more "complexity". There is no reason why reductive evolution, which has occurred so often in the evolution of modern cells, was not as pervasive in ancient time . In fact, an in-depth analysis of ribosomal protein distribution by Poch and co-workers already suggested a few years ago that the ribosome of LACA was probably more complex that the ribosome of any modern archaea .Authors' response: We do not, exactly, disagree and certainly realize the importance of reductive evolution. Still, whether or not we should consider the reconstruction of a complex LACA surprising or not, depends on the perspective. Considering that LACA is supposed to be the common ancestor of one of the 3 domains of life, there might be some element of surprise in this observation. After all, at the earliest stages of the evolution of life, there must have been a dramatic increase in complexity. That this complexification stage, apparently, was over by the time the domain of life became distinct  is, certainly, of note. Alternatively, it is conceivable that LACA is actually not as ancient as one might think but represents a more recent bottleneck in archaeal evolution such that there was a complexification stage after the onset of the archaeal domain but it is inaccessible by comparative genomics.My only criticism of this paper is that the authors have taken a quite conservative view of archaeal phylogeny (only based on 16S rRNA) to analyse gene loss and gain along the archaeal history and to estimate the genome content of LUCA. Indeed, several features of their unresolved multifurcation tree are dubious.N. equitans appears as an isolated lineages (a third phylum)C. symbiosum is grouped with hyperthermophilic Crenarchaeota.Methanopyrus kandleri is shown as an isolated branchMethanopyrus kandleri most likely groups with methanococcales and methanomicrobiales  and that N. equitans is at least sister-group of euryarchaea . As previously indicated, the grouping of C. symbiosum with crenarchaea could be also highly misleading. It should have been interesting to compare the genome content of LACA based on the 16S rRNA phylogeny and the more robust phylogeny based on ribosomal proteins. My feeling is that the nature of LACA  is still a pending question.In all these cases, the authors have chosen to follow the 16S rRNA tree, whereas careful analyses based on ribosomal proteins have shown that Authors' response: We have not really followed the 16S RNA tree but rather deliberately chose a poorly resolved topology so as not to subscribe to any particular phylogenetic hypothesis with respect to issues that are still considered unresolved. We are well aware of the published work on archaeal phylogenies and the two important papers by Brochier et al. are cited. Out of fairness, the likely position of Methanopyrus with Methanococcales and Methanobacteriales, was first reported in Slesarev et al. in 2002, and this cited as well. The wording on Methanopyrus in the text was modified to reflect these reports but we did not modify the tree in Fig. One has to keep in mind that the reconstruction here is by no means supposed to be the final word on the scenario of archaeal evolution but more of an exercise showcasing the utility of the arCOGs. We expect that there will be many more iterations with more genomes, better resolved trees, and better methods of reconstruction, and we certainly hope to be involved.methanogenesis which are spread both vertically and horizontally». In fact, a detailed phylogenetic analysis of genes involved in methanogenesis by Bapteste and co-workers has shown that, surprisingly, although these proteins can be considered as «operational» they have been only transmitted by vertical inheritance in the archaeal domain .Finally, in the discussion of the gene-content tree, the authors wrote «Authors' response: We believe that the issue is not quite resolved yet. The wording in the paper was softened, nevertheless.Bapteste E, Brochier C, Boucher Y.Higher-level classification of the Archaea: evolution of methanogenesis and methanogens.Archaea.1, 353–363 (2005).Brochier, C. Forterre P. and Gribaldo S.Methanopyrus kandleri paradoxArchaeal phylogeny based on proteins of the transcription and translation machineries: tackling the Genome Biology, 5, R17 (2004).Brochier, C., Gribaldo, S., Zivanovic, Y. Confalonieri, F. and Forterre, P.Nanoarchaea: representative of a novel archaeal phylum or a fast evolving euryarchaeal lineage related to Thermococcales?Genome Biology, 6:R42 (2005).Forterre, P. and Philippe, HWhere is the root of the universal tree of life?Bioessays, 21, 871–879 (1999).Lecompte O, Ripp R, Thierry JC, Moras D, Poch O.Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale.Nucleic Acids Res., 30, 5382–5390 (2002).Nanoarchaeum equitans is placed within the Thermococcales in agreement with recent detailed phylogenetic analyses, reinforcing the idea that the basal placement of N. equitans in some trees was due to long-branch attraction artifacts. The two major differences of this gene-content tree with respect to previous accepted molecular phylogenies for the archaea are that all methanogenic euryarchaeota, normally split in at least two large groups in molecular phylogenies, cluster together as they share a large number of methanogenesis-related genes, and that Cenarchaeum symbiosum is placed within the Euryarchaota, in disagreement with its expected position within the Crenarchaeota. Although the type of analyses carried out is not innovative, the new arCOG database presented here will certainly be very useful to improve future genome annotations.This article describes the analysis of genes present in most of the currently available archaeal genome sequences in view of their classification in clusters of orthologous genes specific to the archaea (arCOG). It represents an updated extension of previous comparative genomic analyses of COGs though exclusively devoted to the archaea. As a consequence, the arCOG database produced is more refined, resulting in an increased coverage and resolution. The latter is reflected in the numerical increase of specific archaeal COGs and the accompanying decrease in the number of clusters containing paralogs. The comparison of arCOGs thus defined allows to infer the presence of ~166 core arCOGs, which were likely present in the last archaeal common ancestor (LACA), while 282 and 336 arCOGs appear ancestral to the euryarchaeotal and crenarchaeotal branches, respectively. From the nature of the core arCOGs, the authors conclude that the LACA was a rather complex hyperthermophilic chemoautotroph possessing ~1000 genes. Differential gene gain and loss are predicted to have occurred in the two major archaeal branches. The pattern of arCOG distribution in the different archaeal genomes is used to reconstruct a gene-content tree. Despite biases that may be associated to this approach, which are cautiously recognized by the authors, the tree obtained is largely congruent with widely accepted archaeal molecular phylogenies. Interestingly, I have only a few minor comments or suggestions, as follows:First, it has to be noticed that the euryarchaeal core (282 arCOGs) and the crenarchaeal core (336 arCOGs) are not dramatically larger than the pan-archaeal core, emphasizing the general volatility of archaeal genomes.-are not dramatically larger than the 166 core arCOGs appears quite subjective. It is roughly twice the size. How does this compare with the situation in bacteria? It would be nice to include this information here, and even better, to relate/normalize this information to the average genetic distance in a reference conserved genetic marker, such as the 16S rRNA gene.The affirmation that 282 and 336 arCOGs Authors' response: "Dramatic", certainly, is in the eye of the beholder. We believe the reader will see it that way, so no changes. Comparing to bacteria is dubious because there are no two major groups of bacteria emulating Euryarchaeota and Crenarchaeota. Calibration – complex exercise that goes beyond the scope of this paper.Defining genome volatility would also be useful. Genome volatility has been defined in the literature as the mean volatility of all codons weighted by their frequency within the genome, codon volatility being a measurement related to the non-synonymous versus synonymous mutations . I believe the meaning is more informal and vague here, and also subjective. Can you provide a reference showing that archaeal genomes are "volatile"?Authors' response: Good point, we changed the wording to avoid any wrong connotations, "volatility" is not used anymore.C. symbiosum genome. In page 14, it is mentioned that C. symbiosum falls within the euryarchaeotal part of the gene-content tree. Would you predict that HGT from euryarchaeota may partly explain this observation as some  environmental genomic studies appear to suggest (Lopez-Garcia, Brochier et al, Environ Microbiol 2004, 6:19?Horizontal gene transfer from bacteria has apparently contributed to shape the Authors' response: Yes, a valid point, we included this possibility in the revision and cite the paper.KSM performed the bulk of comparative genome analysis and contributed to the design of computational procedures and algorithms; YIW designed the algorithms and computational procedures, and contributed to genome analysis and software development; AS contributed to software development; EVK initiated the project, contributed to the design of the computational procedure, and wrote the manuscript. All authors read and approved the final version of the manuscript.


When using a conventional relational database approach to collect and query data in the context of specific clinical studies, a study with a new data set usually requires the design of a new database and entry forms. OpenSDE (SDE = Structured Data Entry) is intended to provide a flexible and intuitive way to create databases and entry forms for the collection of data in a structured format.This study illustrates the use of OpenSDE as a potential alternative to a conventional approach with respect to data modelling, database creation, data entry, and data extraction.A database and entry forms are created using OpenSDE and MSAccess to support collection of coronary surgery data, based on the Adult Cardiac Surgery Data Set of the Society of Thoracic Surgeons. Data of 52 cases are entered and nine different queries are designed, and executed on both databases.Design of the data model and the creation of entry forms were experienced as more intuitive and less labor intensive with OpenSDE. Both resulting databases provided sufficient expressiveness to accommodate the data set. Data entry was more flexible with OpenSDE. Queries produced equal and correct results with comparable effort.For prospective studies involving well-defined and straight forward data sets, OpenSDE deserves to be considered as an alternative to the conventional approach. Acquisition of patient data for clinical research is challenging, because routinely collected patient data is often incomplete, fragmented (divided over different data sources), or poorly accessible (on paper or in free text format). Therefore, clinical research projects usually involve dedicated data collection in addition to data recording for routine care. It is quite common for researchers to develop a new dedicated database with data entry screens, each time a new data set is required. Is there an alternative approach for the relatively labor-intensive development of dedicated research databases and separate data collection effort?OpenSDE (SDE = Structured Data Entry) has been developed to support structured recording of data for both research and care, and is designed to accommodate quickly growing and changing data sets . An esseOpenSDE is also used for several specific clinical research projects . Main reason for using OpenSDE, both in the clinical and the research settings, is the flexible and intuitive way of creating a database and user interface for data entry -5.Over the past years, we have often been confronted with questions regarding extraction of data collected with OpenSDE, but so far, only one of our publications focus on extraction of routinely collected patient data . When thTo illustrate the use of OpenSDE as a potential alternative to a conventional relational approach, we used both approaches to collect and extract specific data in the domain of coronary surgery. All steps in the process pass in review: data modelling, database creation, data entry and data extraction.Since data modelling and data entry with OpenSDE have extensively been described elsewhere, emphasis is on data extraction.OpenSDE uses a row-oriented database to achieve flexibility in content coverage. Row-modelling involves a column-to-row transformation, where the new columns are generic. This strategy implies a higher level of abstraction, such that changes to content coverage do not require adaptations to the database structure .The fact that the row-oriented data model itself is abstract means that semantics (meaning and context of the data) are not represented by the database structure . In the A tree represents, for a specific domain, which entities can be described and in what context. A node in the tree is a medical concept and its branching nodes represent its descriptors. An essential principle while constructing a tree is that a concept is represented once, i.e. as a unique node, in the tree. The tree has no 'knowledge' of what nodes are conceptually the same. This is because a path from top to node represents a concept, not the node itself. Hence 'severity' of 'cough' differs from 'severity' of 'chest pain'. Besides the ordering of nodes in a tree, each node has several properties, which define options and constraints for data entry . Custom constraints can also be defined (e.g. systolic blood pressure must be higher than the diastolic blood pressure).Trees are created and maintained via an interactive editor, the domain model editor. Besides basic data types, such as categorical values, numeric, text, and temporal, the expressiveness of OpenSDE also encompasses ranges of values, multiple occurrence of the same tree node (two different skin lesions), progress descriptions (multiple descriptions of the same node to represent course over time), comments, and time-stamps.OpenSDE automatically generates standard entry forms, based on the contents of the tree. For each node, the standard entry form contains entry options for its descriptors. Users can also define custom forms with self-defined sets of tree-nodes to suit specific medical contexts or tasks . These cDuring data entry, the user can traverse the tree to select concepts for description. Upon selection of a concept, OpenSDE presents the associated standard or custom form for data entry.Figure Figure Querying of row-oriented data is not straightforward. Row-oriented data need to be transformed to a conventional format with a one-column-per-parameter structure to be suitable for analysis with commercially available statistical or graphical programs. Without such transformation queries require self-joins and nested sub queries, which make querying much more complex -13.Entity Export supports the selection of the data to be extracted and export of these data in a conventional format . The useMS Access  uses a column-oriented relational data model. It is commonly used to build a database, entry forms, and queries for the recording and extraction of data in the context of clinical research projects.In 1989 the Society of Thoracic Surgeons established a database as an initiative for quality improvement and patient safety.At the Department of Cardio-Thoracic Surgery  medical data, related to coronary artery bypass grafting, are currently collected for several research  and repoThe coronary data set is conceptually hierarchical. Data types used are: categorical values, text, integer, date, and real. Complications, for example, can be selected from a list with predefined categories. There are also basic constraints: cause of death can only be entered if date of death is present. A few free text fields were available to accommodate data entry of items not covered in a list.The data items comprised a total of 173 research parameters where 130 are part of the data collection form of the Adult Cardiac Surgery Database of the Society of Thoracic Surgeons and 46 have been added by the Department of Cardio-Thoracic Surgery.OpenSDE: Building a domain model and entry forms.We defined a domain tree, using the domain model editor of OpenSDE. Data items were ordered in the tree conform their conceptual hierarchy. Properties were assigned to each node to define data type and data entry constraints. Subsequently, we defined several custom entry forms to facilitate data entry. We recorded the time needed for the creation of the tree and the forms.MS Access: Building a relational database and formsWe first designed a third normal form data model to represent the conceptually hierarchical data set . SubsequWe called the resulting conventional database application: Thoraxdb.Per patient, per procedure, we collected data on preoperative risk factors, operative techniques, postoperative data, and complications.We entered data of a group of 52 consecutive coronary artery bypass graft (CABG) patients operated at our department of Cardio-Thoracic Surgery in the period June-July 2004 in both the Thoraxdb and OpenSDE data table (SDETreeNode). Paper-based patient records were used as source of patient information.OpenSDE data:Entity Export was used to generate a conventional relational database from the row modeled data entered with OpenSDE.All the nodes in the domain tree were chosen for export to conventional column-oriented tables. Subsequently, Entity Export created a copy of the corresponding row-modeled data in a conventional format in MS Access, called EntityExportdb. Unused nodes and attributes were removed during extraction.MS Access:Thoraxdb is already in a format suitable for applying SQL queries.The cardio-thoracic surgeons of our hospital defined nine research questions Table  for the The standard facility of MS Access was used for querying both databases (Thoraxdb and EntityExportdb). We translated nine research questions into nine corresponding queries for the Thoraxdb and nine corresponding queries for the EntityExportdb. We compared the query designs, and compared the query results after execution.OpenSDE: Building a domain model and entry formsSince the original data set was hierarchical by nature, the ordering of the parameters in a domain tree was straightforward. Assigning properties and constraints was also straightforward. Ranges of values and multiple occurrence of nodes were not modeled in the domain tree. The resulting domain tree contained 246 nodes, 66 nodes of which represented context (headers), 7 nodes represented units of measure, and 173 nodes represented the actual research parameters. The difference of 3 parameters with the original data set involves patient ID, gender, and date of birth, which are part of patient registration in OpenSDE.Building the domain model and 4 custom entry forms (the remaining 13 forms were standard entry forms) took 12 hours.Thoraxdb: Building a relational database and forms with MS AccessThe design of a third normal form data model took 20 hours. Definition of database, entry forms, and macros took 36 hours. The Thoraxdb application contains 300 attributes, divided over 8 tables, and 13 forms.The table structures of the OpenSDE database and the Thoraxdb are shown in Figure The overall ordering of the data items was very similar as this was determined by the STS data set. Advanced expressiveness of OpenSDE, such as free text comments and progress descriptions were not used. Data entry with OpenSDE was favored over data entry in the Thoraxdb for two main reasons:- More flexible navigation- Overview of all entered dataOpenSDE dataTo obtain the conventional equivalent of all data collected with OpenSDE, we used Entity Export to export all content in a conventional format: EntityExportdb. This resulted in 19 tables. Of these two tables are standard: 1 table containing all recording sessions and one table containing data associated with the high levels of the tree. The remaining 17 tables correspond to the 17 main topics in the tree.Since we exported all data, time using Entity Export was neglectable.To illustrate the added value of the data conversion by Entity Export, we also designed and executed some queries directly on the SDEtreenode table OpenSDE data format without using Entity Export.ThoraxdbQueries were directly designed for the conventional Thoraxdb.Since Thoraxdb and EntityExportdb had a different table structure, there were differences in the design of the nine queries. Differences in query complexity were neglectable. Only query 9 required 1 join in Thoraxdb versus no join in EntityExportdb. The other queries involved either the exact same number of joins and attributes or differed slightly in the number of attributes involved.All nine queries provided results that corresponded correctly with the content of both databases: exactly all data that met the query criteria (no more and no less) were present in the query results.Medical data is by nature hierarchical. In medical descriptions, concepts are described by more detailed concepts. This is also recognizable in the structure of the Table of Contents in medical textbooks. Therefore, creating the domain tree was intuitive and straightforward. To create a good unambiguous domain tree, however, requires thorough understanding of the principles of domain modelling and the conceptual meaning of the various properties. At our hospital clinicians without technical skills actively participate in domain modelling. Ganslandt also reports that such modelling does not require technical skills . Main reClinicians cannot be expected to be familiar with normalization: clinicians generally do not receive training in data modelling during their curriculum. Normalization requires both specific training in data modelling and knowledge of the domain of application. Since both skills are rarely present in the same person, the data modeller and the domain expert have to work together. Misunderstanding may result in improper modelling.An advantage of OpenSDE is the possibility of rapid prototyping. Since OpenSDE generates standard entry forms, based on the domain tree, the modeller can immediately see the effect of any change in the domain tree on data entry.Although OpenSDE offers more expressiveness , it was not used in the context of this straightforward data set. As mentioned in the results section, the person who performed the data entry in both systems favored OpenSDE for two main reasons:- Flexibility of navigation: In OpenSDE she could easily navigate to any node in the tree, either by selecting it directly in the tree or via a search string. As data in paper records are not recorded in a fixed order it is convenient to be able to enter the data in the order they become available. In the Thoraxdb, she could only navigate through the forms.- OpenSDE presents an overview of all data entered during the session in the order of the tree, irrespective of the order or form in which data have been entered. Our data entry person could easily keep track of what she had entered so far. In Thoraxdb, she could only view entered data when she opened the corresponding form.In this study we extracted all data recorded in OpenSDE at once to obtain a conventional equivalent of the Thoraxdb. The number of resulting tables is directly related to the properties assigned to the nodes in the tree. When a node is designated as a 'core entity' all its branching nodes will be exported to one corresponding table. If the modeller assigns the 'core entity' property at a higher level this will result in fewer tables with more attributes.When using Entity Export in the context of one specific query, the user can make a specific selection of relevant nodes from the tree, which will result in the two standard tables plus as many tables as there are 'core entity' nodes involved.The use of Entity Export to convert the abstract OpenSDE data format to a conventional table format involves an extra step. The reason for this step is two-fold:- Data in a conventional format is more easy to query than data in a row-oriented format.- Since Entity Export presents the domain tree for data selection, the user does not need to select the data set to be analyzed from the less intuitive tables in third normal form.To illustrate the query differences between the two conventional databases we show the design of Query 5 (What is the number of complications per operation location?) for the conventional Thoraxdb figure . AlthougDesign of Q5 was most complex in the original SDETreeNode table , and execution took noticeably more time than query 5 in the other 2 databases. This is a result of the abstraction in the original SDETreeNode table. First, a specific parameter (treenode) can only be extracted via the link between the TreeNodePathId in the data table (SDETreeNode) and the TreeNodeName in a reference table (SDEDomainModelItem). Second, a query involving two research parameters involves 1 inner join of the data table SDETreeNode. SDETreeNode has to be joined with itself (inner join) because the data representing place of operation and complications are stored in different rows of the same table. Hence, three different parameters would require 2 inner joins. In fact, n parameters require n-1 inner joins. Inner joins exponentionally slow down query execution. Direct querying of the original SDETreeNode table is, therefore, only feasible for relatively simple queries, involving 1 or two attributes. Entity Export solves this problem through data conversion from the abstract row-oriented structure to conventional tables.It should be mentioned, that the result for one of the queries in the Thoraxdb could only be obtained after specific data manipulation. Three fields  had categorical values: none, 1,2,3,4, or 5. We converted the data type to integer and the values to 0 through 5 respectively. The numerical representation was required for the calculation of an average amount of distal anastomoses per patient.As illustrated by the need to change categorical values into numeric values, it is important at design time to take into account the type of research questions that will need to be answered. However, one can never foresee all research questions in advance and different research questions may involve different design preferences.Apart from the definition of data types, relationships between tables, or the ordering of concepts in a domain tree, one has to be cautious with respect to semantic equivalence: the possibility to enter the same finding in more than one way. Semantic equivalence is undesirable, irrespective of any research question, as it increases the chance of inconsistent data or overlooking data. Hence, thorough study of the semantics of the data model is essential prior to querying.In research settings, recording of the research data items usually happens in addition to data collection for routine care. To put the research data in the proper context, part of the data needs to be recorded twice.Ideally, data recording for research is integrated with data recording for routine patient care. Using a conventional data model for structured data recording in the context of patient care has been extremely challenging, especially for large medical domains. The main reason is that the data set that needs to be entered is unpredictable: very many findings are possible while a few apply to a specific patient.OpenSDE accommodates data recording for research as well as routine care, also in large domains like general pediatrics . It is iAnalysis of routinely recorded patient data shows that users actually use the expressiveness of OpenSDE as they prefer. The large expressiveness of OpenSDE implies freedom of choice how to record data, which results in differences in recording of the same findings. Physicians appear to differ in their use of free text, they differ in level of detail with which they record, but they may also choose different concepts during data entry. The latAn important pitfall in modelling is semantic redundancy, which is present when a concept is represented by more than one node or combination of nodes in the tree. Semantic redundancy may also cause differences in data recording. When clinicians are new to modelling, they tend to model the context in which they address medical topics. For example, 'edema' is relevant in the context of cardiac disease, renal disease, trauma, infection, etc. Each concept, however, has to be represented once in a domain tree, whereas it may occur on multiple forms. The differences found in routinely recorded data make querying difficult and complex. Hurdles in data extraction are free text, missing data, and conceptual identical data that are structured differently .The results of the current study indicate that well-defined research data sets that can be accommodated with a conventional database can also be accommodated with OpenSDE with comparable query effort. For such datasets, however, OpenSDE presents a more intuitive and flexible strategy for the construction of database and user interface. OpenSDE offers conditional data checklists to promote the completeness and unambiguity required for that subset of care data, needed for research.Relational databases are pre-eminently suited for businesses, who record which customers order which products, which suppliers offer which parts, the progress of orders, amounts in stock, etc.. These dWhen flexibility in content is important, i.e. when one expects the required content to change relatively frequently over time, a row-model is the preferred choice.Another issue pertains to the required level of customization of the application. OpenSDE has many features for customization without the need for programming . These fIn the next version of OpenSDE, currently under development, expressiveness is more explicitly modelled, and unpredictable use of expressiveness by the user can be controlled as needed.In this study, OpenSDE was experienced as an flexible and intuitive tool to create a database and data entry interface for the collection of data in the context of well-defined prospective clinical research projects.Entity Export provided an intuitive way to select data for analysis. Although query reliability and complexity differ slightly between Entity Export generated output and conventional databases, query effort is comparable.An important pitfall, that is independent of the choice of a row model or conventional model, is the danger of semantic redundancy. This danger requires specific attention while designing and querying databases. Minimizing options for unpredictable, ad hoc, data entry will greatly help to improve the analyzability of the data set.OpenSDE offers intuitive design and the flexibility to cope with quickly changing and evolving datasets, whereas Entity Export provides an adequate tool to produce data in a conventional format. For prospective studies involving well-defined and straightforward data sets, OpenSDE deserves to be considered as an alternative to the conventional approach.The authors declare that they have no competing interests.ACV had primary responsibility for design and conception of the study, participated in analysis of the data, writing and revising of the manuscript.AMvG participated in the conception and design of the study, analysis of the data and has been involved in revising the manuscript.MdW participated in interpretation of the data and has been involved in revising the manuscript.AB participated in the conception of the study and the revising of the manuscript.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: