This research aimed to investigate whether demographic factors are similarly related to retrieval of object and proper names.The sample included 5,907 individuals above age 70 who participated in the Health and Retirement Study between 2004 and 2012. Participants were asked to name two objects as well as the US President and Vice President. Latent growth curve models examined the associations of age, education, and self-rated health with baseline levels and change trajectories in retrieval.Age and education were more strongly related to retrieval of proper names than to retrieval of object names, both for baseline scores and for change trajectory. Similar effects of self-rated health emerged for both types of stimuli.The results show that examining object names and proper names together as indication of cognitive status in the HRS might overlook important differences between the two types of stimuli, in both baseline performance and longitudinal change. A recent report shows that 30% of people above age 65 complain of difficulties in word retrieval, whereas 64% complain of difficulties in retrieval of proper names . Such diOlder adults often report that proper names are more elusive than are other types of words , 2. ReseSeveral demographic variables have been associated with naming. Many studies have shown that increased age is related to greater difficulties in word retrieval , 7. HoweWhile education attainment is known to be related to the level of cognitive performance, there are inconsistent findings regarding the effects of education on the trajectory of cognitive decline –13. SomeResearch has also shown a relationship between common chronic health conditions in non-demented individuals and general cognition in later life. Thus, blood pressure, diabetes, or cardiovascular disease have been associated with poorer cognitive abilities , 15, altThe aims of the current research are to compare both baseline levels and rates of decline in retrieval of object names and proper names in individuals over the age of 70. In addition, we compare the associations between age, education, and self-rated health and baseline performance as well as the associations between these demographic variables and the trajectory of change over an eight-year period. Our goal is to determine whether the same demographic factors relate to baseline and to change trajectories to the same extent for both types of stimuli. To do so, we use data from individuals who participated in five biannual waves of the HRS, and analyze these data with LGCM. We expect all demographic variables to relate to baseline performance but make no predictions as to the associations of these factors with the change trajectory or as to possible differences in their associations across the two tasks.The sample consisted of 5,907 individuals who participated in the Health and Retirement Study (HRS) between 2004 and 2012. The HRS is a representative panel of US citizens over the age of 50 and their spouses of any age who are tested biannually. Detailed information regarding sampling procedures have been described elsewhere [Respondents were between age 70 and age 102, 86.2% of the sample were white, and 59.2% were women ; "What do you call the kind of prickly plant that grows in the desert?" (Cactus). We used the sum of the two items as the outcome variable (range 0–2).Two items evaluated retrieval of proper names: "Who is the President of the United States right now?"; "Who is the Vice President?". We used the sum of the two items as the outcome variable (range 0–2).We analyzed the effects of age, education, and self-rated health, as assessed in 2004. Self-rated health was measured with the question: “Would you say your health is excellent, very good, good, fair, or poor?”. Responses were coded on a scale of 1 (poor) to 5 (excellent).We first calculated descriptive statistics and correlations between variables. Next, we used Structural Equation Modeling (SEM) with Amos version 23 to estimate parallel LGCMs of the two naming outcome variables. To establish LGCMs, we followed the following steps:The first step prior to establishing LGCMs requires the establishment of weak factorial invariance with regard to the outcome variables. This ensures that the items are consistently related to the overall construct over time. We examined weak factorial invariance by setting factor loadings of each variable as equal across waves. Like-items were allowed to correlate across waves. The disturbances of these constructs were specified as correlated within each wave.To examine the longitudinal relationships between the two outcome variables, LGCMs were fitted within the SEM framework. The model allows for the simultaneous examination of growth trends for the two outcomes of interest to examine associations between baseline (intercept) and change trajectory (slope).This model was estimated in several steps. We first examined each outcome variable separately (running two separate LGCMs) in order to establish the change trajectories that result in the best fit to the data. We assessed models in which the change trajectory was estimated as changing linearly . We also assessed a non-linear model, in which the first and last waves of the data were fixed to different nonzero values and any remaining loadings were free, as well as quadratic and cubic models of change trajectories. The Akaike’s information criterion (AIC) and Bayesian information criterion (BIC) were used to compare model fit, with lower values indicating better fit.After establishing adequate fit indices for each of the LGCMs separately, the two LGCMs were examined together as a single unconditional multivariate model. Covariances between baseline levels and change trajectories were estimated in this model.Once the shapes of the change trajectories were established (based on the fit indices), we examined whether the baseline  and change trajectories  of the two outcome variables  were comparable. We used a series of models, in which (a) the baseline of the two outcome variables was restricted to be equal against an unrestricted model; and (b) the change trajectories of the two outcome variables were restricted to be equal against an unrestricted model. A significant chi-square difference indicates that the restricted model is significantly worse, and that the unrestricted model is preferable.To examine the conditional model, we entered age, years of education, and subjective health ratings, as assessed in 2004, as time invariant predictors of the baseline levels and the change trajectories of the two outcome variables.We examined a series of restricted models to determine whether the effects of the predictors on the baseline scores and the change trajectories of the two outcome variables were comparable . A significant chi-square value indicates that the restricted model is significantly worse and that effects are different.We followed accepted recommendations for estimation of goodness-of-fit . In addiMissingness ranged between <1% and 15% across variables. The data were not missing completely at random. Therefore, missing values were replaced using multiple imputation (MI), which is a preferred technique for handling missing data and has numerous advantages over other approaches . MI invoχ2 statistics were computed using an online interactive calculation tool [Bivariate associations were examined using pooled data from cross-tabulations, and ion tool . We cond2  = 908.00, p < .001, TLI = .918, CFI = .941, RMSEA = .061 .As a first step of our main analyses, we tested the measurement model of the two latent constructs over the five time points, with cross-wave correlations between errors of the same indicators and factor loadings of like-items constrained for equality across waves. The model demonstrated good fit to the data: χNext, the unconditional model was examined. The fit indices for the various shapes of change trajectories are presented in Baseline scores of object names were higher than were baseline scores of proper names (see the chi-square differences in Age, education, and subjective health ratings at baseline were entered as potential predictors of the baseline and change trajectories of the two outcome variables. A series of constrained models was performed to evaluate whether the associations of age, education, and subjective health ratings with the baseline and change trajecotry differed for the two outcome variables (see the chi-square difference tests between the unrestricted and restricted models in In an additional sensitivity analysis, we restricted the analysis to those who had complete data on all five testing waves. Results were similar, with very few exceptions: age was not a significant predictor of the baseline score of object names, and education was not a significant predictor of the change trajectory of object names. The second sensitivity analysis of individuals who retrieved 3 or 4 names at initial testing led to very similar results as the ones reported for respondents who had data on at least three waves. Detailed results are available upon request.Previous analyses of cognitive measures on the HRS examined object names and proper names together, implicitly assuming that their similarities were greater than their differences . Our finCognitive studies that compared retrieval of object names and names of famous people suggested that naming of people is harder mostly because the recognition of famous people from pictures activates less background knowledge . HoweverDespite the differences between the cognitive demands of the two types of retrieval, our analyses of the demographic variables showed that production of both object and proper names was related to the same factors. Hence, age, education, and self-rated health were associated with baseline scores as well as with change trajectories on both tasks. The data show that younger age, higher education, and higher self-reported health associated with better baseline scores as well as with more moderate decline over time, whether participants were asked to name objects or to retrieve the names of the President and Vice President. These findings are in line with previous studies in which older adults were shown to retrieve fewer object names as well as fewer proper names than did younger adults . The resYet, while the same demographic variables were related to retrieval of object names as well as proper names, their associations differed across stimuli type. Specifically, age and education were less strongly associated with baseline retrieval of object names than with baseline retrieval of proper names, and the same was true with regard to their association with the trajectory of decline. We speculate that older and less educated adults followed the news less closely than did younger and more educated people. Because knowledge of object names is well established and does not depend on current political interest, the effects of age and education were weaker for retrieval of object names than for retrieval of proper names. In contrast, self-rated health was similarly associated with baseline performance on the two tasks, as well as with the trajectory of change on the two tasks. While self-rated health is a good predictor of mortality , it coulFurthermore, the baseline level of naming was associated with the change in performance on the object naming task, but no equivalent association was found for retrieval of proper names. That is, individuals who started high on the object naming task declined more mildly on this task than did individuals who started with lower scores on this task. No similar associations were found for the retrieval of proper names. These findings might reflect the protective effects of cognitive reserve , 29, witImportantly, while the two tasks differed in baseline scores, in change trajectories, and in their associations with demographic factors, participants who retrieved more object names also retrieved more proper names, and this positive correlation was seen at baseline as well as across all testing waves. In addition, a steeper decline in one outcome variable was associated with a steeper decline in the other variable. These findings suggest that the two tasks measure related retrieval skills. According to the Transmission Deficit Hypothesis , 30, 31,We acknowledge that the analyses presented here have some limitations. First, naming was tested with only few items, so that possible decline had a restricted range. This limitation is a byproduct of the size of the sample and is offset by the strengths of a longitudinal study that included thousands of observations. Second, any longitudinal study involves a test-retest practice effect. It is possible that the practice effect was stronger for object names than for proper names because the names of objects did not change over the eight-year follow up, while the names of the President and Vice President did. Third, the HRS involves a short survey rather than an in-depth cognitive investigation, limiting inferences about the mechanisms that underlie retrieval of object and proper names. However, we believe that the analysis of demographic factors highlights important differences between retrieval of the two types of stimuli that cannot be studied in a small-scale cross-sectional study. Finally, the fact that participants had to retrieve different proper names after the 2008 elections, while object names did not change at that point is a limitation of our study. The names of the President and Vice President were chosen because they were supposed to be equally familiar to all participants, yet future research should use names that are not only equally familiar at a given time, but that remain stable and involve no new learning.In conclusion, the results of the current study further demonstrate the disproportionate difficulty associated with retrieval of proper names in healthy old age. They also show that examining object names and proper names together as indication of general cognitive decline or of a general decline in naming ability might overlook important differences between the two types of stimuli. As retrieval of the two types of stimuli is impaired in dementia , 32, fut


Tegillarca granosa  were dated. The dates obtained are used to calculate rates of accumulation for the shell mound deposits. These demonstrate highly variable rates of accumulation both within and between mounds. We assess these results in relation to likely mechanisms of shell deposition and show that rates of deposition are affected by time-dependent processes both during the accumulation of shell deposits and during their subsequent deformation. This complicates the interpretation of the rates at which shell mound deposits appear to have accumulated. At Wathayn, there is little temporal or spatial consistency in the rates at which mounds accumulated. Comparisons between the Wathayn results and those obtained from shell deposits elsewhere, both in the wider Albatross Bay region and worldwide, suggest the need for caution when deriving behavioural inferences from shell mound deposition rates, and the need for more comprehensive sampling of individual mounds and groups of mounds.We report the results of 212 radiocarbon determinations from the archaeological excavation of 70 shell mound deposits in the Wathayn region of Albatross Bay, Australia. This is an intensive study of a closely co-located group of mounds within a geographically restricted area in a wider region where many more shell mounds have been reported. Valves from the bivalve  Tegillarca granosa (syn. Anadara granosa (Linnaeus 1758)), have been recorded near to the tidal estuaries of the four rivers  that feed into the bay , hav the bay , these fambaquis .Here we use results of an intensive study of a sample of shell mounds from one area within Albatross Bay to consider some of the issues involved in dating these types of deposits. In many situations, archaeologists are limited by the amount of material suitable for dating. For example, charcoal preservation often places severe constraints on where samples for radiocarbon age determination may be obtained . The samT. granosa SMDs in the Albatross Bay region, or across northern Australia. For example, Faulkner [T. granosa shell mounds were initiated sometime between 4,400 and 5,300 BP, and while mounds appear to have ceased forming some 1,800–1,600 years ago, middens continued to form until the early twentieth century or later. These conclusions were based on eight determinations from two shell mounds and a smaller deposit referred to as a midden. Similarly, small sample sizes have characterized previous work on the Weipa deposits. Here we analyse the impact of greatly increased numbers of radiocarbon determinations on interpretation of the chronology of mound formation.We tackle these questions in the context of reporting the results of 212 radiocarbon determinations from the excavation of 70 SMDs in the Wathayn region of Albatross Bay . These aFaulkner , 12 obtaFaulkner  reportedFaulkner  reportedT. granosa, accounting for ~95% by weight of all shell material. Other mangrove and mudflat species were present but in very small quantities, along with small quantities of fish and marsupial bones, bone and stone artefacts recovered from one excavation sample at the Kwamter mound, and deposits of charcoal. Radiocarbon dates bracketed the formation of the mounds to the past two millennia and the youngest date is 235±110 radiocarbon years BP (I 1737) from the Kwamter mound, consistent with use up until the period of European contact and corresponding with Roth’s [Bailey , 16, 17 h Roth’s  observath Roth’s , 20, 21.T. granosa-dominated shell mound formation was confined to the last one to two millennia, and that there was a considerable hiatus  between the stabilisation of sea level following the last post-glacial rise and the initiation of shell mounding activity. That T. granosa were present in the region at least 4,000 years ago was, however, attested by shell midden deposits in the Walaemini rockshelter at Princess Charlotte Bay on the eastern side of Cape York Peninsula [In summarising the then record of shell mound formation around the Gulf of Carpentaria and Cape York Peninsula, Bailey  noted theninsula .Since then a number of additional studies have been conducted on the Weipa shell mounds, by Morrison , 25, 26 The research reported here is one such study. The sampling technique we adopted, described below, allows us to discuss the timing of shell mound formation at a single geographic location, and to consider the variability in rates of accumulation over time. The relatively broad spatial sample of mounds we studied also allows us to comment on variability in the places where mound formation occurred. But while our sampling strategy provided a great deal of this information, it also imposed limits on what we could infer from the dates we obtained. The implications of these limits will also be discussed.T. granosa inhabits intertidal areas over much of the Indo-Pacific region . While . 390 in . Studies. 390 in ), thoughp. 30 in ) report adequate .Nevertheless, bulk harvesting poses a number of logistical issues. First, because of the high shell-weight to meat-weight ratio and the need to heat the shells to remove the meat and make it palatable, containers such as bags are essential, and the energetic cost of transportation is high, imposing a strong incentive to find a location for processing the shells as close as possible to the harvesting area. Canoes or boats may improve the efficiency of transportation and increase the distance to the processing location.Processing poses a second issue, for even if collecting the molluscs is relatively simple, opening large numbers to gain access to the meat is best done centrally, with the aid of fire. Heat opens the bivalves, so placing them in or near a fire greatly aids the efficiency of meat extraction. This process is succinctly described by Bailey (pp. 137–138 in ) and is Finally, once the meat is extracted, there is the issue of shell disposal. Because of the relatively small size of the bivalves and the low meat-weight to shell-weight ratio, a given weight of meat generates a large quantity of shell. The simplest and most energetically efficient way to dispose of the shells is to discard them where the molluscs are processed, and there are reports by Aboriginal people today that the mounds were places where the shells were opened and the extracted meat then taken elsewhere (pp. 259 in ). In theThe literature on SMDs contains a range of explanations as to why large-volume deposits–shell mounds–were formed. Some authors attribute the concentration of shells to the remains of intensive food extraction supporting, perhaps, large populations of people , 38. SamT. granosa, was likely always to have been high and variable, a function of the large volume of material that must be processed to gain a sufficient quantity of food. This has several important implications for sampling, the more so when it is the voluminous material  that provides the datable sample.These varied functions are not mutually exclusive, but how shell mounds were formed and for what purposes does have an impact on the chronology of mound formation, and hence on subsequent interpretations of mound function. Whatever the purpose of shell mounds, the rate of shell deposition, at least in the case of Firstly, if shells are deposited in large volumes, the rate at which shell deposition occurs will appear to be rapid. This is because each depositional event, or set of events, will create a large volume of deposit. Therefore, there is some chance that samples selected from different depths within a deposit will, in fact, date the same event . This is, of course, also possible in non-shell matrix deposits, but is less likely to occur for samples separated in depth unless the volume of material deposited within a short period of time is also high. This means that the chronology of an SMD may look quite different to the chronology of another type of deposit when the same sampling protocol  is employed. Hausmann and Meredith-Williams  have recSecondly, it may be difficult to detect gaps in the depositional history of SMDs and therefore to infer either continuity of occupation or periods of abandonment. Inferences of continuous occupation are often made on the basis of uniform rates of deposition. If, for instance, sediment continues to be deposited in a cave or rockshelter at a reasonably constant rate and this sediment contains cultural material, then it is reasonable to suggest that occupation was continuous relative to the rate at which sediment was deposited. In principle, the same is true of shell mounds. However, because of the relatively large volume of shell deposited in one or a closely time-related set of discard events, the rate at which a shell mound accumulates may appear to be very rapid, and thus may appear to reflect continuous occupation. Cessation of deposition or abandonment may appear to be less common, dependent to a very large degree on the number of samples that are dated in a vertical sequence. In reality, of course, the episodic nature of shell deposition as a measure of the occupational history of the people who deposited the shells is dependent on the temporality of the processes by which material accumulates.Thirdly, shell mounds that look similar may in fact have quite different depositional histories. Because the volume of shell discarded at any one time is relatively large, small differences in the number of depositional events on different mounds may lead to marked differences in the volume of material deposited. Put another way, a small number of depositional events, each involving a large number of shells, may potentially create a deposit that has similar dimensions to one that represents the accumulations from many depositional events where the amount of material deposited each time was smaller. Where large volumes of deposit are created, one could easily imagine situations where gaps in the depositional record are missed by the particular sampling procedure employed, especially where mounds appear to be stratigraphically homogeneous . OccupatFourthly, when accumulation rate is measured as the amount of material deposited over a particular period of time it is assumed that time appears only in the denominator of the calculation. However, shell may be subject to diagenesis dependent on local environmental variables   and the Napranum Aboriginal Shire Council on behalf of the Traditional Owners.Our shell sampling strategy at Wathayn aimed to address two key questions:What is the chronology of SMD formation within a single geographical area?Is there any spatial pattern in shell matrix deposit formation within that area?To do this, we needed to obtain multi-date chronologies from as many sequences as possible within time and budget constraints, and to ensure that the dated sequences came from shell matrix deposits over the full locational range. The locations of all of the SMDs at Wathayn were obtained by a variety of methods:The database of SMD locations previously compiled by RioTintoAlcan (Weipa) Pty Ltd as part of their cultural heritage surveys;Inspection of high resolution aerial images;Aerial survey from a light plane; andIntensive on-foot survey of the study area.A total of 158 SMDs were located by a combination of these methods . The SMDOnce located, all of the SMDs were trimmed of vegetation and surveyed using a Leica C10 Terrestrial Laser Scanner (TLS), with target locations fixed in 3D space using a Differential Geographic Positioning System (DGPS) . To expo3 from aragonite to calcite) prior to dating [Shell and charcoal samples were selected from observable stratigraphic units within each of 49 SMDs, including the basal and uppermost deposits (n = 149). Additional samples were collected from the side walls of six of the trenches to try to document the within-mound chronological variability (n = 58). All of the samples were prepared and analysed at the Waikato Radiocarbon Laboratory in Hamilton, New Zealand, following standard radiometric and AMS radiocarbon protocols , 48. TheT. granosa shells from the mounds, an initial test using three “paired” charcoal/shell determinations from the same stratigraphic units was undertaken to ascertain the local marine reservoir correction value (ΔR) for this region. All three ΔR results , therefore it is not possible to determine if accumulation rates varied within the individual mounds. However, for other mounds with more than two age determinations, changes in accumulation rates within each mound can be assessed. For example, WPSM50 and WPSM58 exhibit slow, relatively uniform accumulation rates  and variable  accumulation rates. Two other mounds, WPSM68 and WPSM151, exhibit medium to low deposition rates but these are based on only two age determinations per mound. Mounds with medium rates of deposition tend to be older than 2,000 BP, with the exceptions being WPSM148, WPSM151, WPSM152, and WPSM155.et al. [Age determinations from the six shell mounds with multiple sets of samples collected from the centre to the outside edge of the feature  indicateet al. .T. granosa in northern Australia by indigenous people led, at times, to the generation of large volumes of shell valves that required disposal. The process of disposal most evident in the archaeological record was the formation of shell mounds. Rapid shell accumulation rates sometimes resulted in the formation of very large shell mounds. However, variability in accumulation rates resulted in mounds of different sizes and shapes. Once discarded, the shell as well as the shell deposit was subject to changes depending on the local micro-environment. Because both shell accumulation and post-depositional deformation and diagenesis are time dependent, time is a factor in both the numerator and denominator in commonly used accumulation rate calculations, complicating how the rate of accumulation in shell mounds should be interpreted.The central processing of large numbers of The results obtained from the Wathayn study area illustrate how rates of accumulation vary in ways predicted by our earlier hypotheses about how mounds accumulate. The mounds we dated vary considerably in age, from 4,000 cal BP to within the last 500 years. Many of the shell mounds have ages around 2,000–2,500 cal BP. Rates of deposition vary considerably, from less than 10 to several hundred centimetres per 100 years. Mounds with ages that fall in the range 2,000–3,000 cal BP accumulated somewhat more rapidly than mounds before and after this period but there is little spatial consistency in mound accumulation rates from any time period and, in some cases, mounds located adjacent to each other accumulated at different rates.For many of the mounds we studied, the available radiocarbon determinations indicate variable rates of accumulation. Mounds with uniform but slow rates of accumulation are rare. For a larger number of mounds, rates of accumulation change markedly within a single mound. For some, rates of accumulation are high at the base of the mound and low at the mound surface, and for others this difference is reversed.There is also a variable relationship between rates of accumulation and mound structure. In some mounds, an older core is covered by more recent deposits, with covering layers of shell at both the centre and periphery showing similar ages. For other mounds, the core of the mound accumulated more rapidly than deposits on the periphery. The situation is reversed in one of the mounds, where deposits at the centre accumulated more slowly than those on the periphery. In other cases, the pattern of accumulation is more complex, with mounds showing both relatively slow and rapid rates of accumulation at the centre and on the periphery of the mound as well as at the base and toward the top of the mound.T. granosa to a central place to process them with fire, then it is possible to imagine shells accumulating at different rates in different parts of a mound, something that would be very difficult to detect given commonly used sampling techniques based on the excavation of squares or trenches, or extraction of cores.Variability in the rate of shell mound accumulation is not limited to mounds in our Wathayn study area. Dates obtained from soil and bone collagen samples from shell mounds by Pluckham and colleagues  indicateAs discussed above, accounts of shell mound formation around the world provide a variety of behavioural explanations for mound formation based on mound size and shape, and rate of accumulation. However, the results of our Wathayn study suggest that caution is needed when comparing shell mound form and age.”Dating” mounds is not as simple as it may appear, given the ways in which deposits both accumulate and are transformed through time. The lesson from the Wathayn study is that the present-day form of shell mounds may hide a complex formational history. If the situation at Wathayn is in any way typical of other shell mounds, then a great deal of care is needed in assessing regional chronologies and in the interpretation of mound functions. Both the substantive dating results from Wathayn, and the evidence of variability in rates of accumulation within and between mounds, indicate that simply taking lots of “spot” dates from a group of mounds within the region at large, as advocated, for example, by Morrison , may leaAll of the 158 shell mounds from Wathayn, located along a 5 km stretch of the Embley River near Weipa in far north Queensland, Australia, were investigated in this study, although not all were dated. As a result, we have pushed back the chronology of shell mound formation in the Weipa area 1,500 years earlier than identified in previous studies. Mound accumulation in the period 1,800–2,300 cal BP is indicated, a period previously identified as a time when there was a low probability of mound formation. In addition, rather than simply seeking to refine phases of occupation in the region, we utilised the large number of dated samples from the mounds to investigate variability in the rates of accumulation both within and between mounds. Results indicate that there is considerable variability in the rate of mound formation even among mounds from one limited geographic area. Results of this study also raise questions about how rates of shell mound accumulation should be calculated, since both accumulation and diagenesis are time-dependent processes that feature on both sides of the accumulation rate equation. Our results also raise the issue of how to sample shell mounds to understand potential variability in shell accumulation rates, and indicate that the excavation and sampling strategy we used needs to be extended to fully address this issue. This requirement poses formidable logistical challenges, given the number and volume of shell mounds in many regions and the huge quantities of shell deposits that might have to be sampled. Excavating small samples by bucket and auger, as advocated by Cannon , 64 for S1 File(XLSX)Click here for additional data file.


Nanomaterials is focused on the continuing implementation of nanomaterials and nanostructures in the development of more sensitive and more specific sensing devices. As a result, these new devices employ smaller sensing elements and provide more “real time” capability. Often, the inclusion of nanomaterials leads to sensing elements for targets that were previously inaccessible. The nanostructures employed in sensor development include (among others): nanowires, semiconductor particles, various allotropes of carbon and imprinted polymeric spheres. Nanoparticles, in general, exhibit physical properties that not only differ from the parent bulk material, but also from other nanoparticles that are of different dimensions. This uniqueness offers more opportunity to fine-tune a sensor in order to discriminately detect one component of a complex mixture. The reports in this issue of the journal utilize the properties of nanomaterials to create novel sensing systems.This Special Issue of per se, the utility of this procedure to those wishing to monitor one type of biomaterial in a mixture of DNA, is clear and was shown to result in a purified solution of double-stranded DNA. We should expect reports utilizing the technique in sensing to appear in the near future.Huang and Liu  describeet al. [2 in air. This interesting study compared the relative response of prismatic nanoparticles annealed at two very different temperatures to the two atmospheric pollutants. High temperature annealing led to a selective CO sensing element, while a lower temperature treatment provided material that could not differentiate between the two analytes. Electrospun fibers, on the other hand, were found to be ideal for the selective detection of NO2.Hijiri et al.  report o2, SnOx, NiO and CuxO were deposited and treated with nitrogen or sulfur donating molecules. By means of their new inverse hard and soft acids and bases (IHSAB) model, the authors provide a guide to the development of new sensing materials.Laminack and Gole  have stuIn a review, Song and Choi  describeA more general review, contributed by Yoon , looks aThe range of sensor applications and the wide variability in sensor properties discussed in this issue indicates that the application of nanomaterials in sensing technology, a relatively new field of research, has a healthy and promising future. I encourage you to read through this Special Issue and use the valuable information provided therein to help us move forward in this exciting area.


The recognition of patient safety is now occupying a prominent place on the health policy agenda since medical errors can result in adverse events. The existence of confusing drug names is one of the most common causes of medication errors. In Iran, the General Office of Trademarks Registry (GOTR), for four years (2010–2014) was responsible for approving drug proprietary names. This study aimed to investigate the performance of the GOTR in terms of drug names orthographic similarity using the SOLAR model.Drugs.com and Medicines Complete. Pair of drugs whose names look orthographically similar with different indications were identified. Then, the SOLAR model was utilized to determine orthographic similarity between all pair of drug names.First, 100 names were randomly selected from the GOTR’s database. Then, each name was searched through pharmaceutical websites including Martindale , The mean of match values of these 100 pairs of drug was 77% indicating the high risk of similarity. The match value for most of the reviewed pairs (92%) was high (≥66%). This value was medium (≥ 33% and <66%) just for 8% of the pairs of drug. These results indicate high risk of confusion due to similarity of drug names.The stewardship of the GOTR in patient safety considerations is fundamentally problematic. Thus, as a best practice, we recommend that proprietary names of drugs be evaluated by an entity within the health system. While an entity within the health system should address patient safety considerations, the GOTR is responsible for intellectual property rights. The recognition of the importance of patient safety is now increasing and garnering renewed regulatory interest since medical errors can result in adverse events from the inappropriate therapy . As clinWHO has a constitutional mandate to “develop, establish and promote international standards with respect to biological, pharmaceutical and similar products”. This Organization collaborates with International Nonproprietary Name (INN) experts as well as national nomenclature committees in order to select a single name for each medication that should be of worldwide acceptability. While generic medicines are marketed under a non-proprietary or approved name instead of a proprietary or brand name, the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement does not hinder countries from allowing generic substitution. Besides, competition between pharmaceutical companies and generic producers has been regarded to be more effective than negotiations with pharmaceutical companies in reducing the cost of drugs .Full responsibility of the process of screening and approving drug proprietary names was delegated to the General Office of Trademarks Registry (GOTR) within the State Organization for Registration of Properties for a four-year time interval (2010–2014) and this entity was responsible for approving drug proprietary names before market entry. The naming principle consists of two components: ‘patient safety issue and intellectual property rights’.This study aimed to investigate the performance of the GOTR in terms of drug names orthographic similarity using the SOLAR model.Drugs.com and Medicines Complete. Through this search, pair of drugs whose names look orthographically similar were identified. In addition, indications for Iranian approved drug names and those drug names exist in the world were reviewed. In the case of similar indication, the identified similar pair of drug was omitted and was replaced by another similar pair of drug with different indication. Then, the self-organizing lexical acquisition and recognition (Solar) model of visual word recognition was utilized to determine orthographic similarity between all pair of drug names. The Solar model was used because of its capacity for stable self-organization, its spatial coding scheme, its combination of serial and parallel processes, and its chunking mechanism. The model also introduces a novel mechanism to explain word frequency effects. Another distinctive feature of the model is its incorporation of a novel opponent processing mechanism for performing lexical decision , first 100 drug proprietary names were randomly selected from the GOTR’s database. Then, each name was searched through pharmaceutical websites including Martindale , decision . The ortth word node, this set of letters is denoted Li, and the number of letters in this set  is denoted li. The weight between a letter node and a word node is equivalent to the value of that letter node’s activity in the spatial code for that word.A spatial code can be written as a vector consisting of n elements, where n is the number of letters in the input string and the values in the vector represent the activities of the corresponding letter nodes. Spatial codes always use a monotonically descending series to code letter position. For the ii a difference dji is computed by subtracting from sj (the activity of the jth letter node) the corresponding weight zji, i.e.,Therefore, the first step involves computing a set of signal-weight differences. For each of the elements in the set Lji(x) that is symmetrical around x = dji:i can then be found by dividing the peak of the superposition function by the number of comparison Letters (li), that is,Each signal-weight difference is then associated with a continuous function fthat is,Mimax(Fi(The results of The first column displays the generic name of the proprietary drugs name (second column) which approved in Iran. The next column shows the similar overseas drug names, with different indication of the local ones, which can be generic or proprietary names . The last two columns show the match values (orthographic similarity rate) and the rate of risk, respectively, based on the Solar . However, some of overseas drug may not exist in Iran pharmaceutical market; however, some similar pairs are generic names that are available in Iran . Furthermore, with regard to the existence of many representative pharmaceutical companies which import drugs into Iran, overseas proprietary drugs are also available in Iran market . Furthermore, the import of any of these overseas drugs is probable.The current findings indicate the high level 92) of orthographic similarity between local drug proprietary names and overseas drug names. However, there are limited studies on the actual rate of this type of medication error in Iran. The similar names of drugs as the main factor affecting medication errors, so that in 23.40 of the medication errors have been associated with drugs similar names 2 of orth. In thisThe performance of the GOTR in terms of screening similar names and patient safety consideration was too weak. One reason for such a weak performance can be the nature of the GOTR; the GOTR, compared to entities within the health system is fundamentally a different entity with various functions. The GOTR’s employees are not individuals with sufficient mastery in the field of medicines and they are not even health professionals. Accordingly, there were many failures in the performance of the GOTR from a patient safety viewpoint. The responsibility for screening drug names in developed countries is always associated with an entity related to health system. Medicines and Healthcare Products Regulatory Agency in UK , Food anLimitation of the study: inevitably, our study has not been able to answer a number of questions and in fact has revealed a few new ones. Further research is therefore required. For example, in the future, the question has to be answered is the number of medication errors occurred in Iran due to the orthographic similarity of proprietary drug names. Another issue has to be addressed is the severity of risks due to orthographic similarity of drug names and their impact on patient safety.Naming principle consists of two components: ‘patient safety issue and intellectual property rights’. However, the GOTR’s function is necessary for initial naming of drugs and before market entry, it terms of intellectual property rights, it cannot ensure medication safety. Thus, as a best practice, we recommend that proprietary names of drugs be evaluated by an entity within the Food and Drug Organization and the health system. While an entity within the health system should address patient safety considerations, the GOTR can be responsible for intellectual property rights. However, these two elements are different in theory, but in practice not black-white and eventually both should be guaranteed. Furthermore, pharmaceutical manufacturers should meet international criteria (mainly WHO) regarding proposed names, however, there is no guarantee and an entity is still needed to monitor the pharmaceutical manufacturers’ adherence to such criteria.Ethical issues  have been completely observed by the authors.


Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.Mass drug administration for elimination of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect.Bill & Melinda Gates Foundation. Plasmodium falciparum malaria in the past 15 years, many countries still have endemic transmissionNCT01872702) and rapidly reduce transmission.5Despite the gains made towards elimination of In September, 2015, WHO's Malaria Policy Advisory Committee recommended for the first time the use of MDA in specific circumstances: when transmission is close to being interrupted, vector control, effective surveillance, and access to case management are at high coverage, and importation of infection is minimal; as a component of accelerated elimination in areas of the Greater Mekong Subregion, which are under threat of multidrug resistance; or for malaria epidemics or during complex emergencies.To help with the Malaria Policy Advisory Committee's decision making, an evidence review group was established to synthesise available evidence for the effect of MDA on transmission of malaria.Evidence before this studyWe did not do a search of published work, because three comprehensive reviews have been published in the past 4 years. A Cochrane review done in 2013 found two cluster-randomised trials, eight non-randomised controlled studies, and 22 uncontrolled before–after studies of mass drug administration. Most studies showed a substantial initial effect on parasitaemia. However, there was little evidence for effects beyond 6 months. Two further comprehensive reviews published in 2015 had wider inclusion criteria, and included published and unpublished work and studies not yet published. These reviews showed that mass drug administration was implicated in local elimination of malaria in some settings, particularly remote areas with small populations and low initial malaria transmission, but not in areas of higher transmission. Mass drug administration has been simulated in several mathematical modelling studies but, as in field studies, many factors—such as the number of doses given, number of rounds of treatment, choice of drugs, local malaria transmission intensity, and outcomes of interest—have varied greatly, all of which are likely to affect outcomes.Added value of this studyIn this study, a consortium of modelling groups investigated the degree of consensus of four established malaria transmission models in terms of the main determinants of the effect of mass drug administration and how large an effect on prevalence is likely to be achieved. In consultation with partners who are doing field trials of mass drug administration, we chose various programme options  that were considered logistically feasible. We standardised many inputs and outputs of the models, such as initial slide prevalence, outcomes of interest, and implementation options. Our analysis showed—despite many differences in assumptions between the four models, for example about the underlying transmission dynamics of malaria—broad consensus between the models on how mass drug administration should be implemented to optimise effects, and the settings in which such programmes will be most effective.Implications of all the available evidenceHigh coverage in the target population and mass drug administration in more than 1 year are important to maximise reductions in transmission. Reductions in transmission last longest in low-transmission settings but, unless elimination and prevention of reintroduction are achieved, malaria transmission will return to pre-intervention levels after the programme of mass drug administration finishes.We report the results of the Malaria Modelling Consortium's MDA model comparison and their implications for the utility of MDA. Our aim for this analysis is to help with decisions on the relative prioritisation of MDA within wider malaria-control strategies.Malaria-control programmes implementing MDA need to decide on several operational factors, including the number of rounds, timing, and frequency of treatment. Furthermore, the effect of MDA can be influenced by epidemiological factors in each setting, such as malaria transmission level and infection importation rates. The Malaria Modelling Consortium collaborated with partners doing field trials of MDA to identify probable scenarios for MDA deployment and common operational choices that would need to be made within realistic logistic constraints.P falciparum parasite rate in 2–10-year-olds (PfPR2–10) before MDA, intermediate seasonal variation in transmission with one rainy season, and no importation of infection. In further simulations, we varied operational factors that are of primary interest because they can be adjusted in an MDA programme: the number of rounds per year, the effective coverage of each round, the interval between rounds, and the duration of the MDA programme. Each model was used to do a multivariate analysis that simulated the baseline conditions with every combination of the selected parameters  in the third year after the final round of MDA. The models assessed represent four different ways of simulating malaria transmission and MDA, and a summary of their characteristics and functionality is given in 29The outcome metric was the percentage reduction in annual mean all-age prevalence of EMS and EAO are or have been employed by the study funder, and were involved in data collection, analysis, and interpretation, and writing of the Article. However, they were not involved in study design The funder had no further role in study design; data collection, analysis, or interpretation; or writing of the Article. The corresponding author had access to all study data and was responsible for the final decision to submit for publication.In all four models, simulated prevalence fell substantially immediately after MDA  as a resPfPRPCR differed between models because we standardised these initial conditions to 5% slide prevalence in 2–10-year-olds, and the models make several different assumptions, for example about the relation between slide and PCR prevalence. The EMOD DTK and MORU models predicted a reduction in PfPRPCR of 64% in the third year after MDA, OpenMalaria a reduction of 58%, and Imperial a reduction of 19%. These differences were caused by many different assumptions, including the relation between entomological inoculation rate, prevalence, and the basic case reproduction number (R0); the effect of case management; the degree of stochastic variability; and the dynamics of immunity.Although the four different models showed similar trends in the effects of MDA with time, substantial differences were noted in both simulated pre-intervention transmission and the magnitude of the effect . Pre-intPfPRPCR in all models. For example, the median percentage reduction in PfPRPCR in the standard scenario at 30% coverage was 15% (range across models 10–30); at 70% coverage, it was 61% , the most important operational factor determining effect is the proportion of the population who do not receive any treatment in any round . ImplemePfPRPCR if MDA was done during the dry season or at the end of the rainy season, as previously found in similar analyses by the separate models.PfPRPCR were as much as 1·45 times greater if MDA was done in the dry season or at the end of the rainy season than at the beginning of the rainy season. Seasonal timing has less of an effect on PfPRPCR in the OpenMalaria and MORU models. In a setting with two rainy seasons per year, we predicted that timing of MDA had less of an effect, because transmission was more evenly spread throughout the year. At a given mean baseline slide prevalence, MDA was predicted to be marginally more effective in a seasonal setting (at the optimum time) than in a non-seasonal setting.In settings with one rainy season a year, all models predicted greater reductions in The introduction of MDA while vector control was simultaneously removed led to a sudden and large increase in simulated all-age prevalence, and the subsequent MDA programme did very little to reduce this shift even in the short term . We predicted, therefore, that an MDA programme of this type is insufficient to replace vector control, even at the highest levels of coverage.PfPR2–10), the percentage reduction in PfPRPCR was considerably lower in all the models compared with that in a setting with 5% prevalence. We predicted that, even with high coverage (90%), three rounds per year, and 2 years of intervention, PfPRPCR 3 years later would be reduced by only a median of 48% (range across models 19–95) from its pre-intervention level, compared with 80% (range across models 56–100) in the setting with 5% baseline prevalence. This disparity is because transmission rebounds more rapidly in a higher transmission area. However, the absolute reduction in transmission is greater in higher prevalence settings because more infections are cleared.In a high prevalence setting , based on data from Zanzibar,2–10 is lower, imported cases would be instrumental to increasing transmission. MDA more easily caused stochastic extinction in smaller than in bigger simulated populations in all the models. Finally, some evidence (only tested with the MORU model) suggested that MDA with artemisinin-combination therapies could speed up the selection of artemisinin-resistant parasite strains (When PfPR strains . HoweverAlthough individual models predicted different magnitudes of the effects of MDA, we found substantial consensus on which factors have the greatest influence on these effects, including both the characteristics of the programme and the setting in which MDA is applied. Percentage reductions were predicted to be highest in low-transmission settings and smaller populations, but were more transient in other settings, in line with evidence from field studies.We did not formally analyse which differences between the models created the variation in predicted effects of MDA. MDA can substantially affect transmission in the short term, leading to different transmission dynamics from those analysed in in-depth comparisons of models of the effects of RTS,S.A key next step for the modelling groups is to continue using data from forthcoming trials of MDA to further validate the models and to continue efforts to understand how and why model predictions differ, such as under the HIV, tuberculosis, and neglected tropical diseases model consortiums.The value of our simulations is that they show that, despite many differences in assumptions, there is a consensus between models on the relative influence of MDA operational characteristics. Many of our results accord with findings from MDA for lymphatic filariasis,


The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods.The online version of this article (doi:10.1186/s13073-017-0509-y) contains supplementary material, which is available to authorized users. Recent progress in DNA-sequencing technologies has ushered in an era of rapid and cost-effective genome sequencing, enabling clinical applications  and the To assess the potential pathogenicity of genetic variants, singly or in combinations, it is useful to assess their frequency in control or general populations, as already mentioned. Public databases are burgeoning with information about genetic variants in humans and in many model organisms. Resources such as dbSNP , dbVar , COSMIC VHL, which are proximal to the binding site of VHL for its ubiquitination target HIF1A [The biomedical research community is fortunate to have access to such a wealth of information, but its sheer size and disparate nature are also daunting. In addition to public databases, hundreds of DNA- and RNA-sequencing experiments are revealing manifold genetic variants and mutations each year, and an increasing number of these can be linked to protein structure. For example, protein structure analysis of a novel variant in the ubiquitin-protein ligase TRIM11, observed in individuals affected with inflammatory bowel disease, helped determine that the variant is more likely to affect protein–protein interactions rather than protein folding and stability . Functioet HIF1A .Simultaneously, there has been great progress in characterizing the 3D structures of proteins , 20, botHowever, the connections between genetic variations and protein structure are not always easy to find. A few computational tools have begun to emerge  workshop was hosted at the Institute for Systems Biology in Seattle, Washington. The goal of the workshop was to explore the state of the field connecting genetic variation and 3D protein structure, and to bring together some of the key researchers working on interpreting genetic variation data. The workshop consisted of a mixture of talks, discussion sessions, and breakout groups. The program is available at the workshop website . Twenty-After all the presentations and discussion sessions concluded, workshop participants separated into two breakout groups to brainstorm about how the research community as a whole could accelerate progress in the field in ways that individual laboratories could not.Adoption or development of standardized formats for the various major data types .Mechanisms to scale up the information exchange to large-scale queries using big data technologies such as DataFrames  and BigQUse of ontologies to standardize the terminology for the exchange of data and knowledge. These ontologies already mostly exist, and need only be specified as the standard, although some extension may be required.Selection of initial tools that should be part of a pilot phase of the development and initial deployment of the interoperability framework.Development of a tool registry and portal that would serve as a web-accessible resource for finding relevant tools, their inputs and outputs, and also reference data files that can be used to demonstrate and validate the tools and their interoperation.Breakout group 1 discussed existing ontologies, tools, and datasets in the field and considered potential architectures for an integrative framework, focusing on how tools and resources could be made more interoperable to enable more widespread use of the tools and integration of inputs and outputs among the tools. Important aspects that emerged in the discussion include:How to increase the actionability of variants observed in patients. Beyond facilitating access to knowledge on the structural impacts of variants, there is a need for a metric of confidence in the predicted impact. Gene-editing technologies are likely to enhance experimental studies of salient variants.The need to recognize multi-variant interactions within single genes and proteins and mutation effects on protein–protein, protein–nucleic acid, or protein–ligand and drug interactions. Also, annotation of the context in which each variant could have an effect is important. For instance, information on cell types or cellular conditions in which specific interactions or protein complexes are formed, as well as annotation of epistatic relationships with mutations elsewhere in the genome, can help in interpreting a mutation’s influence on the cell.How to improve the interpretation of variants affecting splicing. A proposal was made to create a mechanism for collecting donated RNA-seq data to derive a comprehensive set of splice variants and interpret them in the context of protein structure. It may also be useful to organize data on splice variants by type of alternative splicing , so there would be a benefit from implementing an interoperation framework.How to identify the target audiences. Scientists, tumor boards, clinical geneticists, developers of targeted drugs, patients, and lay people with an interest in genetic testing were all identified as possible audiences.How to improve documentation and outreach. Suggestions included the development of documentation videos and tutorials, and contributing to Wikipedia sections describing the impact of variants on protein structure, building on current experience such as the Protein Standards Initiative  of the HBreakout group 2 discussed unmet needs, ranging from improvements in structural interpretation of splicing variants to more effective dissemination of knowledge to clinical geneticists, tumor panels, and the general public. Salient questions and points that were discussed include:The workshop has already begun to positively impact collaboration and interoperability in the wider research community. For example, an immediate outcome from discussions that occurred during the workshop was that links pointing researchers to the MuPIT resource  were addHere we review methods that use 3D structural information from the PDB to predict the effect of missense mutations; mapping other types of mutations  remains an open challenge. In Table A first set of methods predicts thermodynamic properties related to mutations: (1) change in protein stability , 58–72; A second set of methods , 83–88 pFew prediction methods are purely based on 3D structural information, with the exception of FoldX , which uMost tools to predict the effect of mutations are available online. However, there is a wide variety of input formats and scope of prediction . The majority of the 3D protein structure-based tools take PDB residue numbers of the mutated sites as input  using multiple tools is generally not possible. For instance, it would be useful to run tools that predict multiple effects of mutations simultaneously, such as protein stability and interruption of protein–protein and protein–nucleic acid binding. A further limitation is the input by PDB or UniProt residue position, since SNVs are annotated using genomic coordinates. Mapping between genomic and protein coordinate systems is error prone due to, for example, different genome assembly versions and alternative splicing. Where a mapping from genome to UniProt is possible, SIFTS  and CRAVCurrent tools that predict the effect of missense mutations are based on either protein sequence information, 3D structural information, or both. Tools predict either biophysical changes or effect on phenotype. Those that use 3D structural information and visualization offer additional insights by providing locations of mutations in a 3D context, which is not possible using sequence-based prediction. For example, multiple mutations on a protein can be visualized and potential 3D hotspots can be identified. In the next section, we describe a framework to overcome the large heterogeneity of tools, which limits their usefulness, ease of use, and hinders comparative performance assessments.To facilitate innovation in this field, we recommend the development of a framework of common formats and application programming interfaces (APIs) that enable the many resources available to interoperate more effectively both at the individual variant level and at large scales. We further recommend the development of a portal that can be used to annotate the current state of tools in the field and guide users on how these tools can interoperate and be used to address different research questions. The outline of the recommended GVto3D framework takes its lead both from our wider review of the field as well as from the presentations and discussions that occurred among those members of the research community who attended the workshop; its design incorporates the needs and existing efforts of these researchers.Figure A second component of the portal will be the definition of standard APIs so that information can be sent to and requested from different tools in the same way, thereby reducing software development overheads, which are typically encumbered with different tools using different APIs. It is envisaged that new third-party tools will use the API natively while API adapters will be developed in order to bridge with pre-existing third-party tools. The API enables seamless interoperability between different variant-related tools and also a standard access to multidirectional mapping among genomic, protein sequence, and protein structure coordinates. These mappings will be made available through APIs and as downloadable data files. Mappings will be kept up to date based on the update schedules of the underlying data sources , freeing developers from maintaining and updating copies of these data. Once several similar resources support the standard APIs, the site can be further developed into an aggregation portal, where a query at the portal can be automatically farmed out to multiple resources, and the results collated and returned to the user in a single batch. This framework advances the FAIR principles of findability, accessibility, interoperability, and reusability  for all The use of standard file formats and standardized representations of data enable interoperability of prediction tools, for example, the output from one tool can be passed as input into a second tool, and can thereby simplify the comparison of different methods. The standardized formats are also essential components of a reusable set of integrated tools (software stack), including tools for reading and interpreting data files (file parsers), APIs, and visualization tools. Most of the current tools use a variety of inputs and outputs, placing a large burden on the user to transform data. Standard file formats and uniform APIs will be at the core of future services that will combine and compare different approaches. Various platforms and tools have different schedules and reliability of upgrades; keeping track of versions is important as changes to software may have large effects on the results.The VCF file format , despiteRegarding genome nomeclature, the Human Genome Variation Society, which aims to foster the discovery and characterization of genomic variations, including population distribution and phenotypic associations, has established guidelines and recommendations for the nomenclature of gene variations, and serves as an international standard .Progress in this field depends on global collaboration and the sharing and reuse of tools. APIs provide protocols to enable this collaboration. Tools wrapped in standard APIs present a consistent interface to heterogeneous tools, enhancing interoperability, and shielding the user from changes to the underlying software. As an example, many prediction tools that use 3D protein structural information define the location of mutations at the protein level using either UniProt or PDB coordinates. Mapping genomic coordinates to 3D protein structure is non-trivial and error prone. Robust APIs that can perform this mapping with up-to-date 3D information using both types of protein coordinates can augment existing tools that are based on just linear protein sequence coordinates.Moreover, progress in the prediction of the effect of mutations and use of 3D structural information depend on the availability of well-designed training, test, and validation sets. The tool repository will be a place to share datasets, as well as protocols and references (metadata) for how these datasets were generated. Validation sets, accompanied by well-documented tutorials or vignettes, will include a subset of variants with clearly understood effects that can be used to test the output of available resources. Eventually these can serve as a set of unit tests for the framework itself.The GVto3D workshop held in Seattle in February 2017 represents an important step towards spurring collaboration and advancing progress in proteogenomics research. The disparate nature of current tools and resources and lack of interoperability contribute to slower progress in the field than might otherwise be possible. Development of a community-driven interoperability framework for integrating genetic variation resources and protein structure resources promises further expansion of our understanding of the functional implications of genetic variation. While the use of 3D structural features has enabled the atomic-level exploration of the effects of mutations , the accuracy, scope, and scale of predictions are still limited. The proposed framework will enable pooling of data sources and tools, and collaborative development.However, there will be substantial challenges as we move forward with design of the framework. The first challenge is establishing a durable user base for the framework. One possible approach is to engage a few key laboratories to take the lead as early adopters, and assume that the framework will gain wider community acceptance through their example. We propose a more user-centered design approach, however, which emphasizes an iterative process of engaging multiple communities of practice in conceptualizing, developing, and rolling out the framework; the GVto3D workshop was a first step in this direction. Second, questions of sustainability are also pertinent here, insofar as how such a system will be maintained, and who will be responsible for its ongoing maintenance. Here, we propose an approach that we envision will become self-sustaining through the deployment of open-source technologies in an engaged community. Third, standardization is a key component of any interoperability project, which in this case depends upon work to enhance usage of certain de facto standards, and to establish other standards, including the creation of standard APIs. Working closely with the community of potential framework users, as well as with standard-setting bodies, such as the Global Alliance for Genetics and Health and the Proteomics Standards Initiative of the Human Proteome Organization, will be important for helping these standards gain further traction.Taken together, the user-centered framework we have outlined above—a Tool Registry and a set of standardized formats and common APIs based on deployment of open-source materials—aims to bring the FAIR principles to bear on current and emerging tools while enabling their broader usage across multiple communities of practice. The result promises to be more rapid progress in research that can make use of GVto3D resources and eventual applications to precision medicine, while ensuring that methods and outcomes are findable, accessible, interoperable, and reusable.Benchmark dataset: A curated and well-studied dataset that can be used to evaluate the relative performance of analysis methods and algorithms.File parser: A computer program module that interprets the structure of input data and breaks the input into well-defined parts that can then be used by other parts of the computer program.Rosetta energy terms: Rosetta  estimateSoftware stack: A set of software subsystems or components designed to work together as a platform.Variant Call Format: A standard format of a text file used for storing genome sequence variations relative to a reference genome.Additional file 1: Table S1.shows tools that use three-dimensional structural information from the Protein Data Bank to predict the effect of missense mutations. 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A standardized set of quality measures for juvenile idiopathic inflammatory myopathies (JIIM) is not in use. Discordance has been shown between the importance ascribed to quality measures between patients and families and physicians. The objective of this study was to assess and compare the importance of various aspects of high quality care to patients with JIIM and their families with healthcare providers, to aid in future development of comprehensive quality measures.Surveys were developed by members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Juvenile Dermatomyositis Workgroup through a consensus process and administered to patients and families through the CureJM Foundation and to healthcare professionals through CARRA. The survey asked respondents to rate the importance of 19 items related to aspects of high quality care, using a Likert scale.p < 0.05). Of particular importance, however, was consensus between the groups on the top five most important items: quality of life, timely diagnosis, access to rheumatology, normalization of functioning/strength, and ability for self care.Patients and families gave generally higher scores for importance to most of the quality measurement themes compared with healthcare professionals, with ratings of 13 of the 19 measures reaching statistical significance (Despite overall differences in the rating of importance of quality indicators between patients and families and healthcare professionals, the groups agreed on the most important aspects of care. Recognizing areas of particular importance to patients and families, and overlapping in importance with providers, will promote the development of standardized quality measures with the greatest potential for improving care and outcomes for children with JIIM. The juvenile idiopathic inflammatory myopathies (JIIM) represent a group of rare conditions with the common feature of muscle weakness, the most frequent of which is juvenile dermatomyositis (JDM). These are chronic conditions, often associated with long-term morbidity due to the disease itself and medication toxicities, which can lead to significant functional impairment. While there are well documented clinical and laboratory criteria for assessment and ongoing monitoring of disease activity in patients with JIIM, and published core sets of outcome measures including disease activity and damage assessment , 2, therQuality measures have been developed and adopted largely to enable the evaluation of the quality and performance of healthcare delivery by a healthcare provider or entity. They facilitate standardized comparisons of clinical care across care providers and are becoming increasingly important in assessing healthcare delivery processes and outcomes . At the The Patient-Reported Outcomes Measurement Information System (PROMIS) measures are quickly becoming standards in evaluation of clinical practice monitoring for a multitude of disease processes, including the rheumatic diseases . InvolviThe development of quality measures in JIIM, with a focus on PROs, is critical for giving medical providers the tools to monitor and treat patients with the disease in a manner that reflects the desired health outcomes of patients. This is also important for providing patients, parents, and caregivers the tools and information they need to make informed decisions about their healthcare. At the same time, the correlation between patient-reported and physician-reported outcome measures is not clearly established, with some studies suggesting significant discordance –10.In this study, we sought to assess the importance of various aspects of high quality care to patients with JIIM and their families and assess the concordance with the importance ascribed by physicians and other clinical care providers. The ultimate goal of this work is to develop a standardized set of quality measures for use by pediatric rheumatologists and health professionals to aid in the assessment and long-term monitoring of patients with this disease.A survey was developed by members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Quality Measures Workgroup through a consensus process. First, a list of candidate themes important in the clinical care of patients with JIIM was generated in round robin fashion, based on discussion among the ten workgroup members  at an annual CARRA meeting. This was followed by selection of a draft list to include on the survey, using nominal group technique. Following the workgroup session, the survey underwent review and editing for additional input, suggestions regarding missing items, and evaluation of comprehensibility/readability by three parent members of the CureJM Foundation, a nonprofit organization dedicated to enhancing awareness and raising research funds for juvenile myositis. The final included list of variables then underwent an additional review online by the workgroup members for final approval.The survey questions gathered information on patient demographics, myositis characteristics, functional disability, and asked respondents to rate the importance of 19 aspects of high quality care: timely diagnosis, access to rheumatology (ease of getting an appointment), access to dermatology, access to physical therapy, medication counseling, monitoring of medication toxicity, medication tolerance, discontinuation of steroids/prednisone, discontinuation of medications, normalization of labs, overall quality of life, ability for self-care/activities of daily living, resolution of pain, resolution of fatigue, resolution of rash, normalization of functioning/strength, school attendance, work attendance, and minimizing hospital/clinic visits. For these questions, respondents were asked to rank each measure independently on a 5-point scale, with “1” indicating very low importance and “5” indicating the greatest importance.https://www.surveymonkey.com/r/JM_QI). This database included contact information for approximately 1500 families of patients with JIIM. Responses were collated and data were abstracted in a standardized database for analysis. IRB approval was obtained at one institution and participants were informed that consent to participate was implied by completion of the questionnaire.In June 2014, the survey was distributed electronically via e-mail to patients and family members of patients with JIIM through the CureJM Foundation patient and family database  in June 2015, with an additional reminder in July 2015 (https://www.surveymonkey.com/r/9WG3WWB). These responses were collated and data were abstracted in the same standardized database for analysis. IRB approval was obtained at one institution and participants were informed that consent to participate was implied by completion of the questionnaire.The survey sent to patients and families of patients with JIIM was adapted for use with healthcare professionals. The survey questions assessed characteristics of the responding healthcare professionals and asked respondents to rate the importance of the same 19 quality of care themes. The survey was electronically distributed via e-mail to all registered CARRA healthcare professionals in the CARRA database .Student t-test comparisons were used to assess difference in the ranking of quality themes between parents and families and healthcare professionals. We used 2-tailed Student t-tests with Overall, there were 194 respondents (approximate response rate of 13%) to the survey, the majority of whom were parents of children with JIIM and the remainder of whom were mainly other relatives acting as caregivers. Most respondents described significant functional impact when the disease was at its worst, but currently had well-controlled disease, with minimal or no impact within the preceding two weeks . There were also no significant differences found in the ratings between patients reporting high and low levels of current functional limitations.In subgroup analysis, there was no significant difference in rating of quality themes when comparing patients diagnosed in the past two years, compared to patients diagnosed more than 2 years ago, except for normalization of labs  to the healthcare professional survey: 82 (95%) pediatric rheumatologists, 2 (2.5%) pediatric nurse practitioners, and 2 (2.5%) adult rheumatologists, all practicing in the United States (89.5%) and Canada (10.5%). Respondents were evenly divided among clinicians with 1–5 years of experience (25%), 6–10 years (22.6%), 11–20 years (23.8%) and more than 20 years (28.6%). Most respondents reported following less than 15 patients (80.7%), with only seven respondents (8.4%) reporting following more than 30 patients with JIIM.Healthcare professionals rated timely diagnosis as the most important aspect of high quality care, followed by normalization of functioning/strength and access to rheumatology Fig. .p < 0.05)  Fig. .Table 2THealthcare providers and systems are increasingly focused on patient centered care, with the ultimate goal of improving care in a manner most relevant to patients. This study was performed to identify and compare the importance of various aspects of high quality care to patients and families with JIIM and their healthcare providers, to help guide the future development of a standardized set of clearly defined quality measures that are relevant to both clinical care providers and patients and their families. This is an area of great need in JIIM, as standardized quality measures are important for improving the assessment and long-term monitoring of patients with chronic diseases . While cPrevious work completed by the Outcome Measures in Rheumatology (OMERACT) myositis working group, and others, has also shown the importance of patient input in the development of PROs in myositis . Using qThere are limitations to consider in our work. The patient and family and healthcare professional surveys did not undergo formal reliability or validity testing, as they were exploratory in nature. The healthcare provider survey was sent to the entire CARRA membership, with a response rate of approximately 22%. While this rate can be considered low, it is similar to the response rates in other recent CARRA surveys  and is cThe patient and family survey was sent to members of the CureJM Foundation, which may represent a specific demographic population rather than the entire population of patients and families with JIIM. For example, the majority of patients appeared to be in remission, with relatively low disease impact at the time of the survey. The survey was also administered solely in English, which likely excluded a subset of patients. Furthermore, the majority of respondents were parents, not patients, which may alter the perspective and responses as well, although this is common in pediatrics. This was likely due to greater parent membership in the CureJM Foundation, compared with patients. Finally, the quality measurement themes that were presented for ranking of importance were selected and incorporated into the survey by healthcare providers and three parent reviewers, but there may be other measures that are important to patients and families that they were not given the opportunity to rank. This would benefit from additional input from a broader patient and family audience through focus groups and other methods of communication.In general, the overall rankings of importance of all the variables were scored higher by patients and families compared to healthcare providers. Although this could be an accurate measurement, it may reflect the differences in perspective when comparing patients’ and providers’ experiences and goals. It is also likely that healthcare professionals are more accustomed to scales/rankings, leading to a larger range of rankings when compared to patients and families. This may have been minimized if the ratings were measured in an ordinal scale, which should be applied to future work. In addition, these differences may be related to the finding that patients and families are more likely to use temporal comparisons , while clinicians appear to use social comparisons (considering measures based on the full range of disease in the population) .We had hypothesized that there might be differences in the ranking of importance of all of the themes based on duration of disease or current level of functional impairment from disease among patients and families, but this was not shown in statistical analysis. This may have been due to the relatively low percentage of patients with any current functional impact, as nearly 70% of respondents reported minimal or no current functional impact from JIIM at the time of their response to the survey. Access to dermatology was rated lowest by patients and families compared to other items and may have been influenced by the fact that the survey was administered by a group of rheumatologists through CARRA.Healthcare professionals must be thoughtful in aligning standardized quality measures with those that are considered important by patients and their families, to ensure that the patient voice and perspective is being incorporated into decision making for disease assessment, monitoring and treatment. Attention to quality measures that are important to patients and their families will also promote partnership in care and alignment of goals between patients and care providers which may, in turn, help to improve adherence to therapy, satisfaction, and outcomes. Understanding and appreciating differences in the perceptions of relative importance of the aspects of quality care between these groups should be considered in future plans to design and implement a standardized set of quality measures for this disease, with particular attention paid to those areas that showed overlapping highest importance . With limited resources, the integration of measures that are considered important by both patients and families and clinicians may allow for future pragmatic collection of high-yield outcome measures, and maximize the opportunities to measure and improve outcomes for children with JIIM. To move this work forward and reach that goal, the themes discussed here will need to be explored and transformed into clearly developed quality measures with robust measurement specifications. This will require discussion of the measurement domains and methods, as well as the tools and methodology that are required to assess the variables. Some of the quality of care themes explored here will more readily translate into specific quality measures for use by individual pediatric rheumatologists. For example, quality of life can be assessed with the use of validated tools , while tThe results of this study support prior work showing differences in the relative importance that patients and families ascribed to various quality measures, compared with healthcare providers. This highlights the importance of obtaining input and feedback from patients and families when designing and implementing quality measures for use in monitoring disease activity, progress and response to treatment. This study found that the top five themes for quality care ranked by patients and families and healthcare professionals were overlapping, suggesting that these domains should be given special attention and incorporated into future quality measure development for JIIM.