text:
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Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials. JAMA. 2009;302(9):977–984. doi:10.1001/jama.2009.1242
© 2023
Author Affiliations: INSERM, U738, Paris, France, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Bichat-Claude Bernard, Département d'Epidémiologie Biostatistique et Recherche Clinique, Paris, France and Université Paris Diderot, Faculté de Médecine, Paris, France (Drs Mathieu, Boutron, and Ravaud); Hôpital Gabriel Montpied, Service de Rhumatologie, Université Clermont 1, Faculté de Médecine, Clermont-Ferrand, France (Dr Mathieu); Ottawa Methods Centre, Ottawa Hos pital Research Institute and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada (Dr Moher); and Centre for Statistics in Medicine, University of Oxford, Oxford, England (Dr Altman).
Context As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial's findings in member journals.
Objective To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes.
Data Sources and Study Selection MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors.
Data Extraction For each included article, we obtained the trial registration information using a standardized data extraction form.
Results Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23).
Conclusion Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent.
In 2005, the International Committee of Medical Journal Editors (ICMJE) initiated a policy requiring investigators to deposit information about their randomized controlled trial (RCT) design into a clinical trial registry before participant enrollment as a precondition for publication of the trial's findings in member journals.1 This policy required that principal investigators of all clinical trials starting enrollment after July 1, 2005, to register information about the study prior to participant enrollment. Registration usually involves reporting information on the 20 items proposed by the World Health Organization registration advisory group in April 2004.2 The research community has embraced this policy, as seen by a marked increase in trial registration around the time of the implementation of the ICMJE policy.3 This great idea of trial registration switched rapidly from being ignored to being irresistible and trial registration that was some years ago the exception is now the rule.4
ClinicalTrials.gov received 30 new trial registrations per week, on average, before the implementation of the policy and 220 new trials per week, on average, since then.5
One of the main objectives of trial registration is to help achieve transparency in results and to make information about the existence and design of clinical trials publically available.6-14 This policy should permit knowledge sharing about the key elements of clinical trials and help decrease the risk of selective reporting of outcomes that was previously identified in published results of RCTs.15-17
Our study had 4 objectives: to assess the proportion of registered trials in a sample of RCTs whose results were recently published in journals with high impact factors; to compare in registered trials the primary outcomes registered with those reported in subsequent publications; to determine whether outcome reporting bias favored significant primary outcomes; and to compare general medical journals and specialty journals in terms of the proportion of registered trials and differences in primary outcomes.
We searched MEDLINE via PubMed to identify all reports of RCTs assessing treatments in 3 medical specialties (cardiology, rheumatology, and gastroenterology) indexed during 2008. This search was performed at least 3 months after the publication of articles (ie, up until March 2009). We used the limits of study type ("randomized controlled trials") and journal type: the 10 journals indexed with the highest impact factors among the general and internal medicine category and the 10 journals indexed with the highest impact factors among journals in each of the 3 specialties, according to the Institute for Scientific Information Web of Knowledge (2007). The list of journals is in
the Box. We focused on these 3 medical areas because of their important representation in clinical practice and clinical research. We decided to select only reports published in journals with the highest impact factor because they are all peer-reviewed and tend to be of higher quality.18
Journals Requiring Trial Registration for Publication, No. of Trials Included in Study
General Medicine
Annals of Internal Medicine, 3; Archives of Internal Medicine, 9; BMJ, 0; CMAJ, 0; JAMA, 21; PLoS Medicine, 1; Lancet, 34; New England Journal of Medicine, 45
Circulation, 20; Circulation Research, 0; Journal of the American College of Cardiology, 29
Annals of the Rheumatic Diseases, 11, Arthritis Research & Therapy, 0; Clinical and Experimental Rheumatology, 0; Journal of Rheumatology, 7; Osteoarthritis and Cartilage, 4; Rheumatology, 9; Seminars in Arthritis and Rheumatism, 0
American Journal of Gastroenterology, 30; Clinical Gastroenterology and Hepatology, 0; Gastroenterology, 17; Gastrointestinal Endoscopy, 8; Gut, 7; Hepatology, 17; Journal of Hepatology, 3
Journals With No Information About Registration, No. of Trials Included
Annals of Medicine, 0; Annual Review of Medicine, 0
Basic Research in Cardiology, 0; Cardiovascular Research, 0; European Heart Journal, 12; Heart Rhythm, 2; Journal of Molecular and Cellular Cardiology, 0; Nature Clinical Practice: Cardiovascular Medicine, 0; Trends in Cardiovascular Medicine, 0
Arthritis and Rheumatism, 31; Nature Clinical Practice: Rheumatology, 0; Scandinavian Journal of Rheumatology, 0
Inflammatory Bowel Diseases, 3; Nature Clinical Practice: Oncology, 0; Seminars in Liver Disease, 0
One of us (S.M.) systematically examined the 2008 "Instructions for Authors" of the selected journals and checked whether they clearly requested the registration of the trial before submission of an article and referred to ICMJE guidelines about trial registration or to trial registration in general (the Box).
The title, keywords, and abstract of retrieved citations were assessed by 1 of us (S.M.). Articles were included if the study was identified as an RCT, which was defined a comparative study reporting a random assignment of participants (reporting "random," "randomized" etc) anywhere in the report. We excluded commentary or discussion articles, observational studies (cohort studies, case-control studies, and cross-sectional studies), meta-analyses, ongoing studies, articles for which only the abstract was available, follow-up studies, and duplicate publications. After reading the full-text article, studies with no primary outcome explicitly identified anywhere in the text were also excluded.
One reviewer (S.M.), who was not blinded to authors and their affiliations, journal names, or funding sources, extracted all data using a standardized data extraction form. The following data were extracted.
The journal name and its 2007 impact factor were extracted. Data on the funding source of each published study was collected and categorized as no funding, government, industry, private nonprofit, other source, or not reported.19
From each published report, we reviewed the number and nature of the reported outcomes. An outcome was defined as a variable that was intended to be compared between randomized groups to assess the efficacy or harm of an intervention.15 Primary outcomes were those that were explicitly reported as such in the published article, along with the time frame of assessment. If none was explicitly reported, we used the outcome stated in the sample size estimation. If none was explicitly identified in the text or in the sample size calculation, the article was excluded. If information was available, we compared the primary outcomes explicitly reported as such in the published article with that stated in the sample size calculation.
For each published trial report, 1 of us (S.M.) systematically searched whether the trial was registered. We checked whether the authors reported registering their trial and whether the registration number was included in the published article.
When no registration number was reported in the published article, the corresponding author was contacted by e-mail to ask whether the trial was registered, and if so, in which registry, and the associated registration number. An initial e-mail was followed by 2 others a week apart when there was no response, initially. If we received no answer from the corresponding author, we searched the following clinical trial registries: ClinicalTrials.gov (NCT),20 International Standard Randomized Controlled Trial Number Register (ISRCTN),21 and the registry of the country of the first or corresponding author (for example Australian New Zealand Clinical Trial Registry [ACTR] or Nederlands Trial Register [NTR]). We also searched the World Health Organization registry search portal.22
To identify the record of these trials in the registries, we proceeded as follows:
We searched for the reference of the published article in the registry.
If the reference of the published article was lacking in the registry, we checked whether the principal investigator and the funding source matched those reported in the article. When it did, the record was selected and data were extracted.
When multiple registry records were found after the article title was used as the search string, we checked the experimental treatment, the comparator, the design, and the sample size to select the adequate report. We encountered no ambiguous situation.
If no registration number was found at the end of this process, the published article was considered not registered.
For each registered trial, we collected the dates reported as being the registration date and the start and end dates of participant enrollment. The ICMJE, in 2005, defined studies starting before July 1, 2005, as having to be registered before September 13, 2005, and studies starting after July 1, 2005, as having to be registered before the onset of participant enrollment. We analyzed the date of registration for both times separately. Finally, we excluded studies registered after the end of the study because it was not possible to evaluate the risk of outcome reporting bias in such studies.
We reviewed the number and nature of reported outcomes. An outcome was defined as a variable that was intended for comparison of randomized groups to assess the efficacy or harm of an intervention.15 Primary outcomes consisted of outcomes explicitly reported as such in the trial registration, along with the time frame of assessment. If none was explicitly identified, the trial's primary outcome was considered not registered.
For those explicitly identified, we checked whether it was reported with a clear description (ie, primary outcome reported with time-frame assessment). For example, "blood pressure" is not a clearly specified outcome. Ideally, we sought an unambiguous definition (eg, change in systolic pressure from baseline at 12 months). To take into account the amendments and possible changes by the data provider that could occur any time after the initial registration, when feasible, we checked all changes in the protocol that were available using a specific function (eg, "History of Changes" in ClinicalTrials.gov archive site).
For reports included in this study, we evaluated the consistency between the primary outcome(s) reported in the registry and those in the published article. For this analysis, we selected only trials registered before the end of the study, which gave a clear description of the primary outcome in the registry. For the end of the study, we used the date reported in the registry. If the term currently recruiting was in the registry, the study was excluded. If the terms ongoing, or not recruiting were in the registry, we noted the date reported in the part "end of the study" and analyzed the study according to this date. If the study was registered after the date of the end of the study reported in registry, we considered that the study was registered after the study completion. We collected information on the primary outcome reported in the article and that reported in the registry. We defined a discrepancy between the registered and published primary outcomes as follows: if the 2 were clearly different (eg, blood pressure and death) or were evaluated at a different times (eg, pain at 3 months and pain at 6 months).
If the 2 primary outcomes were different because the one reported in the registry was more imprecise than that reported in the article, we classified the study as having "imprecise outcome registration." For example, in a study assessing rheumatoid arthritis, the registered primary outcomes were "clinical disease activity and radiographic change," but the published ones were "DAS28-ERS<2.6 and the modified total Sharp score."
Each primary outcome that was considered imprecise was confirmed by 2 of us (I.B., P.R.), with disagreements resolved by consensus.
We defined major discrepancies according to a modified classification of Chan et al15:
The registered primary outcome was reported as a secondary outcome in the published article.
The registered primary outcome was omitted in the published report.
A new primary outcome was introduced in the published article (ie, a registered secondary outcome that becomes primary in the article or an outcome that does not appear at all in the registry but is introduced as primary in the article).
The published primary outcome was described as a secondary outcome in the registry.
The timing of assessment of the registered and published primary outcomes differed.
If the registry of the published text contained several primary outcomes, we applied the previous definition for each primary outcome. Discrepancies were identified by 1 of us (S.M.) and were confirmed by 2 other members (I.B., P.R.), with disagreements resolved by consensus.
We extracted the P values from the full-text article for all the primary outcomes that were registered and for all the outcomes reported in the article. We quoted results according to statistical significance: results significantly supporting or refuting the study intervention or favoring 1 of the groups in trials with 3 or more groups (ie, P < .05), results that did not reach statistical significance (ie, P ≥ .05), or unclear results. The same classification of results—significant, not significant, and unclear—for equivalence or noninferiority trials was according to the margin of equivalence set.
A discrepancy was considered to favor statistically significant results when a new statistically significant efficacy primary outcome was introduced or when a nonsignificant one was omitted or defined as nonprimary in the published article, according to the Chan classification.15 We also judged the discrepancy as positive when a new, statistically nonsignificant safety primary outcome was introduced in the published article. In fact, a new, statistically nonsignificant safety primary outcome was considered if the experimental drug had no more adverse effects than the comparator even though the trial was not powered to show a difference. The influence of some discrepancies could not be assessed because the published text contained no results concerning the registered primary outcome. Consequently, the positivity or negativity of the discrepancy was considered impossible to conclude, so the study was considered not assessable.
Median and interquartile ranges (IQRs) for quantitative variables and number of articles (percentages) for categorical variables were calculated for each study characteristic. Proportions of registered articles or differences in primary outcomes between general medical journals and specialty journals were compared by the χ2 test or Fisher exact test, if necessary. Comparisons between general medical journals and specialty journals for quantitative variables involved the t test. P < .05 (2-tailed) was considered statistically significant. Statistical analysis involved use of SAS version 9.1 (SAS Institute Inc, Cary, North Carolina).
Of the 829 references retrieved, 413 reports were selected after screening titles, abstracts, and keywords (Figure). Five articles reported the results of 2 RCTs, and for these, we focused only on the first RCT whose results were reported.
The description of included articles is presented in Table 1. Of the 323 retained articles, 114 (35.3%) were published in general medical journals and 209 (64.7%) in specialty journals. Fifteen specialty journals (ie, 48 articles; 14.9%) provided no guidance on trial registration in their instructions to authors.
The clinical content for 44.0% of the articles was cardiology; 31.6%, gastroenterology; and 24.5%, rheumatology. An industry funding source was reported for 182 articles (56.3%), 76 (66.7%) of the 114 articles published in general medical journals, and 106 (50.7%) of the 209 in specialty journals.
Sixty-six articles (20.4%) provided no description of the sample size calculation for the trial. When the sample size calculation was reported, the primary outcome identified in the text and that used for sample size calculation was the same for 243 articles (94.6%) but differed for 14 articles (5.4%).
A total of 147 trials (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12.1%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome.
The proportion of registered trials was greater for articles in general medical journals than for those in specialty journals (111 of 114 [97.4%] vs 123 of 209 [58.9%]; Figure). All but 3 articles published in a general medical journals reported the registration number. Among specialty journal articles, 94 trials (76.4%) reported the registration number, 23 (18.7%) were provided by the corresponding author, and 6 (4.9%) were found after searching clinical trial registries for trials.
Most of the trial protocols were registered in either ClinicalTrials.gov (197 of 234 [84.2%]) or ISRCTN (28 of 234 [12.0%]).
Of the 323 articles assessed, 48 (6.7%) were published in a journal containing no information about trial registration in the instructions for authors, and 32 of these trials were registered. Sixty-nine trials published in journals that mentioned registration in their instructions for authors were not registered.
Of the 234 trials that were registered, 87 (37.2%) were not taken into account because they were registered after the completion of the study (n = 45), because of imprecise or missing description of the primary outcome or the timing of its assessment in the registry (n = 39), or both (n = 3; Figure).
Among the 147 remaining reports, the primary outcomes of 46 articles (31.3%) differed from that registered (Table 2); this proportion was similar for general medical journals (22 of 75 [29.3%]) and specialty journals (24 of 72 [33.3%]; P = .73). The discrepancies consisted of the introduction of a new primary outcome in the article (ie, a secondary outcome or an absent outcome in the registry that becomes a primary outcome; 22 of 147 [15.0%]), omission of the registered primary outcome from the article (15 of 147 [10.2%]), published primary outcome registered as a secondary outcome (8 of 147 [5.4%]), a registered primary outcome reported as a secondary outcome in the article (6 of 147 [4.0%]), and timing of assessment different in the article and the registry (4 of 147 [2.7%]). Nine articles had 2 reasons for differences in primary outcomes.
For the 46 articles with a discrepancy between the registry and the published article, the influence of this discrepancy could be assessed only in half (23 of 46). Among them, 19 of 23 (82.6%) had a discrepancy that favored statistically significant results (ie, a new, statistically significant primary outcome was introduced in the published article or a nonsignificant primary outcome was omitted or not defined as the primary outcome in the published article).
For the 147 trials registered before the end of the participant recruitment, 101 had a clear description of the primary outcome in the registry that matched the published primary outcome; the proportion was not different between general medical and specialty journals. These trials represent less than half of the 234 registered trials (101 of 234; 43.2%).
To evaluate trial registration and selective outcome reporting bias, we identified a sample of 323 recently published RCTs in cardiology, gastroenterology, and rheumatology. Most journals provided guidance on trial registration in their instruction to authors section. Only 147 trials (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly identified). Registration was missing for 90 trials (27.9%). Forty-five trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study with no or an unclear description of the primary outcome. Furthermore, 31.3% (46 of 147) of trials adequately registered showed some evidence of selective outcome reporting. Of these 46 articles, when the primary outcome description was available, 82.6% of differences in primary outcomes between the registration and article (19 of 23) favored reporting statistically significant results, with the remainder unclear. Finally, when comparing general medical journals and specialty journals, results of trials published in general medical journals were more often adequately registered, but selective outcome reporting did not differ between the 2 types of journals.
A main goal of trial registration is to enhance transparency of research and accountability in the planning, conduct, and reporting of clinical trials, an objective achieved by making available details about the trial.1,23,24 Therefore, adequate registration should be a safeguard against publication bias. A major step has been achieved with the ICJME initiative for trial registration, and the existence of all trials is now publicly available. However, after this first step, the quality and timing of registration still needs improvement. Consistent with our results, Reveiz et al25 found that among the 275 respondents to a survey sent to a random sample of corresponding authors of published clinical trials, only 21% of them had registered all of their ongoing trials since 2005, but 47% stated that they would provide the 20 World Health Organization data set items to a registry for all their future clinical trials.26 In 2005, Zarin et al27 found inconsistent quality of information for trials registered in ClinicalTrials.gov. Sekeres et al28 reported frequent omission of scientific leadership (name of the study chair or principal investigator; 355 of 1388 [26%] and contact e-mail addresses, 855 of 1388 [62%]) in trial registration.
Adequate trial registration could also be a great opportunity to evaluate and limit other biases such as outcome reporting bias. However, our results highlight that editors and peer reviewers did not take advantage of the transparency provided by registration. Although they had the opportunity to check outcome reporting bias by comparing submitted manuscripts to information available for the trial registration, we found some evidence of selective outcome reporting in 28% of the articles adequately registered.
Previously, Chan et al16 reported a difference in primary outcomes between trial protocols and publications for 40% of the trials the authors analyzed. In another study, these authors found 62% of trials with at least 1 primary outcome that was changed, introduced, or omitted from that in the submitted protocol15; among the 51 trials with major discrepancies, 16 (31.4%) had discrepancies that favored statistically significant primary outcomes in the articles. In a recent survey of protocols and subsequent publications from the Lancet, major differences were observed for the primary outcome in 11 of 37 trials.29 The results of these different studies performed with specific samples of trials (trials approved from 1990 to 1998 in Canada and between 1994 and 1995 in Denmark or trials published in a specific journal), and a different method could not be directly compared with our results, which were obtained in a large sample of recently published articles from various journals.
These results highlight several issues. First, it is important for the entire scientific community to endorse and adhere to the requirement for trial registration before the beginning of participant enrollment in a trial. Although most trials with results published in general medical journals with high impact factors were registered, several did not respect the deadline of registration imposed by editors. Furthermore, less than half of the trials with results published in specialty journals were registered. The involvement of institutional review boards30 and funders of trials31 has been advocated to help to enforce trial registration. Legislation making trial registration mandatory could also be a major incentive for trial registration. Despite many journals following the ICMJE guidelines and requiring a registration number for publication, some journals use vague language such as "We encourage the registration of all interventional trials" [emphasis added] in their instructions to authors. A lack of clarity in submission guidelines journal guidance might help explain inadequate trial registration. Unclear language has also been suggested for a lack of adherence to reporting guidelines.32
Second, if the data in registries are not sufficiently detailed, with some sections not reported or inadequately reported, these data will not be useful. The sponsor and principal investigator are responsible for a trial's proper registration. Furthermore, quality control procedures of trial registries could be improved.
Trial registration provides a good opportunity for editors, peer-reviewers, and policy makers to identify outcome reporting bias and other deviations from the planned study to prevent such distortions from reaching publication. Outcome reporting bias is widely accepted as being a major problem that deserves more attention.15,16,33-35 Recently, the Cochrane collaboration has developed a tool to assess the overall risk of bias of trials included in systematic reviews. Selective outcome reporting is one essential component of this tool.36 As highlighted in our results, which confirm earlier findings,16 changes to the outcomes reported mainly favored statistically significant results over statistically nonsignificant results. Such changes made after seeing all the results lead to biased and misleading results and are unacceptable. Possible reasons are to provide evidence that the treatment should be prescribed to patients or perhaps simply to increase the chance of acceptance of the report for publication, but the determinants of this bias need to be investigated further. Before the requirement of trial registration, evaluation of outcome reporting bias was difficult because it implied obtaining the trial protocol. Thanks to trial registration, identifying and quantifying outcome reporting bias as routine is feasible when appraising the quality of published results of an RCT.
This study has some limitations. First, we selected only trials published in journals with a high impact factor; for more than 90% of the selected reports, these journals endorsed trial registration in their instructions for authors. Consequently, these results probably underestimate the amount of inadequate and nonexistent trial registration. Second, this study was restricted to 3 medical specialties, which could cause difficulties of generalization. Third, of the 234 registered trials, 195 (83.3%) enrolled participants before the implementation date specified in the ICMJE policy regarding trial protocol registration (ie, July 1, 2005). Consequently, the results could improve for trials beginning after that date because researchers are more likely to be aware of this rule and editors could be stricter for such trials. However, of the 39 trials with the first participant enrolled after the July 1, 2005, deadline, only 5 were registered before the onset of the study and 4 more after the end of the study. Furthermore, some trials may not have been adequately registered or data were not updated in the registry after protocol amendments, and the registered primary outcome was different from that specified in the protocol submitted to the research ethics committee. Finally, we focused on only primary outcomes and did not address the problem of unreported secondary outcomes.
To obtain the full benefit of clinical trial registration, the active participation of different stakeholders is needed. First, the sponsor and principal investigator should ensure that the trial details are registered before enrolling participants. Second, the comprehensiveness of the registration should be routinely checked by editors and readers, especially regarding the adequate reporting of important items such as the primary outcome. Third, editors and, possibly, peer reviewers should systematically check the consistency between the registered protocol and the submitted manuscript to identify any discrepancies and, if necessary, require explanations from the authors. Finally, the goal of trial registration could be to make available and visible information about the existence and design of any trial and give full access to all trial protocols37 and the main trial results.3
Recently, ClinicalTrials.gov has introduced the reporting of basic results associated with registered trials. When authors report results—mandatory in the United States for trials of drugs (including biologics) and devices subject to Food and Drug Administration regulation—it will be increasingly difficult to hide information.
In conclusion, although trial registration is now the rule, careful implementation of trial registration, with full involvement of authors, editors, and reviewers is necessary to ensure publication of quality, unbiased results.
Corresponding Author: Philippe Ravaud, MD, PhD, Département d'Epidémiologie Biostatistique et Recherche Clinique, Hopital Bichat-Claude Bernard, Paris, France, Université Paris 7 (email@example.com).
Author Contributions: Dr Ravaud had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mathieu, Boutron, Ravaud.
Acquisition of data: Mathieu, Boutron, Ravaud.
Analysis and interpretation of data: Mathieu, Boutron, Moher, Altman, Ravaud.
Drafting of the manuscript: Mathieu, Boutron, Ravaud.
Critical revision of the manuscript for important intellectual content: Mathieu, Boutron, Moher, Altman, Ravaud.
Statistical analysis: Mathieu, Ravaud.
Obtained funding: Ravaud.
Administrative, technical, or material support: Moher, Ravaud.
Study supervision: Ravaud.
Financial Disclosures: None reported.
Funding/Support: French Society of Rheumatology supported Dr Mathieu during his clinical research board.
Role of the Sponsor: The French Society of Rheumatology had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
This article was corrected online for error in data on 9/10/2009, prior to publication of the correction in print.


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Warning: There are minor spoilers ahead.
If you see "The Amazing Spider-Man 2," there's a scene midway through the movie that shows Peter Parker (Andrew Garfield) exploring an abandoned subway station in New York City that supposedly ran along the D line.
Parker heads to the Roosevelt station to find out the truth about his deceased parents and stumbles upon a secret subway car that served as his father's secret lab.
If you're not familiar with New York City — and even if you are — you're probably wondering whether the Roosevelt station is real.
It is.
While there are plenty of abandoned subway stations in NYC, these are the two likeliest locations the film refers to.
1. The Roosevelt Ave. Station
In Queens, there's a Roosevelt Ave. station that was built for the Independent subway system. It consists of a trackless tunnel that was never finished after the Great Depression and World War II. Instead, it's used for storage.
From Columbia.edu:
The Queens Boulevard subway was part of the Independent Subway planned by the Board of Transportation in 1924. It opened in August 1933 as far as Roosevelt Ave, December 1936 to Union Turnpike, and April 1937 to 169 St in Jamaica. The subway has several provisions for extension to additional Independent Subway routes announced in 1929 and known as the Second System.
At Roosevelt Ave, an upper level terminal station was built for a Second System route and never used. The upper level station is on the same level as the mezzanine of the open station and is sited just east of it. The terminal had a center island platform with a trackway on each side.
NYCsubway.org has some photos you can view of the abandoned station. You can check them out here.
2. President Franklin D. Roosevelt's secret station
Underneath the Waldorf Astoria Hotel in New York City, there's a hidden station called Track 61.
It was built as a private railway that traveled to and from nearby Grand Central Station.
President FDR reportedly used the track for transport to hide the fact he had Polio while campaigning for his fourth term. The track is supposedly still in use as an escape train for presidents visiting NYC and was most recently used by President Bush.
At one point in "The Amazing Spider-Man 2," Parker considers FDR has something to do with the hidden station, basically just because of the name Roosevelt.
Take a look at it:
The BBC did a special on Track 61 where they headed to Grand Central station to check out the hidden platform.
They traveled down a secret historic passage that Grand Central won't admit exists.
Here's what the space looks like once you get to the bottom:
According to Grand Central Station's Dan Brooker, the platform had one customer, President Roosevelt.
Brooker says his private train held a special train car that held his limo.
The President and his limo would head into this elevator and be lifted right into the Waldorf-Astoria.
The armored train car still sits in the station.
Gothamist has some more great photos of Track 61.

subset: commoncrawl


text: Photo Information Sgt. Maj. Matthew J. Grither, command sergeant major for Combat Logistics Battalion 31, 31st Marine Expeditionary Unit and a native of St. Louis, MI, swings with a child of the Nagomi Nursing Home for Children here, Dec. 22. Marines and Sailors of CLB-31 visited the home to play with the children and hand out toys donated from the Toys for Tots program. The 31st MEU is the only continuously forward-deployed MEU and is the Marine Corps' force in readiness in the Asia-Pacific region. Photo by Cpl. Jonathan G. Wright Download Details Share CLB-31 gives the present of joy to children without families 26 Dec 2012 | Cpl. Jonathan G. Wright PRINT SHARE HENOKO, Okinawa, Japan -- "It never gets old," said Petty Officer 3rd Class Matthew R. Minteer, corpsman with Combat Logistics Battalion 31, 31st Marine Expeditionary Unit. "I could visit 100 places like this and get the same satisfaction as I do today." Marines and Sailors from CLB-31, 31st MEU spent the first day of their Christmas liberty period visiting residents of the Nagomi Nursing Home for Children here, Dec. 22. Acting as a home and school for children under the age of 18, the nursing facility has approximately 30 children in its care. Children have fallen under the facility's care for a wide number of reasons, ranging from insufficient parental support to abandonment. Tucked away near the Okinawa Institute of Science and Technology, the 14-year-old home offers on-site elementary to high school-grade teachers, helping the children live as normal lives as they can. "Once they are 18, they are required to go out and make a life of their own, so we help them as much as we can before then," said Dai Shimabukuro, head care giver of the Nagomi Nursing Home for Children. "We educate them and help them look for job opportunities and places to live, but they rarely have outside visitors to play and socialize with. That's where the CLB-31 personnel come in. After building a good relationship with the home, Navy LT Kyu Lee, command chaplain for CLB-31, was given the opportunity to bring service members and spend a day with the children. Many Marines and Sailors jumped at the opportunity. "Those that choose to do nothing but drink and party make up a small part of the overall American presence on Okinawa," said Lee, a native of San Diego, Calif. "Part of who they are is helping others no matter the sacrifice, and one day of their free time is negligible when they're visiting local Okinawan children." Aside from playing with the children, the Toys for Tots charity donated 40 toys to the home. Additionally, the volunteers and kids shared a barbeque lunch, enjoying hamburgers, hot dogs, drinks and cupcakes. The 31st MEU often conducts community relations projects similar to this event while deployed throughout the Asia-Pacific region, visiting orphanages, painting schools and cleaning up trash. "You can never do enough of these, because it always helps someone and positively impacts them for life," said Minteer, a native of Tampa, Fla. "The smiles on their faces when we come to play is better than any present we can give, and it's always a great feeling to do it." The 31st MEU is the only continuously forward-deployed MEU and is the Marine Corps' force in readiness in the Asia-Pacific region.


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University of Michigan
Runs his own tutoring company
Carl taught upper-level math in several schools and currently runs his own tutoring company. He bets that no one can beat his love for intensive outdoor activities!
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University of Michigan
Runs his own tutoring company
Carl taught upper-level math in several schools and currently runs his own tutoring company. He bets that no one can beat his love for intensive outdoor activities!
We're now going to look at a coin problem, dealing with amount of money and various coins. I have $2.20 cents comprised of nickels, dimes and quarters. I have twice as many dimes as quarters, and the same number of nickels as dimes, how many of these do I have?
So, when dealing with any sort of word problems, I always end up making a diagram or chart or, some sort of way of piecing together all my information. So, we have in this case, three different denominations. We have nickels, dimes and quarters, and we know that in total, we have $2.20. So, we now have the denominations worked out, we also need to work. We can figure out the number of each coin we have.
So we know that we have twice as many dimes as quarters and common mistake in this stuff is trying to figure out which you actually have more, which variable is x, which variable is twice x, 2x. So we know that we have twice as many dimes as quarters so that tells us we have more dimes, so that means we have to take our amount of quarters multiply it by 2 to find the number of dimes.
So quarters I know I have x of those, we have twice as many dimes so this is then going to be 2x. You can always check your work if I have three quarters, I would then have 6 times, twice as many dimes as quarters.
The problem also tells us that we have the same numbers of nickels as dimes. So if we have 2x dimes, we also then have 2x nickels. For now dealing with coin problems, you need to make sure you distinguish between the number of coins and the actual amount that these coins is worth.
So in this case say x is 1, that's telling me I have one quarter, but I also know that means I have 25 cents. If I have one quarter that means I would have two dimes that are worth 20 cents, so that distinguishing factor between the two coins versus 20 cents.
If you figure out how much you have, you just multiply the number you have by the denomination, so if I have x quarters, I just have .$25x, 4 quarters would give me $1, .25 times 4. The same idea for dimes except this time I know I have 2x dimes, so you take the amount of dimes times how much it's worth, add that to the number of quarters. The same idea for nickels, the number of nickels times the amount they're worth.
Now we have a equation to make sure we're adding these all up and that is going to be equal to our total amount, the amount of quarters plus the amount in dimes, plus the amount in nickels. Distribute this through 2 times .05 is just .1x, 2 times .1, .2x plus .25x is equal to 220. Combine like terms so .1 plus .2 is .3, plus .25 is .55x is equal to 220, divide by .55 end up with x is equal to 4. Again making sure we always answer what the question is asking for.
So here we found x is 4, x we said is the number of quarters, the question is actually asking for the number of each denomination, so we know that we have 4 quarters and we know we have twice as many dimes, so that means we have 8 dimes and the same number of dimes as nickels which would mean we have 8 nickels as well.
So taking our word problem, making this sort of diagram, these sort of thought, turning into an equation which we then solved.


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Samsung Galaxy Tab 3 could be double trouble as 8- and 10.1-inch variants leak
Everyone loves two at a time, right?
The sound of Samsung Galaxy Tab 3 speculation is reaching a cacophonous state and the latest leak claims to have the specs for two tablets destined for the new range.
Details turned up on Greek site Techblog which reckons it has exclusive information of the next slates to come out of the Korean firm, reporting that 8-inch and 10.1-inch models are on the way.
According to the leaked specs, the Samsung Galaxy Tab 3 8 will sport an 8-inch 1280 x 800 display, 1.5GHz dual-core processor, 2GB of RAM, 3MP rear camera, 1.3MP front camera, 4500mAh battery and run Android Jelly Bean.
It will apparently measure a svelte 209.6 x 112.1 x 6.95 mm - smaller than the 7.9-inch iPad mini - and weigh in at a tidy 330g, slightly heavier than its Apple counterpart.
Big brother
Over in the 10.1-inch Samsung Galaxy Tab 3 court, the larger tablet is said to pack a screen with the same resolution plus the same processor, cameras and operating system as its 8-inch brother.
RAM will apparently be dropped to 1GB, while battery is boosted to 7000mAh in the 10.1-inch version.
In terms of dimensions this edition is set to be smaller and lighter than the 9.7-inch iPad 4 - which we find hard to believe - with the leaked specs endowing the 10.1-inch Samsung with a 256.7 x 175.3 x 8.7 mm and 533g body.
Check out Samsung's
to discover loads more about the infinite possibilities of the GALAXY Note II
If the leak is correct you'll be able to pick both tablets up in 3G and 4G variants, with the 3G models going on sale in May, while the superfast LTE versions will arrive in June/July.
Via SamMobile
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John joined TechRadar over a decade ago as Staff Writer for Phones, and over the years has built up a vast knowledge of the tech industry. He's interviewed CEOs from some of the world's biggest tech firms, visited their HQs and has appeared on live TV and radio, including Sky News, BBC News, BBC World News, Al Jazeera, LBC and BBC Radio 4. Originally specializing in phones, tablets and wearables, John is now TechRadar's resident automotive expert, reviewing the latest and greatest EVs and PHEVs on the market. John also looks after the day-to-day running of the site.
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By Darren Allan


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Game Launcher Creator V2 arrives and is better than ever before! This revolutionary desktop software allows you to design and develop your own custom game launchers with no programming at all. Using it's intuitive WYSIWYG (Drag 'n Drop) interface, you can literally design professional looking, custom game launchers in minutes!
Featuring lots of customizable objects such as buttons, images, cloud images, videos, GIFs and much more! Also featuring a built-in game update system and a professional and advanced online patching system for your games!
Feature List - Screenshots - Download


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I like this upstate New York cottage from interior designer Shawn Henderson. Comfy, cozy, understated, fitting for the setting. Love the living room with the exposed beamed ceiling and the wood furniture with the ticking stripe cushions. And then there is the copper tub in the master bath…love that.
I would call this cottage well edited. Definitely gives off the vibe of being a outside of the city country home with out screaming "I am a country cottage". i would like to spend a weekend getaway here!
What do you think of this cottage home? Like or dislike? My favorite room is the living room. Which do you like best.
Happy Thursday!
P.S. Tomorrow, I am going to bring you a tour of a new cute little vintage shop I discovered this past weekend here in Los Angeles.
P.P.S. Am about to go sign a lease on some very very small office space for COCOCOZY today. Just need a new place for my operations assistant and possible intern to work out of during business hours. The office is small small small, it is in a shabby older building but in a good location (right in the heart of Beverly Hills). The owner says he'll put in new hardwood floors for me. There is also room for expansion in the building if I need more space. It is only about 400 square feet of space and has a strange partition with louvered windows in it too. It is in a great location – near my day job office – so I could easily pop by during lunch if I had to. We're currently working in a space that will not do and I have to move COCOCOZY business offices as soon as possible. This tiny tiny office is very expensive for the size because of where it is located. Does the rule about location, location, location apply to office space too? What would you do? Tiny offices in a shabby building in Beverly Hills or slightly bigger offices in who knows what kind of building elsewhere? Should I wait or sign? We are not doing a showroom yet…hopefully that will come in 2013…this is just a place for my peeps to work out of during the day. Argggghhhhhhh. My appointment is at 3pm with the lease office. Help. Here are some pictures.
|A view of part of the small office space in Beverly Hills. (above and below)
P.P.P.P.S. Wish I had pictures of other options. I went to look at a space in the Pacific Design Center (PDC). The space at the PDC had low ceilings and no windows and it totally made me feel claustrophobic. It was larger than this tiny space for sure but had no windows…yikes. The pros of this tiny space in Beverly Hills are that it is centrally located, there are windows that look right onto Beverly Drive (a block from Rodeo), it has windows that open and it has light. It is small small small small for the money though. Oh dear. I have a huge decision making problem. Help.
P.P.P.P.P.S. Would look forward though to decorating this small space though. Have ideas for a cute work space already.
P.P.P.P.P.P.S. On another note, SM is so fabulous…she is working on some great things for COCOCOZY that I'll be able to squawk about later this year. Very excited. Will also tell you who SM is at a later date as well!
P.P.P.P.P.P.P.S. Have a great day! xo


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Traffic People
Traffic People was born in the heart of London on the Portobello Road and Camden in 2002, looking to bring a contemporary twist for the woman who desires a timeless design with the right amount of naughtiness to reflect her unique inner style. Traffic People was devised out of a love for vintage inspired fashion and beautifully dressed women of eras past; Lauren Bacall, Anita Pallenburg, Ava Gardiner and Bianca Jagger to name a few. The Traffic People design ethos is to encompass the latest fashion trends in a contemporary style with a vintage, edgy feel with the use of beautiful and unique print and details. Originally influenced by the styles that pervaded the 20s and 30s, Traffic People have supplemented these styles bringing in timeless designs as the 50s wiggle dress and giving a nod to the fun stylings of the 70s disco glamour era."
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Creating one interesting character is hard enough — but when it comes to writing a whole novel or series of books, you have to create dozens of them. How can you keep your supporting cast from seeming like cookie-cutter people? There's no easy answer, but a few tricks might help you create minor characters who don't feel too minor.
Here are 10 secrets for creating a supporting cast that sticks in your readers' minds.
Top image: Ejay Mercado II. All other images by Stanley Von Medvey.
It's the curse of science fiction and fantasy — these genres need worldbuilding. And worldbuilding means lots of people. Your spaceship needs crewmembers, your magical kingdom needs knights and warrior nuns. A world that's populated by stick figures will feel like a barely sketched world.
And most really beloved books have one thing in common — minor characters, who get a fraction of the column inches of the protagonists, wind up becoming audience favorites. This isn't really an accident: A main character needs to be sympathetic and engaging, but a supporting character needs to do much more — the supporting cast hold your scenery up and either sell the fundamentals of your story, or fail to. If they fail, you fail.
This is something I've struggled with for years, and have been grappling with a lot lately. Out of all my obsessing over how to create a supporting cast with staying power, here are some guidelines I've come up with:
1) Give them at least one defining characteristic.
The master of "sprawling supporting cast," for my money, is Dickens. He probably created a few thousand people, out of thin air, over the course of his career, and many of them are so recognizable they've become words in the English language. One thing you'll notice about Dickens is, his minor characters often just have one really weird quirk that defines them — a weird way of talking, or a strange habit. Think the Aged Parent. People are like this in real life, too — lots of people have one or two habits that you notice the first time you meet them, that stand out in your mind even after you learn more about them.
2) Give them an origin story.
And by origin story, I don't mean "She was born in Somerset, to a family of glove-makers, and she grew up with the scent of glove dye and the endless fingers of unsold gloves, hanging from the ceiling over her crib." I mean, an origin story like a superhero has an origin story. Your main character doesn't necessarily need an origin story, because you've got the whole book to explain who he/she is and what he/she is about. But a supporting character? You get a paragraph or five, to explain the formative experience that made her become the person she is, and possibly how she got whatever skills or powers she possesses. This is more important that bullshit like what her favorite color is, or what she eats for breakfast. (I don't care what most people's favorite color is in real life, much less in fiction. Unless it's like infrapurple or something.)
3) Make sure they talk in a distinctive fashion.
This goes back to making sure all your characters don't talk alike. Possibly, if you followed the advice in item #1, you've already given your character a verbal quirk, like he always says "wellum" before every declarative sentence. Either way, you still have to make sure your characters don't all talk the same. Some of them talk in nothing but short sentences, others in nothing but long, rolling statements full of subordinate clauses and random digressions. Or you might have a character who always follows one long sentence with three short ones. Some of your characters talk mostly in Anglo-Saxon words, others mostly in Latin words. Some of them only talk in sentence fragments, or avoid nouns almost entirely. ("Gone to war. Won't be back." He looked at his feet. "Sorry to break the bad news.") It's a disaster if your main character talks the same as all your other characters — but it's also pretty terrible if all the supporting cast speak the same way. One dirty shortcut is to hear the voice of a particular actor or famous person in your head, as one character talks. (In my current novel in progress, I have one person who speaks with the voice of Ricardo Montalban. In my head. I'm hoping this isn't going to look too pathetically obvious in the finished product.)
4) Avoid making them paragons of virtue, or authorial stand-ins.
People who have no flaws are automatically boring, and thus forgettable. And there's nothing worse than a character who is obviously the voice of the author, or a way for the author to wander into the story and interact with the other characters. (This is another reason to make sure your characters all have a distinctive way of speaking — that makes it much less likely that one of them will seem like your mouthpiece.) You can solve both these problems by giving a supporting character a real, identifiable flaw, that threatens to make him unsympathetic but winds up making him more sympathetic in the end. Any character who has foibles, or bad habits, or destructive urges, will always stand out more than one who is pure and wonderful in all ways. And nobody will believe that you've chosen to identify yourself, as the author, with someone who's so messed up. (Because of course, you are a perfect human being, with no flaws of your own.)
5) Anchor them to a particular place
This sounds like a no-brainer — after all, the main reason you need this annoying supporting cast in the first place is, to help with the worldbuilding and stuff. But once you've got your world and you're populating it with random characters, it's all too easy to have them float around with no particular location to call their own. Like, they just hang out on the street, at the corner of Nondescript and Dull. And then the next time you see them, they're out in the forest, near that tree, with the leaves and the branches. (You know the one.) A huge part of making a supporting character "pop" is placing her somewhere. Give her a haunt — some place she hangs out a lot. A tavern, a bar, an engine room, a barracks, a dog track, wherever. It works both ways — by anchoring a character in a particular location, you make both the character and the location feel more real.
6) Introduce them twice — the first time in the background, the second in the foreground.
This is a trick I've been experimenting with. You mention a character in passing: "And Crazy Harriet was there too, chewing on her catweed like always." And you say more about them. And then later, the next time we see that character, you give more information or detail, like where she scores her catweed from. The reader will barely remember that you mentioned the character the first time — but it's in the back of the reader's mind, and there's a little "ping" of identification. It feels like you've seen someone at a party or in a group of friends, and then later you had a conversation with them. It creates a sense of familiarity, when you vaguely remember that you've heard about this character before, and now they're suddenly in focus. (Oh, and by the way, catweed is called that because it makes a "meow" noise when you chew on it.)
7) Focus on what they mean to your protagonists
Again, it sounds like a no-brainer — but this is easy to forget. You're so in love with your world, and with all of the characters and how they interact, that you can rathole. But your main characters are your readers' way into the world — and what matters to your protagonists matters to your readers. (If you've done your protagonist-crafting right, anyway.) We don't care what Blind Simeon thinks of Randolph the Grifter, nearly as much as what your viewpoint character thinks of both of them. (Of course, sometimes having one minor character talk about another can tell you something interesting about both of them.) What does this minor character mean to your hero? What role does he fulfill? What does your hero want or need from Randolph the Grifter? If you know what your hero finds memorable about Randolph, then you're a long ways towards finding what your readers will remember, too.
8) Give them an arc — or the illusion of one.
Arcs are hard. But faking an arc is easy. Writers on television do it all the time. Shakespeare did it all the time, too — read Henry IV, Part 2 and look for Hal's arc. You can create the appearance of an arc by establishing that a character feels a particular way — and then, a couple hundred pages later, you mention that now the character feels a different way. Admiral Hargroves hated children on page 100, but on page 400 he suddenly likes children. We don't get to see Admiral Hargroves' attitudes evolve, or even necessarily find out what changed his mind — we just know that over the course of the story, Admiral Hargroves has been having a whole mental process about children. That's all a fake arc needs: a starting point and an end point. A minor character who changes in some way is automatically more interesting than one who remains constant — even if we take it on trust that Admiral Hargroves wasn't just brainwashed by a cabal of evil children with a brainwashing ray. (Or maybe that's a plus — your readers can construct "evil children" conspiracy theories and mine your text for clues.)
9) The more minor the character, the more caricature-like they may have to be.
This one is debatable — you may be a deft enough author that you can create a hundred characters, all of whom are fully fleshed out, well-rounded human beings with full inner lives. But again, think of Dickens — many of his supporting cast are, frankly, cartoons. Henry Fielding also comes to mind, and so does Douglas Adams. To some extent, this is a stylistic choice, too — some writing styles simply can't support or abide cartoony minor characters. But for your third ensign, who appears for a grand total of two pages, on page 147 and page 398, you may have to go for cartoony if you want him to live in the reader's mind as anything other than a piece of scenery. The other alternative is...
10) Decide which supporting characters you'll allow to be forgettable after all.
And this is probably inevitable. You only have so much energy, and your readers only have so much mental space. Plus, if 100 supporting characters are all vivid and colorful and people your readers want to go bowling with, then your story runs the risk of seeming overwritten and garish. Sometimes you need to resign yourself to the notion that some characters are going to be extras, or that they're literally going to fulfill a plot function without having any personality to speak of. It's a major sacrifice they're making, subsuming their personality for the sake of the major players' glory. And maybe, if your book hits a home run, you can reward them for their selflessness by giving them a beefed-up role in the sequel. Or at least, that's what you can tell them while you exploit their thankless dedication. You selfish bastard.


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Few things in this world are more personal than your DNA. For this reason, databases like the Human Genome Project have always respected the privacy of their participants. By separating individuals' identities from their donated DNA samples, researchers have upheld a standard of "genomic anonymity." Those days are now officially over.
In today's issue of Science, researchers at MIT demonstrate that the identities of volunteers who donate personal genome sequence data can be revealed using only publicly available information. In an interview with io9, lead researcher Yaniv Erlich discusses how the team's search method works, the implications of the method's discovery, and why this could change the way we deal with genetic data.
A Brave New World
"We are living in a brave new world," Erlich tells io9, "a world where more information than ever is readily available online." What happens to this information depends on who's making use of it. In the hands of a scientist, it can be used to study, treat and cure diseases. In the hands of Facebook, it can be used to create powerful new search engines. In the hands of a criminal, it can be used to commit identity theft.
Few people understand the ethically complex nature of information-accessibility better than Erlich. Today, he's a fellow at MIT's Whitehead institute, where he runs a laboratory that creates new tools and algorithms for studying human genomes. But Erlich's background is in computer security. Before he worked at MIT, banks would hire him to find weak points in their electronic infrastructure. In a study recounted in today's issue of Science, Erlich brought his experience in vulnerability to bear on the world of genomics, and with it an end to the current paradigms for managing genetic information.
"Basically, we show that you can take whole genome sequencing data that is posted online and cross-reference it with public genealogy data to infer the identity of [an ostensibly anonymous] donor." And you can do it with Google searches.
The Methodology
The genomic outing process works in stages. Erlich's team began with a batch of "anonymous" whole genome sequences. If the genome belonged to a male, they sought out specific markers on the Y chromosomes known as short tandem repeats, or "STRs."
Unlike other genetic information, sequences on the Y chromosome are passed exclusively from father to son. Similar patterns of STRs are therefore preserved across several generations, and are a great way to trace a paternal line. Needless to say, Y chromosomes — and STRs — are a big deal not only to geneticists, but also to more casual genealogy enthusiasts looking to trace the ramifying arms of their family trees (known formally as "pedigrees"). Consequently, there is no shortage of publicly accessible databases online that link Y-chromosome markers to surname information. Cross reference your STRs with a few of these databases, says Erlich, and suddenly you've got yourself a surname that matches your genome; and with each surname comes a ton of other information about the patrilineal line, including geographical locations and detailed pedigrees.
But a surname can identify tens of thousands of people, which meant Erlich's team's genomes were still, for all intents and purposes, anonymous. So Erlich and his team went deeper by searching public record databases for metadata like age and state of residence (neither is protected under the Hippa Privacy Act). "The combination of surname, age and state is a very strong identifier," Erlich tells io9. "It's rare that you find more than a dozen with the same combination, and all three are very searchable online."
It wasn't long before Erlich's team had found an obituary that perfectly matched the pedigree of one of their surname candidates. He recounts the experience:
Now, we're not giving the exact details, the numbers aren't exact to protect these peoples' identities, but let's say we have nine offspring in this pedigree. We looked at the obituary, we had nine offspring. We looked at the number of males and females and they were the same. We looked at the order of birth, and we got the same order, males and females.
Erlich's team had successfully identified an "anonymous" DNA donor, along with several members of his family. The researchers repeated this process twice over, triangulating in on two more perfectly matched pedigrees. "In the two cases of a dual surname recovery from both grandfathers," write the researchers, "the surname of the father and the maiden name of the mother matched exactly to the grandfathers' surnames, substantially increasing the confidence of the recovery."
"What are the odds that we got all these families, and all their demographic characteristics right by chance?" Erlich asks me. "Less than one in a million."
When all was said and done, the researchers had only directly inferred the identity of five men; thanks to the pedigrees, however, they had managed to breach the privacy of close to 50 individuals, male and female alike.
The Future
Ultimately, the aims of Erlich's study are three-fold.
The first is to illustrate, in no uncertain terms, that the end of genomic (and other "omic"-type data, including proteomics, transcriptomics, microbiomics, etc.) anonymity is at hand. "We're not the first study to talk about issues of genetic privacy," Erlich tells io9, "but we're the first to demonstrate its vulnerability with publicly available data."
The second is to highlight that protecting human privacy is very complicated, and emphasize that things only stand to get more unwieldy from here on out.
It's worth pointing out, for example, that the methodology employed by Erlich and his team is really only relevant, at this time, to participants in the Center for Study of Human Polymorphisms (CEPH) family collection, whose genomes were sequenced as part of the 1000 Genomes Project. As the National Institutes of Health point out in a piece titled "The Complexities of Genomic Identifiability" (the perspective piece is published along with Erlich's findings in today's issue of Science): "the richness of publicly available research data and geneologic information derived from [CEPH participants] and their relatives" is unprecedented — but it won't be for long.
Advances in genomics are rapidly converging in a way that stands to make genomic anonymity an increasingly unrealistic standard. Genomes can now be sequenced more cheaply and rapidly than ever. Genomic applications — from family planning, to preventive medicine, to genetic engineering — are expanding at an ever-accelerating clip. Meanwhile, other forms of metadata are becoming increasingly available. "Just look at online obituaries," notes Erlich. "You don't see much of those as recently as ten years ago, but today they're very common. And they're text, and text is searchable. It's easy."
And moving forward, the genomic outing process will only become easier and easier.
Which brings us to the third (and, according to Erlich, most important) goal of the study: to bring issues of genomic privacy to the attention of the public.
"The main issue right now is not that tomorrow everyone is going to use this strategy to identify genomes and use that to do bad things," says Erlich. "I don't think that's really possible at this point."
"The main issue," he says, "is to recognize this problem early on, so that we can respond to it in an appropriate way in the long term by improving legislation and policy surrounding the handling of genomic information."
It's worth pointing out that Erlich and his colleagues are not at all opposed to public data sharing. "We actually favor it," he tells io9, though he emphasizes that it's not a decision that scientists should make on their own. "There needs to be discussion with the general public about how we should move forward."
What kind of issues are on the table? How about advertisements based on your DNA? (Remember Minority Report?) "Nobody does it yet, that I know of," says Erlich, "but it's completely legal as far as I know." He continues:
Imagine receiving an email that says "you have very desirable traits, would you like to be a sperm donor?" or "You are a rare blood type, please consider donating blood." Do we want to restrict that kind of communication with people?
What about companies that purchase other companies' databases? Let's say I participated in some genetic testing with one company and then another company purchases it. What are my rights?
These aren't all pie-in-the-sky questions, by the way. Some of these scenarios are unfolding right now. Just last month, biotechnology group Amgen Inc purchased Decode Genetics, and with it a DNA database containing tens of thousands of genomes. "What are the rights of these people?" Erlich asks.
Answers to questions like these will be decided in the near future, and they will be arrived at by adhering not to an unachievable goal of anonymity, but a new gold standard for biomedical investigation — one that justly weighs the benefits of research against the risks and sacrifices implicit in publicizing very private information. Whether such a standard can be achieved remains to be seen.
Erlich's team's findings are published in today's issue of Science, along with an accompanying perspective piece from the NIH.


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Mercedes-Benz CL550 Parts
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About Mercedes Benz CL550
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Rule #1 - Be Patient - Rule #2 - Don't ask when, if you don't contribute - Rule #3 - You have coding skills - LinuxMCE's small brother is available: http://www.agocontrol.com
So I ran Diskless_CreateTBZ.sh and rebuilt the MD. Same issue. Probably not relevant, but now the PCM volume level doesn't appear in alsamixer - only the master.


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The importance of the Caribbean Community (CARICOM) countries acting jointly to address their development needs has become acute.With high levels of debt to GDP ratios, widening budget deficits, deteriorating terms of trade, dwindling aid flows, and shocks to their economies by a decline in tourism earnings and a grave contraction of the financial services sector, the majority of CARICOM countries are reeling. Guyana and Suriname are the notable exceptions, having recorded steady economic growth in recent years, largely due to export earnings from their mineral resources, especially gold.{{more}}
In my last commentary, I drew attention to the real possibility that the European Union (EU) â one of the biggest aid donors to the Caribbean region â could reduce their level of aid to all Caribbean states, except Haiti, because they are Middle Income Countries. While the European Commission has stressed that no firm decision has been made on aid reduction to African, Caribbean and Pacific (ACP) states, under the EUâs Multiannual Financial Framework for the period 2014-2020, a âdifferentiated approachâ to aid is being adopted. Already, under this approach, the EU has eliminated traditional aid to 17 countries that are Upper Middle Income countries, and 2 large Middle Income countries.
The EU has made it clear that its differentiated approach ârepresents a budget for investment and growth to ease the pressure on (EU) Member Statesâ finances, focussing on Europe 2020 priorities, impacts and resultsâ. And while the European Development Fund (EDF), under which aid is made available to the ACP states, is being kept separate from the EU Budget, it seems inevitable that the EU â now consisting of many countries that never had colonies in ACP countries â will insist on applying the âdifferentiated approachâ to giving aid to them. In the Caribbean, this means that in calculating allocations for the 11th EDF (2014-2020), Haiti will continue to be a beneficiary and all others could see aid reduced, except âon the basis of country needs, capacities, commitments, performance and potential EU impactâ.
In other words, âneedsâ alone will not be a sufficient basis for aid to Middle Income Countries; their âcommitmentâ and âperformanceâ will also be key determinants.
That is why my last commentary stressed two points: first, the issue âshould command the urgent attention of all Caribbean governments, the CARICOM Secretariat and the Caribbean Development Bankâ, and second, âif ACP Middle-Income countries are to justify why aid should not be reduced now, they must be prepared to show how it will be used effectively to transition to diversifying their economies, enhancing their productive sector, and standing on their own feet. A begging bowl is not enoughâ.
There have been many responses to that commentary, but one of them from a Trade Specialist, David Lewis of Manchester Trade, based in Washington, was particularly forthright. Lewisâ lifeâs work has been Caribbean-oriented. But, he harbours grave doubts that Caribbean governments, the CARICOM Secretariat and the Caribbean Development Bank, are prepared to act in a meaningful way. He said that they âare so out of touch with reality in politics and economics in the Caribbean and more so elsewhere that they will be playing âcatch-upâ to no avail on this oneâ. He was also dubious about Caribbean organisations actually âshowing how the region will transition to diversifying their economies, enhancing their productive sector, and standing on their own feetâ.
Lewis is not alone in his misgivings. EU Representatives in the Caribbean have bemoaned the fact that governments have not actively pursued funding for regional projects that would benefit their countries individually, as well as the region collectively. They have also expressed deep concern about the private sector in almost all CARICOM countries failing to produce projects that could attract EU funding and gain access to EU markets. Other regional commentators have also lamented the reality that, in a beggar-thy-neighbour and non-productive approach, many CARICOM governments have sought solutions to their economic problems in national efforts only, shunning the real benefits that could derive from regional action as well.
National efforts for alleviating the budgetary strains on Governments and for a few infrastructural projects have focused recently on getting help from China and Venezuela. But, regardless of how generous and unquestioning these two governments may be now, their contributions, while welcome, are stop-gaps; they are not addressing fundamental weaknesses that persist.
The EUâs frustration with Caribbean governments and their institutions is not exceptional; other countries and agencies have also expressed their disappointment and dissatisfaction. Among these agencies is the Canadian International Development Agency, which has identified the Caribbean as a priority for its aid.
It is significant that it is since May that the European Commission first advised Caribbean representatives in Brussels of the decision to use a âdifferentiated approachâ to aid. While ACP representatives have been engaged in lobbying and presenting the counter arguments in Brussels, there is urgent need for high-level representation to EU governments, particularly the newer ones that have little knowledge of the Caribbean beyond statistical information.
If, with the help of the Commonwealth Secretariat and the World Bank, CARICOM countries and the Dominican Republic could secure an International Conference on the Caribbean to address their fundamental difficulties of debt; a change in the criteria for concessional financing; differential treatment for trade, based on their small size and limited capacity; deepening regional integration to allow for the creation of pan-Caribbean undertakings that are competitive; and, crucially, building machinery for transportation and storage of agricultural products within the region, many of their problems could be addressed through a co-ordinated approach by donor countries and agencies.
But first, the Caribbean would have to assemble a single dynamic team to prepare a convincing plan with measurable outcomes, performance criteria, and a viable implementation mechanism. Otherwise they wonât be believed.
It is a dark time for the region; emerging into the light requires regional ingenuity, regional commitment and regional action.
(The writer is a Consultant and former Caribbean diplomat)
Responses and previous commentaries at: www.sirronaldsanders.com


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Walking down the red carpet, Tina Fey and Amy Poehler's SNL cast mate Andy Samberg gave Carson Daly a prediction: "They're going to crush it." True to form, the laff-tastic ladies delivered. Here are the high points:
The Dresses. Chic, sleek, glittery. Very hot.
Tam Honks. Intentional flub of Tom Hanks. The man who they claim is wearing prosthetic genitals.
Matt Damon's Relative Fame. "Don't take this the wrong way, but tonight you're basically a garbage person."
Explosion at the Wig Factory. The original name of American Hustle.
Amy Poehler Looks Hottt. Because they cut to a shot of Jennifer Lawrence with Poehler's name underneath.
Julia Louis-Dreyfus Goes Garbo. Now that she's in a nominated movie, Enough Said, she's too cool for TV people. She's vaping and wearing dark glasses.
The Moral Lesson of Gravity. "George Clooney would rather float into space and die than spend one more minute with a woman his own age."
The Excess of Wolf of Wall Street. Poehler: "If I want to see Jonah Hill masturbate at a pool party, I'd go to one of Jonah Hill's pool parties."
Timeliness. "We are going to get this done in three hours. Or as Martin Scorsese calls it: Act One."


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Digital Innovation in the Era of Artificial Intelligence (DIAI-23)
Venue: Amsterdam, Netherlands
Date: September 09-10, 2023
Conference Details
EARC welcomes you to the International Conference on "Digital Innovation in the Era of Artificial Intelligence (DIAI-23)." This gathering of brilliant minds and visionary leaders aims to explore the dynamic landscape where digital innovation and artificial intelligence intersect. Throughout this conference, we will delve into the transformative power of AI, driving digital transformation and reshaping industries. Ethical considerations and governance in the era of AI-driven innovation will also be discussed, emphasizing a responsible and human-centered approach. Join us as we navigate the data-driven future, leverage AI for global growth, and explore the intelligent enterprises that are shaping our connected world..
Evaluation procedure:
All submitted abstracts will be peer-reviewed by the International Scientific Review Board consisting of over experts from different countries.
Each abstract will be reviewed by 3 to 4 reviewers and scored on the basis of the criteria.
Authors will be notified of the acceptance of their abstract(s) within 07 working days after submission. Amendments to the abstract are possible 10 days before the conference date.
All papers presented at the conference will be published with unique Swedish ISBN number.
Please remember that registration is completed when the conference fee is paid.
The conference fee covers Access to All Day 01 Sessions, Coffee break & Lunch during the conference, and Conference Material. Authors/Attendees will receive the Proceedings and the Certificate of participation.
All other expenses of the Authors/Attendees are not covered within the conference fee. Conference organizers and sponsors are not liable for any other unforeseen circumstances and will not mediate in any Visa/travel/accommodation process due to varying bureaucratic policies of EU states.
Important Note
– Bank wire transaction charges are not covered by conference organizers.
– Must send your payment RECEIPT to the conference E. mail (firstname.lastname@example.com).
– The Student Authors/Attendee need to provide proof of student status.
– Conference fee is non-refundable.
– Please advise for your meal category (Vegetarian/Non-Vegetarian) when sending registration confirmation.
Registration Fee
|Early Bird
|Normal Fee
|Faculty / Practitioners
|Students/Additional Author
|Additional Paper(s)
Note: For more details about registration click here.
Conference Day
09:00-09:30 – Registration
09:30-10:00 – Opening Ceremony
10:00-10:30 – Networking & Refreshments Break
10:30-12:30 – Presentation Session 001
12:30-01:30 – Lunch Break
01:30-03:30 – Presentation Session 002
03:30-03:45 – Coffee Break
03:45-04:45 – Session 3
04:45-05:00 – Closing Ceremony
Day 02
Conference second day is reserved for participants own tourism activities (expenses will be borne by him/herself). Let discover the beautiful history and sightseeing of Europe!
Final Paper Submission
- The full article must be submitted as a MS Word file in DOC or DOCX format (PDF format is not accepted).
- Before submitting your paper, please ensure that the English used is clear, concise and coherent. This is especially important if English is not your first language.
- Regarding paper formatting, please follow APA-6 guidelines. Full Paper must not exceed Single Space 05 Pages. Font: Times New Roman, 12 size.
Abstract Submission
- All abstracts/papers should be submitted electronically through the online submission system.
- Abstract should not exceed 300 words and it must clearly indicate the problem, objectives, research methods, results and conclusions.
- All abstracts must be submitted and, if accepted, presented in English.
- The paper author is responsible for ensuring that all co-authors have agreed to be listed on the paper.
- The language of the conference is English. Simultaneous translation will not be provided.
- For oral presentation please bring power point presentation slides. Your presentation is supposed to be 15 minutes followed by a 5-minute question-answer session lead by the track/session chair. You will be provided a laptop connected to the internet and a projector in the conference room. You are allowed to use your own computer.
- Video recordings (.avi, .mp4, and .flv) of virtual presentations will be played at the related session, and presenters will be connected via Skype. Thus, the audiences will be able to ask their questions to the presenter of the virtual presentation.
- For poster presentation, Poster size will be 60cm*84cm. Please make sure to bring your posters in the conference. You will be shown the assigned place for your poster when you register at the registration desk.
- Venue: Mercure Hotel Amsterdam City.
- Address: Joan Muyskenweg 101096 CJ Amsterdam, Netherlands
Our Divisions
The EARC Conference's program is divided into 5 broad divisions. These conference divisions focus on the intersection of digital innovation and artificial intelligence, exploring the opportunities, challenges, and impact of AI-driven advancements across various sectors and domains. A detailed overview of questions each division will address can be found below.


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Friday's Transfer Rumor Roundup: Soldado to Spurs, Agger to Barcelona
With Alvaro Negredo and Stevan Jovetic signed on for a whopping $65 million, Manchester City aren't about to stop their summer spending spree. Now Benfica's Argentine winger Eduardo Salvio is next on their list. The right midfielder would cost a cool $37.5 million and City are tight-lipped on his acquisition. But Benfica are already lining up a replacement for the attacker, who played in 51 games last season and scored 10 goals and added an impressive 13 assists. If City want production from their wide men, Salvio would be a superb buy. Young, energetic and eager to attack from wide areas, he would fit in perfectly with Manuel Pellegrini's new attacking mantra at Man City. The revamp continues.
All has been quite down at White Hart Lane for a few weeks, but Spurs manager Andre Villas-Boas could be set to swoop for Valencia forward Roberto Soldado. The Spanish international striker has been chased by Tottenham for some time, and it's believed that AVB has upped his bid to $30 million for the 28-year-old forward after Soldado impressed at the Confederations Cup. He's captained cash-strapped Valencia for the past few seasons, scoring 81 goals in 141 games. Prolific, hungry and a leader. Exactly what Spurs need. But will Soldado leave his hometown club for London?
Liverpool goalkeeper Pepe Reina could be coming to the end of his Anfield career, with former manager Rafael Benitez hoping to take him to Napoli. Reina, 30, has spent eight seasons with Liverpool but after Brendan Rodgers signed Belgian international Simon Mignolet over the summer, Reina's time as first-choice 'keeper for the Reds looks to be over. A great shot-stopper and good with his feet, Reina would do well in Serie A. But some high-profile mistakes have slipped into his game over the last two years, raising question marks over the Spanish international's future. Reina wouldn't want to sit on the bench at Liverpool. Adios, Anfield.
And the Liverpool exodus looks set to continue, as Danish central defender Daniel Agger could be on his way to Barcelona. The aggressive 28-year-old is hugely admired by Barca boss Tito Vilanova and after the Spanish side won't get Thiago Silva, they've turned to a $18 million move for Agger. Superb in the air and good on the ball, Agger overcame a shaky start at the beginning of his Reds career to become a regular. Liverpool are short of defenders after Jamie Carragher's retirement so they won't to lose Agger. But if Barca come calling, what can you do?
Several Premier League teams are lining up bids for FC Porto's Christian Atsu. The 21-year-old Ghanian has left Porto's preseason tour of Holland and Everton and Spurs are both monitoring the situation. Liverpool are also said to be interested, as Atsu looks to leave the Estadio do Dragao. He only has one year left on his deal and could be snapped up for less than $10 million, as Porto want to cash in rather than lose him for nothing. The skillful winger could fit in at any of the aforementioned clubs, but Everton could perhaps be the best fit as they lack pace going forward from wide areas. Atsu could be a bargain and Roberto Martinez is the master at finding those.


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CHICAGO – Nurses in a maternity ward were knocked off their feet when they heard an unborn baby rapping – in his mother's womb!
"I would never have believed it if I hadn't heard it with my own ears," added Agnes Couperin, a nurses' aide in a private hospital northwest of Chicago.
"I had just prepared the patient for an acoustic procedure that enables mothers-to-be to hear the heartbeat and the other little gurgles their unborn babies make in the womb.
"As soon as I turned on the amplifier, the sound of a rapper reverberated in the examining room. At first, I thought someone had turned on a radio. But the amplifier clearly showed that the rapping had to be coming from the patient's tummy.
"I don't know much about hip-hop or rap, but the little boy could throw down as good as Eminem or Lil' Wayne, that's a fact. One of the other nurses who was there said he thought the boy was rapping "Not Afraid" – Eminem's latest hit.
"All I know is it was clear as a bell and the rhymes were the best I've ever heard. The language was a little R-rated, but it was the best raps I've ever heard."
The only ones not surprised at the incredible crooning fetus are the parents, who are identified only as Donovan and Jamila They said their unborn pride dan joy began rapping in the womb six months after she was conceived.
"it's a miracle… a gift from God which we accept with humility and gratitude," said Donovan a professional musician whose father sang with The Temptations.
"Jamila and I are hip-hop fans. We play Beyonce and Jay-Z night and day at full volume. It's no wonder our unborn baby has already acquired our love for opera.
"We both cried with utter joy and happiness when, lying in bed one night, we first heard that small voice rapping, Forget About Dre.
"In the beginning, I had to put my head to Angela's belly to heard her the rap clearly. Now we can hear my son's raps can be heard clear across the room.
Jamila explained that when not listening to Kanye West and other rap artists, she and Donovan are singing or humming R&B tunes.
"It's only natural that our little baby has followed suit," shad added. "In fact, we went to a psychologist, who tells us it's common for children tolerant and retain words and sons, they hear while in the womb."
Sound experts have listened to the singing fetus and have confirmed that no ventriloquism, tape recordings or any kind of trickeration is involved.
The quality of the son's voice is extremely high, declared an acoustics expert asked not be identified. But I detected an occasional gurgle between breaths. Doctors tell me that's probably because the wombs is filled with fluid. "That makes the fetus sound, at times , ass though he's using auto-tune.


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Kings beat Caps 5-2 and I Hate California
Photo credit: Chris Carlson
Washington Capitals at Los Angeles Kings. Here's Jonathan Coulton's recap of the Caps road trip in California:
Marcus Johansson scored the night's first goal, a 2-on-1 set up by Mike Knuble. Kyle Clifford got one past Tomas Vokoun on a rebound to tie it up. Anze Kopitar added to that late in the first period after Brooks Laich was pilfered. Jack freaking Johnson converted a 3-on-1 and then did the freaking Tebow move as if the world didn't already suck. Then Stoll scored and our eyes started glazing over. Something else happened, but our eyelids were heavy. Johansson looked bored somehow scoring his second of the night. Kings beat Caps 5-2.
By Peter Hassett 12 years ago