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1.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
2.  LabTrove: A Lightweight, Web Based, Laboratory “Blog” as a Route towards a Marked Up Record of Work in a Bioscience Research Laboratory 
PLoS ONE  2013;8(7):e67460.
The electronic laboratory notebook (ELN) has the potential to replace the paper notebook with a marked-up digital record that can be searched and shared. However, it is a challenge to achieve these benefits without losing the usability and flexibility of traditional paper notebooks. We investigate a blog-based platform that addresses the issues associated with the development of a flexible system for recording scientific research.
Methodology/Principal Findings
We chose a blog-based approach with the journal characteristics of traditional notebooks in mind, recognizing the potential for linking together procedures, materials, samples, observations, data, and analysis reports. We implemented the LabTrove blog system as a server process written in PHP, using a MySQL database to persist posts and other research objects. We incorporated a metadata framework that is both extensible and flexible while promoting consistency and structure where appropriate. Our experience thus far is that LabTrove is capable of providing a successful electronic laboratory recording system.
LabTrove implements a one-item one-post system, which enables us to uniquely identify each element of the research record, such as data, samples, and protocols. This unique association between a post and a research element affords advantages for monitoring the use of materials and samples and for inspecting research processes. The combination of the one-item one-post system, consistent metadata, and full-text search provides us with a much more effective record than a paper notebook. The LabTrove approach provides a route towards reconciling the tensions and challenges that lie ahead in working towards the long-term goals for ELNs. LabTrove, an electronic laboratory notebook (ELN) system from the Smart Research Framework, based on a blog-type framework with full access control, facilitates the scientific experimental recording requirements for reproducibility, reuse, repurposing, and redeployment.
PMCID: PMC3720848  PMID: 23935832
3.  Genomics Virtual Laboratory: A Practical Bioinformatics Workbench for the Cloud 
PLoS ONE  2015;10(10):e0140829.
Analyzing high throughput genomics data is a complex and compute intensive task, generally requiring numerous software tools and large reference data sets, tied together in successive stages of data transformation and visualisation. A computational platform enabling best practice genomics analysis ideally meets a number of requirements, including: a wide range of analysis and visualisation tools, closely linked to large user and reference data sets; workflow platform(s) enabling accessible, reproducible, portable analyses, through a flexible set of interfaces; highly available, scalable computational resources; and flexibility and versatility in the use of these resources to meet demands and expertise of a variety of users. Access to an appropriate computational platform can be a significant barrier to researchers, as establishing such a platform requires a large upfront investment in hardware, experience, and expertise.
We designed and implemented the Genomics Virtual Laboratory (GVL) as a middleware layer of machine images, cloud management tools, and online services that enable researchers to build arbitrarily sized compute clusters on demand, pre-populated with fully configured bioinformatics tools, reference datasets and workflow and visualisation options. The platform is flexible in that users can conduct analyses through web-based (Galaxy, RStudio, IPython Notebook) or command-line interfaces, and add/remove compute nodes and data resources as required. Best-practice tutorials and protocols provide a path from introductory training to practice. The GVL is available on the OpenStack-based Australian Research Cloud ( and the Amazon Web Services cloud. The principles, implementation and build process are designed to be cloud-agnostic.
This paper provides a blueprint for the design and implementation of a cloud-based Genomics Virtual Laboratory. We discuss scope, design considerations and technical and logistical constraints, and explore the value added to the research community through the suite of services and resources provided by our implementation.
PMCID: PMC4621043  PMID: 26501966
4.  Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis 
PLoS Medicine  2010;7(1):e1000215.
Hajo Grundmann and colleagues describe the development of a new interactive mapping tool for analyzing the spatial distribution of invasive Staphylococcus aureus clones.
Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe.
Methods and Findings
In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel.
In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.
Please see later in the article for the Editors' Summary
Editors' Summary
The bacterium Staphylococcus aureus lives on the skin and in the nose of about a third of healthy people. Although S. aureus usually coexists peacefully with its human carriers, it is also an important disease-causing organism or pathogen. If it enters the body through a cut or during a surgical procedure, S. aureus can cause minor infections such as pimples and boils or more serious, life-threatening infections such as blood poisoning and pneumonia. Minor S. aureus infections can be treated without antibiotics—by draining a boil, for example. Invasive infections are usually treated with antibiotics. Unfortunately, many of the S. aureus clones (groups of bacteria that are all genetically related and descended from a single, common ancestor) that are now circulating are resistant to methicillin and several other antibiotics. Invasive methicillin-resistant S. aureus (MRSA) infections are a particular problem in hospitals and other health care facilities (so-called hospital-acquired MRSA infections), but they can also occur in otherwise healthy people who have not been admitted to a hospital (community-acquired MRSA infections).
Why Was This Study Done?
The severity and outcome of an S. aureus infection in an individual depends in part on the ability of the bacterial clone with which the individual is infected to cause disease—the clone's “virulence.” Public-health officials and infectious disease experts would like to know the geographic distribution of the virulent S. aureus clones that cause invasive infections, because this information should help them understand how these pathogens spread and thus how to control them. Different clones of S. aureus can be distinguished by “molecular typing,” the determination of clone-specific sequences of nucleotides in variable regions of the bacterial genome (the bacterium's blueprint; genomes consist of DNA, long chains of nucleotides). In this study, the researchers use molecular typing to map the geographic distribution of MRSA and methicillin-sensitive S. aureus (MSSA) clones causing invasive infections in Europe; a MRSA clone emerges when an MSSA clone acquires antibiotic resistance from another type of bacteria so it is useful to understand the geographic distribution of both MRSA and MSSA.
What Did the Researchers Do and Find?
Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 European countries collected almost 3,000 MRSA and MSSA isolates from patients with invasive S. aureus infections. The isolates were sent to the relevant national staphylococcal reference laboratory (SRL) where they were characterized by quality-controlled sequence typing of the variable region of a staphylococcal gene called spa (spa typing). The spa typing data were entered into a central database and then analyzed by a public, purpose-built Web-based mapping tool (SRL-Maps), which provides interactive access and easy-to-understand illustrations of the geographical distribution of S. aureus clones. Using this mapping tool, the researchers found that there was a wide geographical distribution of spa types across Europe with some types being common in all European countries. MSSA isolates were more diverse than MRSA isolates and the genetic diversity (variability) of MRSA differed considerably between countries. Most importantly, major MRSA spa types occurred in distinct geographical clusters.
What Do These Findings Mean?
These findings provide the first representative snapshot of the genetic population structure of S. aureus across Europe. Because the researchers used spa typing, which analyzes only a small region of one gene, and characterized only 3,000 isolates, analysis of other parts of the S. aureus genome in more isolates is now needed to build a complete portrait of the geographical abundance of the S. aureus clones that cause invasive infections in Europe. However, the finding that MRSA spa types occur mainly in geographical clusters has important implications for the control of MRSA, because it indicates that a limited number of clones are spreading within health care networks, which means that MRSA is mainly spread by patients who are repeatedly admitted to different hospitals. Control efforts aimed at interrupting this spread within and between health care institutions may be feasible and ultimately successful, suggest the researchers, and should be strongly encouraged. In addition, this study shows how, by sharing typing results on a Web-based platform, an international surveillance network can provide clinicians and infection control teams with crucial information about the dynamics of pathogens such as S. aureus, including early warnings about emerging virulent clones.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Franklin D. Lowy
The UK Health Protection Agency provides information about Staphylococcus aureus
The UK National Health Service Choices Web site has pages on staphylococcal infections and on MRSA
The US National Institute of Allergy and Infectious Disease has information about MRSA
The US Centers for Disease Control and Infection provides information about MRSA for the public and professionals
MedlinePlus provides links to further resources on staphylococcal infections and on MRSA (in English and Spanish)
SRL-Maps can be freely accessed
PMCID: PMC2796391  PMID: 20084094
5.  Intrastromal Corneal Ring Implants for Corneal Thinning Disorders 
Executive Summary
The purpose of this project was to determine the role of corneal implants in the management of corneal thinning disease conditions. An evidence-based review was conducted to determine the safety, effectiveness and durability of corneal implants for the management of corneal thinning disorders. The evolving directions of research in this area were also reviewed.
Subject of the Evidence-Based Analysis
The primary treatment objectives for corneal implants are to normalize corneal surface topography, improve contact lens tolerability, and restore visual acuity in order to delay or defer the need for corneal transplant. Implant placement is a minimally invasive procedure that is purported to be safe and effective. The procedure is also claimed to be adjustable, reversible, and both eyes can be treated at the same time. Further, implants do not limit the performance of subsequent surgical approaches or interfere with corneal transplant. The evidence for these claims is the focus of this review.
The specific research questions for the evidence review were as follows:
Corneal Surface Topographic Effects:
Effects on corneal surface remodelling
Impact of these changes on subsequent interventions, particularly corneal transplantation (penetrating keratoplasty [PKP])
Visual Acuity
Refractive Outcomes
Visual Quality (Symptoms): such as contrast vision or decreased visual symptoms (halos, fluctuating vision)
Contact lens tolerance
Functional visual rehabilitation and quality of life
Patient satisfaction:
Disease Process:
Impact on corneal thinning process
Effect on delaying or deferring the need for corneal transplantation
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) comprises a range of disorders involving either primary disease conditions such as keratoconus and pellucid marginal corneal degeneration or secondary iatrogenic conditions such as corneal thinning occurring after LASIK refractive surgery. The condition occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. Thinning occurs primarily in the stoma layers and is believed to be a breakdown in the collagen network. This bulging can lead to an irregular shape or astigmatism of the cornea and, because the anterior part of the cornea is largely responsible for the focusing of light on the retina, results in loss of visual acuity. This can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus (KC) is the most common form of corneal thinning disorder and is a noninflammatory chronic disease process. Although the specific causes of the biomechanical alterations that occur in KC are unknown, there is a growing body of evidence to suggest that genetic factors may play an important role. KC is a rare condition (<0.05% of the population) and is unique among chronic eye diseases as it has an early age of onset (median age of 25 years). Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. When patients can no longer tolerate contact lenses or when lenses no longer provide adequate vision, patients are referred for corneal transplant.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last three decades. Yet, despite high graft survival rates of up to 20 years, there are reasons to defer receiving transplants for as long as possible. Patients with keratoconus are generally young and life-long term graft survival would be an important consideration. The surgery itself involves lengthy time off work and there are potential complications from long term steroid use following surgery, as well as the risk of developing secondary cataracts, glaucoma etc. After transplant, recurrent KC is possible with need for subsequent intervention. Residual refractive errors and astigmatism can remain challenging after transplantation and high refractive surgery rates and re-graft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
INTACS® (Addition Technology Inc. Sunnyvale, CA, formerly KeraVision, Inc.) are the only currently licensed corneal implants in Canada. The implants are micro-thin poly methyl methacrylate crescent shaped ring segments with a circumference arc length of 150 degrees, an external diameter of 8.10 mm, an inner diameter of 6.77 mm, and a range of different thicknesses. Implants act as passive spacers and, when placed in the cornea, cause local separation of the corneal lamellae resulting in a shortening of the arc length of the anterior corneal curvature and flattening the central cornea. Increasing segment thickness results in greater lamellar separation with increased flattening of the cornea correcting for myopia by decreasing the optical power of the eye. Corneal implants also improve corneal astigmatism but the mechanism of action for this is less well understood.
Treatment with corneal implants is considered for patients who are contact lens intolerant, having adequate corneal thickness particularly around the area of the implant incision site and without central corneal scarring. Those with central corneal scarring would not benefit from implants and those without an adequate corneal thickness, particularly in the region that the implants are being inserted, would be at increased risk for corneal perforation. Patients desiring to have visual rehabilitation that does not include glasses or contact lenses would not be candidates for corneal ring implants.
Placement of the implants is an outpatient procedure with topical anesthesia generally performed by either corneal specialists or refractive surgeons. It involves creating tunnels in the corneal stroma to secure the implants either by a diamond knife or laser calibrated to an approximate depth of 70% of the cornea. Variable approaches have been employed by surgeons in selecting ring segment size, number and position. Generally, two segments of equal thickness are placed superiorly and inferiorly to manage symmetrical patterns of corneal thinning whereas one segment may be placed to manage asymmetric thinning patterns.
Following implantation, the major safety concerns are for potential adverse events including corneal perforation, infection, corneal infiltrates, corneal neovascularization, ring migration and extrusion and corneal thinning. Technical results can be unsatisfactory for several reasons. Treatment may result in an over or under-correction of refraction and may induce astigmatism or asymmetry of the cornea.
Progression of the corneal cone with corneal opacities is also invariably an indication for progression to corneal transplant. Other reasons for treatment failure or patient dissatisfaction include foreign body sensation, unsatisfactory visual quality with symptoms such as double vision, fluctuating vision, poor night vision or visual side effects related to ring edge or induced or unresolved astigmatism.
Evidence-Based Analysis Methods
The literature search strategy employed keywords and subject headings to capture the concepts of 1) intrastromal corneal rings and 2) corneal diseases, with a focus on keratoconus, astigmatism, and corneal ectasia. The initial search was run on April 17, 2008, and a final search was run on March 6, 2009 in the following databases: Ovid MEDLINE (1996 to February Week 4 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 10), OVID Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2000 and April 17, 2008. The resulting citations were downloaded into Reference Manager, v.11 (ISI Researchsoft, Thomson Scientific, U.S.A), and duplicates were removed. The Web sites of several other health technology agencies were also reviewed including the Canadian Agency for Drugs and Technologies in Health (CADTH), ECRI, and the United Kingdom National Institute for Clinical Excellence (NICE). The bibliographies of relevant articles were scanned.
Inclusion Criteria
English language reports and human studies
Any corneal thinning disorder
Reports with corneal implants used alone or in conjunction with other interventions
Original reports with defined study methodology
Reports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, vision quality of life or patient satisfaction
Case reports or case series for complications and adverse events
Exclusion Criteria
Non-systematic reviews, letters, comments and editorials
Reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
Reports not involving corneal thinning disorders and an intervention with corneal implants
Summary of Findings
In the MAS evidence review on intrastromal corneal ring implants, 66 reports were identified on the use of implants for management of corneal thinning disorders. Reports varied according to their primary clinical indication, type of corneal implant, and whether or not secondary procedures were used in conjunction with the implants. Implants were reported to manage post LASIK thinning and/or uncorrected refractive error and were also reported as an adjunctive intervention both during and after corneal transplant to manage recurrent thinning and/or uncorrected refractive error.
Ten pre-post cohort longitudinal follow-up studies were identified examining the safety and effectiveness of INTAC corneal implants in patients with keratoconus. Five additional cohort studies were identified using the Ferrara implant for keratoconus management but because this corneal implant is not licensed in Canada these studies were not reviewed.
The cohorts implanted with INTACS involved 608 keratoconus patients (754 eyes) followed for 1, 2 or 3 years. Three of the reports involved ≥ 2 years of follow-up with the longest having 5-year follow-up data for a small number of patients. Four of the INTAC cohort studies involved 50 or more patients; the largest involved 255 patients. Inclusion criteria for the studies were consistent and included patients who were contact lens intolerant, had adequate corneal thickness, particularly around the area of the implant incision site, and without central corneal scarring. Disease severity, thinning pattern, and corneal cone protrusions all varied and generally required different treatment approaches involving defined segment sizes and locations.
A wide range of outcome measures were reported in the cohort studies. High levels of technical success or ability to place INTAC segments were reported. Technically related complications were often delayed and generally reported as segment migration attributable to early experience. Overall, complications were infrequently reported and largely involved minor reversible events without clinical sequelae.
The outcomes reported across studies involved statistically significant and clinically relevant improvements in corneal topography, refraction and visual acuity, for both uncorrected and best-corrected visual acuity. Patients’ vision was usually restored to within normal functioning levels and for those not achieving satisfactory correction, insertion of intraocular lenses was reported in case studies to result in additional gains in visual acuity. Vision loss (infrequently reported) was usually reversed by implant exchange or removal. The primary effects of INTACS on corneal surface remodelling were consistent with secondary improvements in refractive error and visual acuity. The improvements in visual acuity and refractive error noted at 6 months were maintained at 1 and 2-year follow-up
Improvements in visual acuity and refractive error following insertion of INTACS, however, were not noted for all patients. Although improvements were not found to vary across age groups there were differences across stages of disease. Several reports suggested that improvements in visual acuity and refractive outcomes may not be as large or predictable in more advanced stages of KC. Some studies have suggested that the effects of INTACs were much greater in flattening the corneal surface than in correcting astigmatism. However, these studies involved small numbers of high risk patients in advanced stages of KC and conclusions made from this group are limited.
INTACS were used for other indications other than primary KC. The results of implant insertion on corneal topography, refraction, and visual acuity in post-LASIK thinning cases were similar to those reported for KC. The evidence for this indication, however, only involved case reports and small case series. INTACS were also successfully used to treat recurrent KC after corneal transplant but this was based on only a single case report. Corneal implants were compared to corneal transplantation but these studies were not randomized and based on small numbers of selected patients.
The foremost limitation of the evidence base is the basic study design in the reports that involved longitudinal follow-up only for the treated group; there were no randomized trials. Follow-up in the trials (although at prescribed intervals) often had incomplete accounts of losses at follow-up and estimates of change were often not reported or based on group differences. Second, although standardized outcome measures were reported, contact lens tolerance (a key treatment objective) was infrequently specified. A third general limitation was the lack of reporting of patients’ satisfaction with their vision quality or functional vision. Outcome measures for vision quality and impact on patient quality of life were available but rarely reported and have been noted to be a limitation in ophthalmological literature in general. Fourth, the longitudinal cohort studies have not followed patients long enough to evaluate the impact of implants on the underlying disease process (follow-up beyond 3 years is limited). Additionally, only a few of these studies directly examined corneal thinning in follow-up. The overall quality of evidence determined using the GRADE hierarchy of evidence was moderate.
There is some evidence in these studies to support the claim that corneal implants do not interfere with, or increase the difficultly of, subsequent corneal transplant, at least for those performed shortly after INTAC placement. Although it’s uncertain for how long implants can delay the need for a corneal transplant, given that patients with KC are often young (in their twenties and thirties), delaying transplant for any number of years may still be a valuable consideration.
The clinical indications for corneal implants have evolved from management of myopia in normal eyes to the management of corneal thinning disorders such as KC and thinning occurring after refractive surgery. Despite the limited evidence base for corneal implants, which consists solely of longitudinal follow-up studies, they appear to be a valuable clinical tool for improving vision in patients with corneal thinning. For patients unable to achieve functional vision, corneal implants achieved statistically significant and clinically relevant improvements in corneal topography, refraction, and visual acuity, providing a useful alternative to corneal transplant. Implants may also have a rescue function, treating corneal thinning occurring after refractive surgery in normal eyes, or managing refractive errors following corneal transplant. The treatment offers several advantages in that it’s an outpatient based procedure, is associated with minimal risk, and has high technical success rates. Both eyes can be treated at once and the treatment is adjustable and reversible. The implants can be removed or exchanged to improve vision without limiting subsequent interventions, particularly corneal transplant.
Better reporting on vision quality, functional vision and patient satisfaction, however, would improve evaluation of the impact of these devices. Information on the durability of the implants’ treatment effects and their affects on underlying disease processes is limited. This information is becoming more important as alternative treatment strategies, such as collagen cross-linking aimed at strengthening the underlying corneal tissue, are emerging and which might prove to be more effective or increase the effectiveness of the implants, particularly in advances stages of corneal thinning.
Ontario Health System Considerations
At present there are approximately 70 ophthalmologists in Canada who’ve had training with corneal implants; 30 of these practice in Ontario. Industry currently sponsors the training, proctoring and support for the procedure. The cost of the implant device ranges from $950 to $1200 (CAD) and costs for instrumentation range from $20,000 to $30,000 (CAD) (a one time capital expenditure). There is no physician services fee code for corneal implants in Ontario but assuming that they are no higher than those for a corneal transplant, the estimated surgical costs would be $914.32(CAD) An estimated average cost per patient, based on device costs and surgical fees, for treatment is $1,964 (CAD) (range $1,814 to $2,114) per eye. There have also been no out of province treatment requests. In Ontario the treatment is currently being offered in private clinics and an increasing number of ophthalmologists are being certified in the technique by the manufacturer.
KC is a rare disease and not all of these patients would be eligible candidates for treatment with corneal implants. Based on published population rates of KC occurrence, it can be expected that there is a prevalent population of approximately 6,545 patients and an incident population of 240 newly diagnosed cases per year. Given this small number of potential cases, the use of corneal implants would not be expected to have much impact on the Ontario healthcare system. The potential impact on the provincial budget for managing the incident population, assuming the most conservative scenario (i.e., all are eligible and all receive bilateral implants) ranges from $923 thousand to $1.1 million (CAD). This estimate would vary based on a variety of criteria including eligibility, unilateral or bilateral interventions, re-interventions, capacity and uptake
Keratoconus, corneal implants, corneal topography, corneal transplant, visual acuity, refractive error
PMCID: PMC3385416  PMID: 23074513
6.  Make it better but don't change anything 
With massive amounts of data being generated in electronic format, there is a need in basic science laboratories to adopt new methods for tracking and analyzing data. An electronic laboratory notebook (ELN) is not just a replacement for a paper lab notebook, it is a new method of storing and organizing data while maintaining the data entry flexibility and legal recording functions of paper notebooks. Paper notebooks are regarded as highly flexible since the user can configure it to store almost anything that can be written or physically pasted onto the pages. However, data retrieval and data sharing from paper notebooks are labor intensive processes and notebooks can be misplaced, a single point of failure that loses all entries in the volume. Additional features provided by electronic notebooks include searchable indices, data sharing, automatic archiving for security against loss and ease of data duplication. Furthermore, ELNs can be tasked with additional functions not commonly found in paper notebooks such as inventory control. While ELNs have been on the market for some time now, adoption of an ELN in academic basic science laboratories has been lagging. Issues that have restrained development and adoption of ELN in research laboratories are the sheer variety and frequency of changes in protocols with a need for the user to control notebook configuration outside the framework of professional IT staff support. In this commentary, we will look at some of the issues and experiences in academic laboratories that have proved challenging in implementing an electronic lab notebook.
PMCID: PMC2810290  PMID: 20098591
7.  A Semantic Problem Solving Environment for Integrative Parasite Research: Identification of Intervention Targets for Trypanosoma cruzi 
Research on the biology of parasites requires a sophisticated and integrated computational platform to query and analyze large volumes of data, representing both unpublished (internal) and public (external) data sources. Effective analysis of an integrated data resource using knowledge discovery tools would significantly aid biologists in conducting their research, for example, through identifying various intervention targets in parasites and in deciding the future direction of ongoing as well as planned projects. A key challenge in achieving this objective is the heterogeneity between the internal lab data, usually stored as flat files, Excel spreadsheets or custom-built databases, and the external databases. Reconciling the different forms of heterogeneity and effectively integrating data from disparate sources is a nontrivial task for biologists and requires a dedicated informatics infrastructure. Thus, we developed an integrated environment using Semantic Web technologies that may provide biologists the tools for managing and analyzing their data, without the need for acquiring in-depth computer science knowledge.
Methodology/Principal Findings
We developed a semantic problem-solving environment (SPSE) that uses ontologies to integrate internal lab data with external resources in a Parasite Knowledge Base (PKB), which has the ability to query across these resources in a unified manner. The SPSE includes Web Ontology Language (OWL)-based ontologies, experimental data with its provenance information represented using the Resource Description Format (RDF), and a visual querying tool, Cuebee, that features integrated use of Web services. We demonstrate the use and benefit of SPSE using example queries for identifying gene knockout targets of Trypanosoma cruzi for vaccine development. Answers to these queries involve looking up multiple sources of data, linking them together and presenting the results.
The SPSE facilitates parasitologists in leveraging the growing, but disparate, parasite data resources by offering an integrative platform that utilizes Semantic Web techniques, while keeping their workload increase minimal.
Author Summary
Effective research in parasite biology requires analyzing experimental lab data in the context of constantly expanding public data resources. Integrating lab data with public resources is particularly difficult for biologists who may not possess significant computational skills to acquire and process heterogeneous data stored at different locations. Therefore, we develop a semantic problem solving environment (SPSE) that allows parasitologists to query their lab data integrated with public resources using ontologies. An ontology specifies a common vocabulary and formal relationships among the terms that describe an organism, and experimental data and processes in this case. SPSE supports capturing and querying provenance information, which is metadata on the experimental processes and data recorded for reproducibility, and includes a visual query-processing tool to formulate complex queries without learning the query language syntax. We demonstrate the significance of SPSE in identifying gene knockout targets for T. cruzi. The overall goal of SPSE is to help researchers discover new or existing knowledge that is implicitly present in the data but not always easily detected. Results demonstrate improved usefulness of SPSE over existing lab systems and approaches, and support for complex query design that is otherwise difficult to achieve without the knowledge of query language syntax.
PMCID: PMC3260319  PMID: 22272365
8.  From documents to datasets: A MediaWiki-based method of annotating and extracting species observations in century-old field notebooks 
ZooKeys  2012;235-253.
Part diary, part scientific record, biological field notebooks often contain details necessary to understanding the location and environmental conditions existent during collecting events. Despite their clear value for (and recent use in) global change studies, the text-mining outputs from field notebooks have been idiosyncratic to specific research projects, and impossible to discover or re-use. Best practices and workflows for digitization, transcription, extraction, and integration with other sources are nascent or non-existent. In this paper, we demonstrate a workflow to generate structured outputs while also maintaining links to the original texts. The first step in this workflow was to place already digitized and transcribed field notebooks from the University of Colorado Museum of Natural History founder, Junius Henderson, on Wikisource, an open text transcription platform. Next, we created Wikisource templates to document places, dates, and taxa to facilitate annotation and wiki-linking. We then requested help from the public, through social media tools, to take advantage of volunteer efforts and energy. After three notebooks were fully annotated, content was converted into XML and annotations were extracted and cross-walked into Darwin Core compliant record sets. Finally, these recordsets were vetted, to provide valid taxon names, via a process we call “taxonomic referencing.” The result is identification and mobilization of 1,068 observations from three of Henderson’s thirteen notebooks and a publishable Darwin Core record set for use in other analyses. Although challenges remain, this work demonstrates a feasible approach to unlock observations from field notebooks that enhances their discovery and interoperability without losing the narrative context from which those observations are drawn.
“Compose your notes as if you were writing a letter to someone a century in the future.”
Perrine and Patton (2011)
PMCID: PMC3406479  PMID: 22859891
Field notes; notebooks; crowd sourcing; digitization; biodiversity; transcription; text-mining; Darwin Core; Junius Henderson; annotation; taxonomic referencing; natural history; Wikisource; Colorado; species occurrence records
9.  WebProtégé: A Collaborative Ontology Editor and Knowledge Acquisition Tool for the Web 
Semantic web  2013;4(1):89-99.
In this paper, we present WebProtégé—a lightweight ontology editor and knowledge acquisition tool for the Web. With the wide adoption of Web 2.0 platforms and the gradual adoption of ontologies and Semantic Web technologies in the real world, we need ontology-development tools that are better suited for the novel ways of interacting, constructing and consuming knowledge. Users today take Web-based content creation and online collaboration for granted. WebProtégé integrates these features as part of the ontology development process itself. We tried to lower the entry barrier to ontology development by providing a tool that is accessible from any Web browser, has extensive support for collaboration, and a highly customizable and pluggable user interface that can be adapted to any level of user expertise. The declarative user interface enabled us to create custom knowledge-acquisition forms tailored for domain experts. We built WebProtégé using the existing Protégé infrastructure, which supports collaboration on the back end side, and the Google Web Toolkit for the front end. The generic and extensible infrastructure allowed us to easily deploy WebProtégé in production settings for several projects. We present the main features of WebProtégé and its architecture and describe briefly some of its uses for real-world projects. WebProtégé is free and open source. An online demo is available at
PMCID: PMC3691821  PMID: 23807872
Web-based ontology editing; knowledge acquisition; collaboration; Protégé; Semantic Web
10.  A scoping review of cloud computing in healthcare 
Cloud computing is a recent and fast growing area of development in healthcare. Ubiquitous, on-demand access to virtually endless resources in combination with a pay-per-use model allow for new ways of developing, delivering and using services. Cloud computing is often used in an “OMICS-context”, e.g. for computing in genomics, proteomics and molecular medicine, while other field of application still seem to be underrepresented. Thus, the objective of this scoping review was to identify the current state and hot topics in research on cloud computing in healthcare beyond this traditional domain.
MEDLINE was searched in July 2013 and in December 2014 for publications containing the terms “cloud computing” and “cloud-based”. Each journal and conference article was categorized and summarized independently by two researchers who consolidated their findings.
102 publications have been analyzed and 6 main topics have been found: telemedicine/teleconsultation, medical imaging, public health and patient self-management, hospital management and information systems, therapy, and secondary use of data. Commonly used features are broad network access for sharing and accessing data and rapid elasticity to dynamically adapt to computing demands. Eight articles favor the pay-for-use characteristics of cloud-based services avoiding upfront investments. Nevertheless, while 22 articles present very general potentials of cloud computing in the medical domain and 66 articles describe conceptual or prototypic projects, only 14 articles report from successful implementations. Further, in many articles cloud computing is seen as an analogy to internet-/web-based data sharing and the characteristics of the particular cloud computing approach are unfortunately not really illustrated.
Even though cloud computing in healthcare is of growing interest only few successful implementations yet exist and many papers just use the term “cloud” synonymously for “using virtual machines” or “web-based” with no described benefit of the cloud paradigm. The biggest threat to the adoption in the healthcare domain is caused by involving external cloud partners: many issues of data safety and security are still to be solved. Until then, cloud computing is favored more for singular, individual features such as elasticity, pay-per-use and broad network access, rather than as cloud paradigm on its own.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-015-0145-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4372226  PMID: 25888747
Cloud computing; Internet; E-health; Medicine; Healthcare
11.  Using participatory design to develop (public) health decision support systems through GIS 
Organizations that collect substantial data for decision-making purposes are often characterized as being 'data rich' but 'information poor'. Maps and mapping tools can be very useful for research transfer in converting locally collected data into information. Challenges involved in incorporating GIS applications into the decision-making process within the non-profit (public) health sector include a lack of financial resources for software acquisition and training for non-specialists to use such tools. This on-going project has two primary phases. This paper critically reflects on Phase 1: the participatory design (PD) process of developing a collaborative web-based GIS tool.
A case study design is being used whereby the case is defined as the data analyst and manager dyad (a two person team) in selected Ontario Early Year Centres (OEYCs). Multiple cases are used to support the reliability of findings. With nine producer/user pair participants, the goal in Phase 1 was to identify barriers to map production, and through the participatory design process, develop a web-based GIS tool suited for data analysts and their managers. This study has been guided by the Ottawa Model of Research Use (OMRU) conceptual framework.
Due to wide variations in OEYC structures, only some data analysts used mapping software and there was no consistency or standardization in the software being used. Consequently, very little sharing of maps and data occurred among data analysts. Using PD, this project developed a web-based mapping tool (EYEMAP) that was easy to use, protected proprietary data, and permit limited and controlled sharing between participants. By providing data analysts with training on its use, the project also ensured that data analysts would not break cartographic conventions (e.g. using a chloropleth map for count data). Interoperability was built into the web-based solution; that is, EYEMAP can read many different standard mapping file formats (e.g. ESRI, MapInfo, CSV).
Based on the evaluation of Phase 1, the PD process has served both as a facilitator and a barrier. In terms of successes, the PD process identified two key components that are important to users: increased data/map sharing functionality and interoperability. Some of the challenges affected developers and users; both individually and as a collective. From a development perspective, this project experienced difficulties in obtaining personnel skilled in web application development and GIS. For users, some data sharing barriers are beyond what a technological tool can address (e.g. third party data). Lastly, the PD process occurs in real time; both a strength and a limitation. Programmatic changes at the provincial level and staff turnover at the organizational level made it difficult to maintain buy-in as participants changed over time. The impacts of these successes and challenges will be evaluated more concretely at the end of Phase 2.
PD approaches, by their very nature, encourage buy-in to the development process, better addresses user-needs, and creates a sense of user-investment and ownership.
PMCID: PMC2175500  PMID: 18042298
12.  Clinical software development for the Web: lessons learned from the BOADICEA project 
In the past 20 years, society has witnessed the following landmark scientific advances: (i) the sequencing of the human genome, (ii) the distribution of software by the open source movement, and (iii) the invention of the World Wide Web. Together, these advances have provided a new impetus for clinical software development: developers now translate the products of human genomic research into clinical software tools; they use open-source programs to build them; and they use the Web to deliver them. Whilst this open-source component-based approach has undoubtedly made clinical software development easier, clinical software projects are still hampered by problems that traditionally accompany the software process. This study describes the development of the BOADICEA Web Application, a computer program used by clinical geneticists to assess risks to patients with a family history of breast and ovarian cancer. The key challenge of the BOADICEA Web Application project was to deliver a program that was safe, secure and easy for healthcare professionals to use. We focus on the software process, problems faced, and lessons learned. Our key objectives are: (i) to highlight key clinical software development issues; (ii) to demonstrate how software engineering tools and techniques can facilitate clinical software development for the benefit of individuals who lack software engineering expertise; and (iii) to provide a clinical software development case report that can be used as a basis for discussion at the start of future projects.
We developed the BOADICEA Web Application using an evolutionary software process. Our approach to Web implementation was conservative and we used conventional software engineering tools and techniques. The principal software development activities were: requirements, design, implementation, testing, documentation and maintenance. The BOADICEA Web Application has now been widely adopted by clinical geneticists and researchers. BOADICEA Web Application version 1 was released for general use in November 2007. By May 2010, we had > 1200 registered users based in the UK, USA, Canada, South America, Europe, Africa, Middle East, SE Asia, Australia and New Zealand.
We found that an evolutionary software process was effective when we developed the BOADICEA Web Application. The key clinical software development issues identified during the BOADICEA Web Application project were: software reliability, Web security, clinical data protection and user feedback.
PMCID: PMC3507671  PMID: 22490389
Clinical software development; Open source; Web; BOADICEA risk model
13.  Molecule database framework: a framework for creating database applications with chemical structure search capability 
Research in organic chemistry generates samples of novel chemicals together with their properties and other related data. The involved scientists must be able to store this data and search it by chemical structure. There are commercial solutions for common needs like chemical registration systems or electronic lab notebooks. However for specific requirements of in-house databases and processes no such solutions exist. Another issue is that commercial solutions have the risk of vendor lock-in and may require an expensive license of a proprietary relational database management system. To speed up and simplify the development for applications that require chemical structure search capabilities, I have developed Molecule Database Framework. The framework abstracts the storing and searching of chemical structures into method calls. Therefore software developers do not require extensive knowledge about chemistry and the underlying database cartridge. This decreases application development time.
Molecule Database Framework is written in Java and I created it by integrating existing free and open-source tools and frameworks. The core functionality includes:
• Support for multi-component compounds (mixtures)
• Import and export of SD-files
• Optional security (authorization)
For chemical structure searching Molecule Database Framework leverages the capabilities of the Bingo Cartridge for PostgreSQL and provides type-safe searching, caching, transactions and optional method level security. Molecule Database Framework supports multi-component chemical compounds (mixtures).
Furthermore the design of entity classes and the reasoning behind it are explained. By means of a simple web application I describe how the framework could be used. I then benchmarked this example application to create some basic performance expectations for chemical structure searches and import and export of SD-files.
By using a simple web application it was shown that Molecule Database Framework successfully abstracts chemical structure searches and SD-File import and export to simple method calls. The framework offers good search performance on a standard laptop without any database tuning. This is also due to the fact that chemical structure searches are paged and cached. Molecule Database Framework is available for download on the projects web page on bitbucket:
PMCID: PMC3892073  PMID: 24325762
Chemical structure search; Database; Framework; Open-source
14.  Analysis and Implementation of an Electronic Laboratory Notebook in a Biomedical Research Institute 
PLoS ONE  2016;11(8):e0160428.
Electronic laboratory notebooks (ELNs) will probably replace paper laboratory notebooks (PLNs) in academic research due to their advantages in data recording, sharing and security. Despite several reports describing technical characteristics of ELNs and their advantages over PLNs, no study has directly tested ELN performance among researchers. In addition, the usage of tablet-based devices or wearable technology as ELN complements has never been explored in the field. To implement an ELN in our biomedical research institute, here we first present a technical comparison of six ELNs using 42 parameters. Based on this, we chose two ELNs, which were tested by 28 scientists for a 3-month period and by 80 students via hands-on practical exercises. Second, we provide two survey-based studies aimed to compare these two ELNs (PerkinElmer Elements and Microsoft OneNote) and to analyze the use of tablet-based devices. We finally explore the advantages of using wearable technology as ELNs tools. Among the ELNs tested, we found that OneNote presents almost all parameters evaluated (39/42) and both surveyed groups preferred OneNote as an ELN solution. In addition, 80% of the surveyed scientists reported that tablet-based devices improved the use of ELNs in different respects. We also describe the advantages of using OneNote application for Apple Watch as an ELN wearable complement. This work defines essential features of ELNs that could be used to improve ELN implementation and software development.
PMCID: PMC4968837  PMID: 27479083
15.  CIS5/405: Web Technology in Healthcare - Delivering Electronic Records Using the Clinical Intranet 
The development of electronic records - EPR & EHR (Electronic Patient Records & Electronic Health Records) - requires the use of innovative technology. With the emergence of web enabled applications, that technology is now available. In this paper, we consider the opportunities afforded by web technology and articulate their vision for making electronic records an affordable reality through the use of the ViewMax Integration Server. It is designed to be used as a discussion document for Health Authorities, Primary Care Groups and Trusts when considering their shared strategies for building electronic records.
Hospitals that have developed, or are developing EPR, have generally adopted one of the following approaches: Big Bang solutions or Interfaced solutions. Whilst both of these models have their merits, both also have significant limitations and disadvantages. With the advent of web technology, a "third way" has emerged. Through the development of e-commerce in the commercial sector, sophisticated Host-to-Web integration tools are now available, providing facilities which would have seemed impossible only a few years ago:
Systems can now be integrated and accessed through an industry standard web browser.
Legacy systems can be provided with a modern, intuitive interface, designed to support the needs of particular groups of users, and data from multiple, disparate systems, applications and screens can be combined into a single web page.
Data from one system can be easily transferred to other applications.
New applications developed using modern databases can be seamlessly integrated with existing host systems.
Most importantly, this new approach enables full interactive access to legacy technologies using a browser, without requiring any modification to host systems.
Utilising the latest Web integration tools it is now possible to incrementally develop cost-effective electronic records.
The hospital is an average acute district general hospital, and runs a PAS and the normal range of departmental systems - pathology, radiology, pharmacy, theatres and maternity. The PAS shares demographic details with the departmental systems via point to point interfaces, so that all use the hospital number as the main patient identifier. The hospital wants to make better use of these systems to meet the following requirements:
Diagnostic result reporting for clinical staff.
Electronic ordering of pathology and radiology services.
Simplified ward based access to PAS ADT functions.
Patient event history.
Discharge letter production.
Web integration tools enable applications to be integrated live within the user interface, and can be used to build "new" applications, by consolidating pieces of functionality from existing and new systems seamlessly within the browser.
PMCID: PMC1761750
Information Management; Electronic Records; Web Technology; Patient Administration System; Host-to-Web
16.  The Process of Installing REDCap, a Web Based Database Supporting Biomedical Research 
Applied Clinical Informatics  2014;5(4):916-929.
Clinical and research data are essential for patient care, research and healthcare system planning. REDCapTM is a web-based tool for research data curatorship developed at Vanderbilt University in Nashville, USA. The Faculty of Health Sciences at the University of the Witwatersrand, Johannesburg South Africa identified the need for a cost effective data management instrument. REDCap was installed as per the user agreement with Vanderbilt University in August 2012.
In order to assist other institutions that may lack the in-house Information Technology capacity, this paper describes the installation and support of REDCap and incorporates an analysis of user uptake over the first year of use.
We reviewed the staffing requirements, costs of installation, process of installation and necessary infrastructure and end-user requests following the introduction of REDCap at Wits. The University Legal Office and Human Research Ethics Committee were consulted regarding the REDCap end-user agreement. Bi-monthly user meetings resulted in a training workshop in August 2013. We compared our REDCap software user numbers and records before and after the first training workshop.
Human resources were recruited from existing staff. Installation costs were limited to servers and security certificates. The total costs to provide a functional REDCap platform was less than $9000. Eighty-one (81) users were registered in the first year. After the first training workshop the user numbers increased by 59 in one month and the total number of active users to 140 by the end of August 2013. Custom software applications for REDCap were created by collaboration between clinicians and software developers.
REDCap was installed and maintained at limited cost. A small number of people with defined skills can support multiple REDCap users in two to four hours a week. End user training increased in the number of users, number of projects created and the number of projects moved to production.
PMCID: PMC4287671  PMID: 25589907
Database management systems; medical informatics; electronic data capture; clinical research; translational research
17.  Analysis of the Security and Privacy Requirements of Cloud-Based Electronic Health Records Systems 
The Cloud Computing paradigm offers eHealth systems the opportunity to enhance the features and functionality that they offer. However, moving patients’ medical information to the Cloud implies several risks in terms of the security and privacy of sensitive health records. In this paper, the risks of hosting Electronic Health Records (EHRs) on the servers of third-party Cloud service providers are reviewed. To protect the confidentiality of patient information and facilitate the process, some suggestions for health care providers are made. Moreover, security issues that Cloud service providers should address in their platforms are considered.
To show that, before moving patient health records to the Cloud, security and privacy concerns must be considered by both health care providers and Cloud service providers. Security requirements of a generic Cloud service provider are analyzed.
To study the latest in Cloud-based computing solutions, bibliographic material was obtained mainly from Medline sources. Furthermore, direct contact was made with several Cloud service providers.
Some of the security issues that should be considered by both Cloud service providers and their health care customers are role-based access, network security mechanisms, data encryption, digital signatures, and access monitoring. Furthermore, to guarantee the safety of the information and comply with privacy policies, the Cloud service provider must be compliant with various certifications and third-party requirements, such as SAS70 Type II, PCI DSS Level 1, ISO 27001, and the US Federal Information Security Management Act (FISMA).
Storing sensitive information such as EHRs in the Cloud means that precautions must be taken to ensure the safety and confidentiality of the data. A relationship built on trust with the Cloud service provider is essential to ensure a transparent process. Cloud service providers must make certain that all security mechanisms are in place to avoid unauthorized access and data breaches. Patients must be kept informed about how their data are being managed.
PMCID: PMC3757992  PMID: 23965254
cloud-computing; eHealth; electronic health records (EHRs); privacy; security
18.  A hybrid solution for extracting structured medical information from unstructured data in medical records via a double-reading/entry system 
Healthcare providers generate a huge amount of biomedical data stored in either legacy system (paper-based) format or electronic medical records (EMR) around the world, which are collectively referred to as big biomedical data (BBD). To realize the promise of BBD for clinical use and research, it is an essential step to extract key data elements from unstructured medical records into patient-centered electronic health records with computable data elements. Our objective is to introduce a novel solution, known as a double-reading/entry system (DRESS), for extracting clinical data from unstructured medical records (MR) and creating a semi-structured electronic health record database, as well as to demonstrate its reproducibility empirically.
Utilizing the modern cloud-based technologies, we have developed a comprehensive system that includes multiple subsystems, from capturing MRs in clinics, to securely transferring MRs, storing and managing cloud-based MRs, to facilitating both machine learning and manual reading, and to performing iterative quality control before committing the semi-structured data into the desired database. To evaluate the reproducibility of extracted medical data elements by DRESS, we conduct a blinded reproducibility study, with 100 MRs from patients who have undergone surgical treatment of lung cancer in China. The study uses Kappa statistic to measure concordance of discrete variables, and uses correlation coefficient to measure reproducibility of continuous variables.
Using the DRESS, we have demonstrated the feasibility of extracting clinical data from unstructured MRs to create semi-structured and patient-centered electronic health record database. The reproducibility study with 100 patient’s MRs has shown an overall high reproducibility of 98 %, and varies across six modules (pathology, Radio/chemo therapy, clinical examination, surgery information, medical image and general patient information).
DRESS uses a double-reading, double-entry, and an independent adjudication, to manually curate structured data elements from unstructured clinical data. Further, through distributed computing strategies, DRESS protects data privacy by dividing MR data into de-identified modules. Finally, through internet-based computing cloud, DRESS enables many data specialists to work in a virtual environment to achieve the necessary scale of processing thousands MRs within days. This hybrid system represents probably a workable solution to solve the big medical data challenge.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-016-0357-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5006527  PMID: 27577240
Big data; Big medical data; Clinical research; Clinical decision support system; Cloud-based system; Double data entry; Electronic medical record; Health service research; Structured data and unstructured data
19.  Finding Web-Based Anxiety Interventions on the World Wide Web: A Scoping Review 
JMIR Mental Health  2016;3(2):e14.
One relatively new and increasingly popular approach of increasing access to treatment is Web-based intervention programs. The advantage of Web-based approaches is the accessibility, affordability, and anonymity of potentially evidence-based treatment. Despite much research evidence on the effectiveness of Web-based interventions for anxiety found in the literature, little is known about what is publically available for potential consumers on the Web.
Our aim was to explore what a consumer searching the Web for Web-based intervention options for anxiety-related issues might find. The objectives were to identify currently publically available Web-based intervention programs for anxiety and to synthesize and review these in terms of (1) website characteristics such as credibility and accessibility; (2) intervention program characteristics such as intervention focus, design, and presentation modes; (3) therapeutic elements employed; and (4) published evidence of efficacy.
Web keyword searches were carried out on three major search engines (Google, Bing, and Yahoo—UK platforms). For each search, the first 25 hyperlinks were screened for eligible programs. Included were programs that were designed for anxiety symptoms, currently publically accessible on the Web, had an online component, a structured treatment plan, and were available in English. Data were extracted for website characteristics, program characteristics, therapeutic characteristics, as well as empirical evidence. Programs were also evaluated using a 16-point rating tool.
The search resulted in 34 programs that were eligible for review. A wide variety of programs for anxiety, including specific anxiety disorders, and anxiety in combination with stress, depression, or anger were identified and based predominantly on cognitive behavioral therapy techniques. The majority of websites were rated as credible, secure, and free of advertisement. The majority required users to register and/or to pay a program access fee. Half of the programs offered some form of paid therapist or professional support. Programs varied in treatment length and number of modules and employed a variety of presentation modes. Relatively few programs had published research evidence of the intervention’s efficacy.
This review represents a snapshot of available Web-based intervention programs for anxiety that could be found by consumers in March 2015. The consumer is confronted with a diversity of programs, which makes it difficult to identify an appropriate program. Limited reports and existence of empirical evidence for efficacy make it even more challenging to identify credible and reliable programs. This highlights the need for consistent guidelines and standards on developing, providing, and evaluating Web-based interventions and platforms with reliable up-to-date information for professionals and consumers about the characteristics, quality, and accessibility of Web-based interventions.
PMCID: PMC4936762  PMID: 27251763
Anxiety; mental health; web-based interventions; internet; technology; consumer; access to health care
20.  e-Health, m-Health and healthier social media reform: the big scale view 
In the upcoming decade, digital platforms will be the backbone of a strategic revolution in the way medical services are provided, affecting both healthcare providers and patients. Digital-based patient-centered healthcare services allow patients to actively participate in managing their own care, in times of health as well as illness, using personally tailored interactive tools. Such empowerment is expected to increase patients’ willingness to adopt actions and lifestyles that promote health as well as improve follow-up and compliance with treatment in cases of chronic illness. Clalit Health Services (CHS) is the largest HMO in Israel and second largest world-wide. Through its 14 hospitals, 1300 primary and specialized clinics, and 650 pharmacies, CHS provides comprehensive medical care to the majority of Israel’s population (above 4 million members). CHS e-Health wing focuses on deepening patient involvement in managing health, through personalized digital interactive tools. Currently, CHS e-Health wing provides e-health services for 1.56 million unique patients monthly with 2.4 million interactions every month (August 2011). Successful implementation of e-Health solutions is not a sum of technology, innovation and health; rather it’s the expertise of tailoring knowledge and leadership capabilities in multidisciplinary areas: clinical, ethical, psychological, legal, comprehension of patient and medical team engagement etc. The Google Health case excellently demonstrates this point. On the other hand, our success with CHS is a demonstration that e-Health can be enrolled effectively and fast with huge benefits for both patients and medical teams, and with a robust business model.
CHS e-Health core components
They include:
1. The personal health record layer (what the patient can see) presents patients with their own medical history as well as the medical history of their preadult children, including diagnoses, allergies, vaccinations, laboratory results with interpretations in layman’s terms, medications with clear, straightforward explanations regarding dosing instructions, important side effects, contraindications, such as lactation etc., and other important medical information. All personal e-Health services require identification and authorization.
2. The personal knowledge layer (what the patient should know) presents patients with personally tailored recommendations for preventative medicine and health promotion. For example, diabetic patients are push notified regarding their yearly eye exam. The various health recommendations include: occult blood testing, mammography, lipid profile etc. Each recommendation contains textual, visual and interactive content components in order to promote engagement and motivate the patient to actually change his health behaviour.
3. The personal health services layer (what the patient can do) enables patients to schedule clinic visits, order chronic prescriptions, e-consult their physician via secured e-mail, set SMS medication reminders, e-consult a pharmacist regarding personal medications. Consultants’ answers are sent securely to the patients’ personal mobile device.
On December 2009 CHS launched secured, web based, synchronous medical consultation via video conference. Currently 11,780 e-visits are performed monthly (May 2011). The medical encounter includes e-prescription and referral capabilities which are biometrically signed by the physician. On December 2010 CHS launched a unique mobile health platform, which is one of the most comprehensive personal m-Health applications world-wide. An essential advantage of mobile devices is their potential to bridge the digital divide. Currently, CHS m-Health platform is used by more than 45,000 unique users, with 75,000 laboratory results views/month, 1100 m-consultations/month and 9000 physician visit scheduling/month.
4. The Bio-Sensing layer (what physiological data the patient can populate) includes diagnostic means that allow remote physical examination, bio-sensors that broadcast various physiological measurements, and smart homecare devices, such as e-Pill boxes that gives seniors, patients and their caregivers the ability to stay at home and live life to its fullest. Monitored data is automatically transmitted to the patient’s Personal Health Record and to relevant medical personnel.
The monitoring layer is embedded in the chronic disease management platform, and in the interactive health promotion and wellness platform. It includes tailoring of consumer-oriented medical devices and service provided by various professional personnel—physicians, nurses, pharmacists, dieticians and more.
5. The Social layer (what the patient can share). Social media networks triggered an essential change at the humanity ‘genome’ level, yet to be further defined in the upcoming years. Social media has huge potential in promoting health as it combines fun, simple yet extraordinary user experience, and bio-social-feedback. There are two major challenges in leveraging health care through social networks:
a. Our personal health information is the cornerstone for personalizing healthier lifestyle, disease management and preventative medicine. We naturally see our personal health data as a super-private territory. So, how do we bring the power of our private health information, currently locked within our Personal Health Record, into social media networks without offending basic privacy issues?
b. Disease management and preventive medicine are currently neither considered ‘cool’ nor ‘fun’ or ‘potentially highly viral’ activities; yet, health is a major issue of everybody’s life. It seems like we are missing a crucial element with a huge potential in health behavioural change—the Fun Theory. Social media platforms comprehends user experience tools that potentially could break current misconception, and engage people in the daily task of taking better care of themselves.
CHS e-Health innovation team characterized several break-through applications in this unexplored territory within social media networks, fusing personal health and social media platforms without offending privacy. One of the most crucial issues regarding adoption of e-health and m-health platforms is change management. Being a ‘hot’ innovative ‘gadget’ is far from sufficient for changing health behaviours at the individual and population levels.
CHS health behaviour change management methodology includes 4 core elements:
1. Engaging two completely different populations: patients, and medical teams. e-Health applications must present true added value for both medical teams and patients, engaging them through understanding and assimilating “what’s really in it for me”. Medical teams are further subdivided into physicians, nurses, pharmacists and administrative personnel—each with their own driving incentive. Resistance to change is an obstacle in many fields but it is particularly true in the conservative health industry. To successfully manage a large scale persuasive process, we treat intra-organizational human resources as “Change Agents”. Harnessing the persuasive power of ~40,000 employees requires engaging them as the primary target group. Successful recruitment has the potential of converting each patient-medical team interaction into an exposure opportunity to the new era of participatory medicine via e-health and m-health channels.
2. Implementation waves: every group of digital health products that are released at the same time are seen as one project. Each implementation wave leverages the focus of the organization and target populations to a defined time span. There are three major and three minor implementation waves a year.
3. Change-Support Arrow: a structured infrastructure for every implementation wave. The sub-stages in this strategy include:
Cross organizational mapping and identification of early adopters and stakeholders relevant to the implementation wave
Mapping positive or negative perceptions and designing specific marketing approaches for the distinct target groups
Intra and extra organizational marketing
Conducting intensive training and presentation sessions for groups of implementers
Running conflict-prevention activities, such as advanced tackling of potential union resistance
Training change-agents with resistance-management behavioural techniques, focused intervention for specific incidents and for key opinion leaders
Extensive presence in the clinics during the launch period, etc.
The entire process is monitored and managed continuously by a review team.
4. Closing Phase: each wave is analyzed and a “lessons-learned” session concludes the changes required in the modus operandi of the e-health project team.
PMCID: PMC3571141
e-Health; mobile health; personal health record; online visit; patient empowerment; knowledge prescription
21.  A novel collaborative e-learning platform for medical students - ALERT STUDENT 
BMC Medical Education  2014;14:143.
The increasing complexity of medical curricula would benefit from adaptive computer supported collaborative learning systems that support study management using instructional design and learning object principles. However, to our knowledge, there are scarce reports regarding applications developed to meet this goal and encompass the complete medical curriculum. The aim of ths study was to develop and assess the usability of an adaptive computer supported collaborative learning system for medical students to manage study sessions.
A study platform named ALERT STUDENT was built as a free web application. Content chunks are represented as Flashcards that hold knowledge and open ended questions. These can be created in a collaborative fashion. Multiple Flashcards can be combined into custom stacks called Notebooks that can be accessed in study Groups that belong to the user institution. The system provides a Study Mode that features text markers, text notes, timers and color-coded content prioritization based on self-assessment of open ended questions presented in a Quiz Mode. Time spent studying and Perception of knowledge are displayed for each student and peers using charts. Computer supported collaborative learning is achieved by allowing for simultaneous creation of Notebooks and self-assessment questions by many users in a pre-defined Group. Past personal performance data is retrieved when studying new Notebooks containing previously studied Flashcards. Self-report surveys showed that students highly agreed that the system was useful and were willing to use it as a reference tool.
The platform employs various instructional design and learning object principles in a computer supported collaborative learning platform for medical students that allows for study management. The application broadens student insight over learning results and supports informed decisions based on past learning performance. It serves as a potential educational model for the medical education setting that has gathered strong positive feedback from students at our school.
This platform provides a case study on how effective blending of instructional design and learning object principles can be brought together to manage study, and takes an important step towards bringing information management tools to support study decisions and improving learning outcomes.
PMCID: PMC4131539  PMID: 25017028
Medical education; Computer supported collaborative learning; E-learning; Information management; Memory retention; Computer-assisted instruction; Tailored learning; Student-centered learning; Spaced repetition
22.  Establishing a Federal and State Data Exchange Pilot for Public Health Situational Awareness 
U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response (ASPR) partnered with the Florida Department of Health (FDOH), Bureau of Epidemiology, to implement a new process for the unidirectional exchange of electronic medical record (EMR) data when ASPR clinical assets are operational in the state following a disaster or other response event. The purpose of the current work was to automate the exchange of data from the ASPR electronic medical record system EMR-S into the FDOH Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE-FL) system during the 2012 Republican National Convention (RNC).
ASPR deploys clinical assets, including an EMR system, to the ground per state requests during planned and no-notice events. The analysis of patient data collected by deployed federal personnel is an integral part of ASPR and FDOH’s surveillance efforts. However, this surveillance can be hampered by the logistical issues of field work in a post-disaster environment leading to delayed analysis and interpretation of these data to inform decision makers at the federal, state, and local levels. FDOH operates ESSENCE-FL, a multi-tiered, automated, and secure web-based application for analysis and visualization of clinical data. The system is accessible statewide by FDOH staff as well as by hospitals that participate in the system. To improve surveillance ASPR and FDOH engaged in a pilot project whereby EMR data from ASPR would be sent to FDOH in near real-time during the 2012 hurricane season and the 2012 RNC. This project is in direct support of Healthcare Preparedness Capability 6, Information Sharing, and Public Health Preparedness Capability 13, Public Health Surveillance and Epidemiological Investigation.
In 2011, FDOH approached ASPR about securely transmitting raw EMR data that could be ingested by ESSENCE-FL during ASPR deployments in the state. Upon conclusion of an agreement for a date exchange pilot, data elements of interest from the ASPR EMR were identified. Due to the modular design ESSENCE-FL Microsoft SQL databases were easily adapted by the Johns Hopkins University Applied Physics Laboratory (JHU/APL) to add a new module to handle receipt of ASPR EMR data including code to process the files, remove duplicates and create associations with existing reference information, such as system-defined geographic regions and age groups. Scripts were developed to run on the ASPR server to create and send updated files via secure file transfer protocol (SFTP) every 15 minutes to ESSENCE-FL. Prior ASPR event deployment data was scrubbed and sent to ESSENCE-FL as a test dataset to ensure appropriate receipt and ingestion of the new data source.
EMR data was transmitted through a central server at ASPR to ESSENCE-FL every 15 minutes during each day of the 2012 RNC (August 26–31). In ESSENCE-FL, configuration allowed the data to be queried, analyzed, and visualized similar to existing ESSENCE-FL data sources. In all, data from 11 patient encounters were successfully exchanged between the partners. The data were used by ASPR and FDOH to simultaneously monitor in near real-time onsite medical response activities during the convention.
Timely access to patient data can enhance situational awareness and disease surveillance efforts and provide decision makers with key information in an expedient manner during disaster response and mass gatherings such as the RNC. However, data are siloed within organizations. The collaboration between FDOH, ASPR and JHU/APL made EMR data sharing and analysis more expeditious and efficient and increased timely access to these data by local, state, and federal epidemiologists. The integration of these data into the ESSENCE-FL system created one location where users could go to access data and create epidemiologic reports for a given region in Florida, including the RNC. To achieve these successes with partners in the future, it will be necessary to develop partnerships well in advance of intended data exchange. Future recommendations include robust pre-event testing of the data exchange process and planning for a greater amount of lead-time between enacting the official agreement and beginning data exchange.
PMCID: PMC3692893
Syndromic surveillance; Public health informatics; Data exchange; Federal and state collaboration
23.  A Holistic Framework to Improve the Uptake and Impact of eHealth Technologies 
Many eHealth technologies are not successful in realizing sustainable innovations in health care practices. One of the reasons for this is that the current development of eHealth technology often disregards the interdependencies between technology, human characteristics, and the socioeconomic environment, resulting in technology that has a low impact in health care practices. To overcome the hurdles with eHealth design and implementation, a new, holistic approach to the development of eHealth technologies is needed, one that takes into account the complexity of health care and the rituals and habits of patients and other stakeholders.
The aim of this viewpoint paper is to improve the uptake and impact of eHealth technologies by advocating a holistic approach toward their development and eventual integration in the health sector.
To identify the potential and limitations of current eHealth frameworks (1999–2009), we carried out a literature search in the following electronic databases: PubMed, ScienceDirect, Web of Knowledge, PiCarta, and Google Scholar. Of the 60 papers that were identified, 44 were selected for full review. We excluded those papers that did not describe hands-on guidelines or quality criteria for the design, implementation, and evaluation of eHealth technologies (28 papers). From the results retrieved, we identified 16 eHealth frameworks that matched the inclusion criteria. The outcomes were used to posit strategies and principles for a holistic approach toward the development of eHealth technologies; these principles underpin our holistic eHealth framework.
A total of 16 frameworks qualified for a final analysis, based on their theoretical backgrounds and visions on eHealth, and the strategies and conditions for the research and development of eHealth technologies. Despite their potential, the relationship between the visions on eHealth, proposed strategies, and research methods is obscure, perhaps due to a rather conceptual approach that focuses on the rationale behind the frameworks rather than on practical guidelines. In addition, the Web 2.0 technologies that call for a more stakeholder-driven approach are beyond the scope of current frameworks. To overcome these limitations, we composed a holistic framework based on a participatory development approach, persuasive design techniques, and business modeling.
To demonstrate the impact of eHealth technologies more effectively, a fresh way of thinking is required about how technology can be used to innovate health care. It also requires new concepts and instruments to develop and implement technologies in practice. The proposed framework serves as an evidence-based roadmap.
PMCID: PMC3278097  PMID: 22155738
eHealth; design; participation; implementation; evaluation; multidisciplinary approach; Health 2.0; Wiki; e-collaboration
24.  The Effect of Patient Narratives on Information Search in a Web-Based Breast Cancer Decision Aid: An Eye-Tracking Study 
Previous research has examined the impact of patient narratives on treatment choices, but to our knowledge, no study has examined the effect of narratives on information search. Further, no research has considered the relative impact of their format (text vs video) on health care decisions in a single study.
Our goal was to examine the impact of video and text-based narratives on information search in a Web-based patient decision aid for early stage breast cancer.
Fifty-six women were asked to imagine that they had been diagnosed with early stage breast cancer and needed to choose between two surgical treatments (lumpectomy with radiation or mastectomy). Participants were randomly assigned to view one of four versions of a Web decision aid. Two versions of the decision aid included videos of interviews with patients and physicians or videos of interviews with physicians only. To distinguish between the effect of narratives and the effect of videos, we created two text versions of the Web decision aid by replacing the patient and physician interviews with text transcripts of the videos. Participants could freely browse the Web decision aid until they developed a treatment preference. We recorded participants’ eye movements using the Tobii 1750 eye-tracking system equipped with Tobii Studio software. A priori, we defined 24 areas of interest (AOIs) in the Web decision aid. These AOIs were either separate pages of the Web decision aid or sections within a single page covering different content.
We used multilevel modeling to examine the effect of narrative presence, narrative format, and their interaction on information search. There was a significant main effect of condition, P=.02; participants viewing decision aids with patient narratives spent more time searching for information than participants viewing the decision aids without narratives. The main effect of format was not significant, P=.10. However, there was a significant condition by format interaction on fixation duration, P<.001. When comparing the two video decision aids, participants viewing the narrative version spent more time searching for information than participants viewing the control version of the decision aid. In contrast, participants viewing the narrative version of the text decision aid spent less time searching for information than participants viewing the control version of the text decision aid. Further, narratives appear to have a global effect on information search; these effects were not limited to specific sections of the decision aid that contained topics discussed in the patient stories.
The observed increase in fixation duration with video patient testimonials is consistent with the idea that the vividness of the video content could cause greater elaboration of the message, thereby encouraging greater information search. Conversely, because reading requires more effortful processing than watching, reading patient narratives may have decreased participant motivation to engage in more reading in the remaining sections of the Web decision aid. These findings suggest that the format of patient stories may be equally as important as their content in determining their effect on decision making. More research is needed to understand why differences in format result in fundamental differences in information search.
PMCID: PMC3875892  PMID: 24345424
personal narratives; decision aids; eye tracking; breast cancer
25.  Effects of using structured templates for recalling chemistry experiments 
The way that we recall information is dependent upon both the knowledge in our memories and the conditions under which we recall the information. Electronic Laboratory Notebooks can provide a structured interface for the capture of experiment records through the use of forms and templates. These templates can be useful by providing cues to help researchers to remember to record particular aspects of their experiment, but they may also constrain the information that is recorded by encouraging them to record only what is asked for. It is therefore unknown whether using structured templates for capturing experiment records will have positive or negative effects on the quality and usefulness of the records for assessment and future use. In this paper we report on the results of a set of studies investigating the effects of different template designs on the recording of experiments by undergraduate students and academic researchers.
The results indicate that using structured templates to write up experiments does make a significant difference to the information that is recalled and recorded. These differences have both positive and negative effects, with templates prompting the capture of specific information that is otherwise forgotten, but also apparently losing some of the personal elements of the experiment experience such as observations and explanations. Other unexpected effects were seen with templates that can change the information that is captured, but also interfere with the way an experiment is conducted.
Our results showed that using structured templates can improve the completeness of the experiment context information captured but can also cause a loss of personal elements of the experiment experience when compared with allowing the researcher to structure their own record. The results suggest that interfaces for recording information about chemistry experiments, whether paper-based questionnaires or templates in Electronic Laboratory Notebooks, can be an effective way to improve the quality of experiment write-ups, but that care needs to be taken to ensure that the correct cues are provided.Graphical abstractScientists have traditionally recorded their research in paper notebooks, a format that provides great flexibility for capturing information. In contrast, Electronic Laboratory Notebooks frequently make use of forms or structured templates for capturing experiment records. Structured templates can provide cues that can improve record quality by increasing the amount of information captured and encouraging consistency. However, using the wrong cues can lead to a loss of personal elements of the experiment experience and frustrate users. This image shows two participants from one of our studies recording their experiment using a computer-based template
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-016-0118-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4759737  PMID: 26900406
Templates; Experiments; Experiment record; Context; ELN; User experience; Study

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