Clinical Study Fourteen-Year Long-Term Results after Gastric Banding
Hindawi Publishing CorporationCopyright Hindawi Publishing Corporation

Christine Stroh
Department of General, Abdominal and Pediatric Surgery
Municipal Hospital
Straße des Friedens 12207548GeraGermany

Ulrich Hohmann
Department of General, Abdominal and Pediatric Surgery
Municipal Hospital
Straße des Friedens 12207548GeraGermany

Harald Schramm
Department of General, Abdominal and Pediatric Surgery
Municipal Hospital
Straße des Friedens 12207548GeraGermany

Frank Meyer
Otto-von-Guericke University
39106MagdeburgGermany

Thomas Manger
Department of General, Abdominal and Pediatric Surgery
Municipal Hospital
Straße des Friedens 12207548GeraGermany

Francesco Saverio Papadia
Clinical Study Fourteen-Year Long-Term Results after Gastric Banding

Journal of Obesity
Hindawi Publishing Corporation201110.1155/2011/128451Received 13 August 2010; Revised 7 October 2010; Accepted 18 October 2010Correspondence should be addressed to Christine Stroh, email@example.com Academic Editor:
Background. Gastric banding (GB) is a common bariatric procedure that is performed worldwide. Weight loss can be substantial after this procedure, but it is not sufficient in a significant portion of patients. Long-term rates for associated complications increase with every year of follow up, and only a few long-term studies have been published that examine these rates. We present our results after 14 years of postoperative follow up. Methods. Two hundred patients were operated upon form 01.02.1995 to 31.01.2009. Data collection was performed prospectively. In retrospective analysis, we analyzed weight loss, short-and long-term complications, amelioration of comorbidities and long-term outcome. Results. The mean postoperative follow up time was 94.4 months (range 2-144). The follow up rate was 83.5%. The incidence of postoperative complications for slippage was 2.5%, for pouch dilatation was 9.5%, for band migration was 5.5% and 12.0% for overall band removal. After 14 years, the reoperation rate was 30.5% with a reoperation rate of 2.2% for every year of follow up. Excess weight loss was 40.2% after 1 year, 46.3% after 2 years, 45.9% after 3 years, 41.9% after five years, 33.3% after 8 years, 30.8% after 10 years, 33.3% after 12 years and 15.6% after 14 years of follow up. Conclusion. The complication and reoperation rate after GB is high. Nevertheless, GB is still a therapeutic option in morbid obese patients, but the criteria for patient selection should be carefully evaluated.

Introduction

Demographic studies worldwide have shown a recent increase in the incidence of morbid obesity, and this condition has been identified as a major public health problem. Nonoperative treatments for weight loss offer limited success and have a high rate of failure. Currently, a Swedish obese subject study has shown that operative treatment of morbid obesity is the only effective therapy [1]. Besides weight reduction, the amelioration of obesity-associated comorbidities is an important consequence of surgical treatment of morbid obesity. Among the variety of restrictive and malabsorptive bariatric procedures, gastric banding has been performed in most countries worldwide. In Germany, GB (besides RYGBP) is the most performed bariatric procedure according to data from a nationwide survey [2].

Because GB has the advantages of being less invasive and a reversible procedure, it has been the procedure of choice for the treatment of morbid obesity for several years in Europe. In 2009, it was the most performed bariatric procedure in the USA.

The aim of our study was to analyze long-term results after GB from 1995 to 2009 and to assess the efficacy of GB for weight loss, improvement of comorbidities, and the incidence of complications.

Materials and Methods

Patients.

Between February 1st 1995 and January 31st 2009, in 200 morbid obese patients, GB was performed at the Municipal Hospital in Gera, Germany. All patients were carefully selected according to IFSO-Guidelines [3].

Data collection was performed prospectively and analyzed retrospectively.

Preoperative characteristics of the patients are listed in Table 1. The operation was performed in 41 (20.5%) men and 159 (79.5%) women with a mean age of 41.5 years. The preoperative BMI was 47.9 kg/m 2 . The mean BMI in men was  we performed all GB procedures (31.5%) with the pars flaccida technique by a standardized laparoscopic approach to avoid posterior slippage. The space between the left crus and the band was closed to avoid lateral slippage by a stitch between the greater curvature and the left crus. We formed a small pouch of less than 20 cc. The pouch was secured by 3 to 5 gastrogastric stitches to avoid anterior slippage.

Postoperative Management.

The patients were followed in our hospital. The first consultation and clinical examination was performed six weeks postoperatively and then every three months for the first two years of followup. Followup examinations were performed twice a year or whenever needed after the second postoperative year.

A liquid diet was recommended for the first 5 days postoperatively. A normal diet was introduced thereafter. During each visit, a standardized fup was performed with documentation of weight, eating behavior, and a short clinical examination. Band adjustments were very rare. The band was adjusted only in cases of weight loss less than 2 kg per month or a less than 25% change in the EBWL after 3 months. In the case of discomfort from a normal diet or reflux symptoms, the filling of the band was reduced.

The injection volume depended on the weight loss and the patient's tolerance as well as his or her eating behaviors.

Results

Followup.

Followup data were available from 83.5% of patients. The mean followup time was 94.4 (6-144) months.

Slippage

Pouch Dilatation (PD).

During the postoperative course, the great majority of our patients developed PD (9.5%, n = 19). A total of 12 patients were operated on by an open technique, and 7 patients underwent a laparoscopic technique. After introduction of the pars flaccida technique, pouch dilatation no longer occurred.

Band Migration.

Band migration occurred in 5.5% (n = 11) of cases. In all patients, the operation was performed using a perigastric placement of the band.

Band Removal.

Band removal was performed in 24 (12%) patients. Five patients wished to have the band removed due to discomfort. In one patient, the band was removed due to her excellent excessive weight loss. In 18 patients, the band had to be removed in case of longterm complications such as band migration in 11 cases and slippage in 2 cases. In 2 cases, the band was removed at an out-of-town hospital without any described reason after a cholecystectomy. Epiphrenic esophageal diverticula, gastric wall necrosis, and acute peritonitis were the reasons for band removal among the other patients (Table 3).

Weight Loss after Gastric

Banding. Weight loss after gastric banding is summarized in Table 5.

Changes in Comorbidities.

During the postoperative period, 85.7% of patients who had previously suffered from diabetes prior to bariatric surgery could significantly reduce their insulin doses. In 14.3% of patients, diabetes was resolved, completely. Amelioration of hypertension was observed in 82.2% of patients.

Postoperative Mortality.

There was no early postoperative mortality. During the followup period, four patients (3 female and 1 male) died. The mean age of these patients was 64.1 (range 50.5-70) years. Two patients died due to their severe comorbidities 6 months and 96 months after GB. One patient died due to gastric cancer 36 months after GB [4]. Another woman died after repair of an abdominal wall hernia 132 months after band implantation.

Discussion

GB is beside RYGBP the most frequently performed bariatric operation worldwide. According to the data of a metaanalysis study, this procedure has been carried out in 95% of countries performing bariatric surgery [5].

When GB was introduced, the results were excellent in comparison with other restrictive bariatric procedures.

In the literature, only a few prospective randomized studies have been reported. These studies compared GB with RYGBP or/and SG. In addition, randomized trials comparing different kinds of bands (low-and high-pressure bands) were also performed. Single center studies report data with low evidence on the complication rates, outcome, and amelioration of comorbidities. In general, patient's outcome after GB is influenced by the incidence of long-term complications. These include slippage, pouch dilatation, and band migration as well as port-site complications and esophageal dilatation. Nevertheless, there are only a few studies examining long-term results with a time period longer than 10 years available in the literature.

In our clinical experience, the results obtained after 14 years show a high complication rate and a weight regain after the 5th year of followup. These data are comparable with data published by Lanthaler et al. [6]. In their data describing young patients, weight loss was very successful within the first 4 years postoperatively [6]; thereafter, the BMI increased slowly. However, the reason for weight regain after that time was not described in detail. In our experience, most of the patients change their eating behaviors to liquids and sweets leading to a high calorie intake.

Nevertheless, an improvement in obesity-related comorbidities was observed in most patients. However, complete resolution of diabetes was less than reported in a published meta-analysis [4]. Reasons for this difference may have been the high BMI of our patients and the early onset of diabetes prior to surgery.

In our retrospective examination with preoperative data collection, the majority of our patients were female, which is consistent with data from the literature [5,6]. The BMI (47.5 kg/m 2 ) in our patients was higher than in most published studies due to the reimbursement problems of bariatric surgeries in Germany.

Slippage and Pouch Dilatation.

Over time, the complication rates for incidences of slippage and pouch dilatation decreased. The drop in the complication rate was the result of a switch from the perigastric to a pars flaccida technique as well as the introduction of next generation bands and the development of band devices especially made for the connecting tube and the port system.

In fact, there was a decrease in the slippage rate from 3.6% in the perigastric approach to 0% in the pars flaccida technique [7].

Pouch dilatation is a long-term complication after GB. The incidence of pouch dilatation is influenced by the surgical approach (open versus laparoscopic) and the technique (perigastric versus pars flaccida). Opening the lesser sac during open band placement leads to a higher incidence of pouch dilatation than the laparoscopic approach, which creates a small retrogastric channel. Data in the literature examining the incidence of pouch dilatation are mostly heterogeneous because most studies include different approaches and techniques. Otherwise, there are only a few reports with a followup period of more than 5 years.

Band Migration.

Intragastric band migration is characterized by a "silent" migration of the band into the stomach [8,9]. Peritonitis symptoms are usually absent, and there are limited retrospective data obtained from long-term studies available [10,11]. The incidence of band migration ranges from 0.6% to 14.4% according to the literature [10][11][12][13]. In a few studies, band migration has been considered as a complication associated with the first 2 postoperative years, which is caused by intraoperative gastric perforation [6,[14][15][16]. In our data, most patients with band migration had an uncritical uptake of nonsteroidal antirheumatic agents, bronchospasmolytic drugs, and anticoagulant substances. Specifically, 26.6% of patients were treated with nonsteroidal antirheumatic substances, 20.2% with anticoagulant substances, and 0.6% with bronchospasmolytic drugs. Therefore, in our opinion, these medications should be considered as potential causes of band migration. Chronic inflammation at the tissue area covered by the band could be a further reason for developing erosion. In our experience, band migration occurs by 30-86 months postoperatively [17]. In addition, the erosion rate has been shown to increase over the long-term followup period [18].

Band erosion can lead to a life-threatening condition in cases of upper gastrointestinal bleeding and bowel obstruction. Therefore, finding a correct diagnosis is essential. In our study, we did not see any port infection in the first 3 postoperative months and after band filling. In the literature, port infection has been reported to be the first symptom of erosion [19]. However, our own data revealed varying intervals between the onset of port infection and the occurrence of erosion.

Thus, the treatment depends on symptomatology. We favor band removal in cases of complete erosion using gastroscopy and an AMI Band Cutter (CJ Medical, Buckinghamshire, Great Britain) [17].

In the literature, a correlation of erosion rate with the band type (high-pressure versus low-pressure bands) has not been described [20].

At the end of the 1990s, repositioning of the band in cases of slippage and pouch dilatation was widely performed. However, data from our study indicated a higher incidence of gastric band migration, and data in the literature have shown disappointing results [17,18,21]. Thus, in cases of slippage and pouch dilatation, most published results and our findings reveal no indication for rebanding [18]. We believe band removal in cases of erosion accompanied by a simultaneous "rebanding" should not be performed because there is a potential risk of infection of the new band. This conclusion is based on the different causes of band erosion, a significantly higher migration rate following intraoperative gastric perforation and the currently available data in the literature. In addition, because of the high failure rate after band revision, a conversion to a Roux-en-Y gastric bypass or biliopancreatic diversion needs to be considered.

Amelioration of Comorbidities.

According to data from a German nationwide survey on bariatric surgery, our reported patients had a significantly higher age and BMI compared with data obtained in the meta-analysis on bariatric surgery patients [5]. In addition, significantly more patients suffered from type-II diabetes mellitus and arterial hypertension in our study. Thus, the consequential higher rate of comorbidities was due to the occurrence of a severe metabolic syndrome. However, the impact of a high preoperative BMI on weight reduction needs to be investigated through a long-term study.

Reoperation

Rate. The reintervention rate per year of followup in our patients was 2.2%. These data correspond to the literature, which reports a reoperation rate between 3 and 4% per year of followup [18].

Excess Weight Loss.

Concerning the EBWL, the literature reports an EBWL of 47.5% from a meta-analysis study. This meta-analysis reported a progression in weight loss for the first 3 years after GB, which was followed by a stable level of weight loss out to 8 years with no detectable regain of weight [22]. Data of long-term studies with a followup time of more than five years are shown in Table 5. Studies comparing weight loss after perigastric technique to pars flaccida approaches have not shown any influence of operation technique on EWL [23]. GB results in a continuous weight loss during the first 3 years and is sustained for up to 5 years. These results are in concordance with data from the Italian Band Group, but not with weight loss patterns observed in Australian data [14,23]. We believe the patients in our study had a lower weight loss due to the higher preoperative BMI and the higher incidence of diabetes type II. For better long-term results, we suggest interdisciplinary teamwork to reduce long-term complication rates, increase weight loss, and ameliorate comorbidities.

Conclusion

GB has been shown to be a safe and efficient bariatric procedure when performed by an experienced surgeon Journal of Obesity 5 using a standardized operation technique. The importance of a close and standardized followup by an experienced multidisciplinary team and the surgeon can result in a decreased complication rate, increased weight loss, and reduced comorbidities.

Furthermore, there are no data in the literature addressing specific criteria, which allow the selection of patients for either restrictive or malabsorptive procedures so as to improve final outcome. To guarantee long-term success after bariatric surgery and to avoid complications, particularly when following combined procedures, lifelong postoperative care is required, which is a specific concern for obesity surgery. Moreover, there is a limited amount of longterm followup data available in the literature and these are from just a few single center studies. Thus, researchers and clinicians should prospectively enroll all patients as indicated by the German multicenter observational study for quality assurance in obesity surgery. This study annually registered parameters such as weight reduction, amelioration of comorbidities, and long-term complications. Subsequently, these data were used to assess the surgical treatment of morbid obesity in Germany [2].

Abbreviations

EWL: Excess weight loss Fup:

.
The slippage rate was 2.5% (n = 5). After an open approach in 3 patients, slippage occurred with a mean followup time of 10.3 (1-24) months. After laparoscopy in 2 patients, slippage occurred with a mean followup time of 18 (12-24) months. The operation was performed in all patients in perigastric approach. After introduction of pars flaccida technique, slippage rate decreased to zero.

Table 1 :
1Demographic data.Gender
Age
BMI
(%)
(years)
(kg/m 2 )
Men
20.5
41.5
52.0
Women
79.5
41.7
46.8
Total
100.0
41.5
47.9

Table 2 :
2Operation data. Operative Technique and Data. Between February 1st 1995 and June 15th 1997, 39 (19.5%) procedures had been performed by one surgeon using open approach technique. In June 1997, we started the GB procedure with a laparoscopic technique used in 80.5% of operations (Table 2). From June 1997 to February 2001, all Lap Bands were placed using perigastric approach. This technique was used in 68.5% of patients. Conversion rate of laparoscopic technique was 7.4% during the first 100 laparoscopic operations. After introduction of the pars flaccida technique in March 2001,Patients total
Mean operation time
(min)
Total
(n)
200
128.1
Open surgery
(n)
39
117.7
Conversion rate
(n)
12
253.3
Laparoscopic approach (n)
161
126.1
Perigastric approach (n)
137
141.3
Pars flaccida technique (n)
63
99.5

52.0 kg/m 2 , which was significantly higher than in women
(46.8 kg/m 2 ).

2.2.

Table 3 :
3Reasons for band removal.Patients
(n)
24
Overall removal rate
(%)
12.0
Discomfort
(n)
5
Excellent excessive weight loss
(n)
1
Migration
(n)
11
Slippage
(n)
2
During cholecystectomy (at out-of-town hospitals) (n)
2
Peritonitis
(n)
1
Stomach wall necrosis
(n)
1
Epiphrenic esophageal diverticula
(n)
1

Table 4 :
4Overall reoperation rate(n)
( % )
Removal rate without slippage and migration
9
4.5
Slippage
5
2.5
Pouch dilatation
19
9.5
Migration
11
5.5
Disconnection
9
4.5
Reoperation due to failure
8
4.0
Patients in total
61
30.5
Reoperation rate per year of FUP
2.2

patients, the band was explanted without any substitution.
The total number of patients requiring reoperation was
significantly higher in the open approach group (31.3%, n =
43) versus the pars flaccida group (3.2%, n = 3). Data for
reoperation are shown in Table 4. The reoperation rate was
2.2% per year.

Table 5 :
5Excess body weight loss in comparison with literature.Author
Year
n
EWL in %
Y e a r so fF U P
1
2
3
5
8
1 0
1 2
1 4
Belachewet al. [24]
2002
763
40
50.0
50
O'Brien and Dixon[25]
2002
706
47
52
53.0
57.0
Weiner et al. [26]
2003
984
59.3
Martikainen et al. [27]
2004
123
36
38
30.0
Biagini and Karam [28]
2008
591
66.7
72.6
82.3

2009
200

40.2
46.3
45.9
41.9
33.3
30.8
33.3
15.6
Strohet al. [2]
n = 175
n = 157
n = 147
n = 122
n = 80
n = 53
n = 15
n = 1

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Journal of NeuroEngineering and Rehabilitation Development of an automated speech recognition interface for personal emergency response systems

Melinda Hamill
The Institute of Biomaterials and Biomedical Engineering
University of Toronto
TorontoONCanada

Vicky Young firstname.lastname@example.com
Department of Occupational Science and Occupational Therapy
Intelligent Assistive Technology and Systems Lab
University of Toronto
TorontoONCanada

Jennifer Boger email@example.com
Department of Occupational Science and Occupational Therapy
Intelligent Assistive Technology and Systems Lab
University of Toronto
TorontoONCanada

Alex Mihailidis firstname.lastname@example.com
Department of Occupational Science and Occupational Therapy
Intelligent Assistive Technology and Systems Lab
University of Toronto
TorontoONCanada

Journal of NeuroEngineering and Rehabilitation Development of an automated speech recognition interface for personal emergency response systems
10.1186/1743-0003-6-26BioMed Central Page 1 of 11 (page number not for citation purposes) Methodology * Corresponding author
Background: Demands on long-term-care facilities are predicted to increase at an unprecedented rate as the baby boomer generation reaches retirement age. Aging-in-place (i.e. aging at home) is the desire of most seniors and is also a good option to reduce the burden on an over-stretched long-term-care system. Personal Emergency Response Systems (PERSs) help enable older adults to age-in-place by providing them with immediate access to emergency assistance. Traditionally they operate with push-button activators that connect the occupant via speaker-phone to a live emergency call-centre operator. If occupants do not wear the push button or cannot access the button, then the system is useless in the event of a fall or emergency. Additionally, a false alarm or failure to check-in at a regular interval will trigger a connection to a live operator, which can be unwanted and intrusive to the occupant. This paper describes the development and testing of an automated, hands-free, dialogue-based PERS prototype.Methods: The prototype system was built using a ceiling mounted microphone array, an opensource automatic speech recognition engine, and a 'yes' and 'no' response dialog modelled after an existing call-centre protocol. Testing compared a single microphone versus a microphone array with nine adults in both noisy and quiet conditions. Dialogue testing was completed with four adults.Results and discussion:The microphone array demonstrated improvement over the single microphone. In all cases, dialog testing resulted in the system reaching the correct decision about the kind of assistance the user was requesting. Further testing is required with elderly voices and under different noise conditions to ensure the appropriateness of the technology. Future developments include integration of the system with an emergency detection method as well as communication enhancement using features such as barge-in capability.Conclusion:The use of an automated dialog-based PERS has the potential to provide users with more autonomy in decisions regarding their own health and more privacy in their own home.

Background

Falls are one of the leading causes of hospitalization and institutionalization among older adults 75 years of age and older [1,2]. Studies estimate that one in every three older adults over the age of 65 will experience a fall over the course of a year [3,4].

In addition to an overall decline in health, aging is also often accompanied by significant social changes. Many older adults live alone and become isolated from family and friends. Social isolation combined with physical decline can become significant barriers to aging independently in the community, a concept known as agingin-place [5]. Aging-in-place allows seniors to maintain control over their environments and activities, resulting in feelings of autonomy, well-being, and dignity. In addition to promoting feelings of independence, aging-in-place has also been shown to be more cost-effective than institutional care [6]. However, while aging-in-place is often ideal for both the individual and the public, elders are faced with pressure to move into nursing facilities to mitigate the increased risk of falls and other health emergencies that may occur in the home when they are alone.

Personal emergency response systems (PERSs) have been shown to increase feelings of security, enable more seniors to age-in-place, and reduce overall healthcare costs [7][8][9]. The predominant form of PERSs in use today consist of a call button, worn by the subscriber on a neck chain or wrist strap, and a two-way intercom connected to a phone line. If help is needed, the subscriber presses the button and a call is placed immediately to a live operator via the intercom. The operator has a dialog with the subscriber, determining the problem and co-ordinating the necessary response, such as calling a neighbour, relative, or emergency response team.

Drawbacks to this approach include the possibility of a high rate of false alarms to the emergency call centre and the subsequent inundation of worried and unsolicited calls to the subscriber. In a study of older women who owned a PERS, many expressed apprehension of unexpected voices and visits from strangers, resenting the need to figure out "why a stranger is talking in my house" and "finding that they show up to check on me" [10]. False alarms typically occur as a result of an accidental button press or failure, on the part of the user, to respond to regularly scheduled check-ins. According to one-call centre manger, false alarms may account for as many as 85% of call-centre calls [11]. False alarms where first responders are sent to the home may further burden limited emergency resources and delay emergency responders from attending to true emergencies. Apart from the worry it may cause family and friends, false alarms may also result in financial losses because of reduced work hours for a friend or relative attending to a false alarm, or resulting from emergency responders having to break down a door or window to get into a home.

Additionally, subscribers to PERSs are not always pleased with the system's usability and aesthetics. Many older adults feel stigmatized by having to wear the push-button activator and current systems place a substantial burden on the subscriber as he/she must remember to wear the button at all times and must be able to press it when an emergency occurs (i.e., the subscriber must be conscious and physically capable) [9]. Finally, some older adults are hesitant to press the button when an emergency does occur because they either downplay the severity of the situation or are wary of being transferred to a long term care facility [8,9].

To circumvent these deficiencies several research groups are exploring the possibility of incorporating PERSs into an intelligent home health monitoring system that can respond to emergency events without requiring the occupant to change his/her lifestyle. Some researchers have devised networks of switches, sensors, and personal monitoring devices to identify emergency situations and supply caregivers and medical professionals with information they need to care for the individual being monitored [12,13]. Through these types of PERSs, the user does not need to wear a physical activator or push anything for an emergency situation to be detected.

One novel technique developed employs computer vision technology (e.g., image capture via video camera) and artificial intelligence (AI) algorithms to track an image of a room and determine if the occupant has fallen [14]. Alternatively, Sixsmith and Johnson [12] used arrays of infrared sensors to produce thermal images of an occupant. The research presented in this paper assumes that a tracking system similar to these will be used to trigger an alarm to the PERS. Regardless of the detection method, once a PERS alarm has been triggered, there is a need to coordinate the response effort with the user. Involving the user allows him/her to maintain control over decisions regarding his/her own health and enables the PERS to provide the appropriate type of response. However, just as with a commercially available push-button triggered PERS, most of the automated PERSs under development immediately connect the user with a call centre when an alarm is triggered [15].

The research described in this paper presents the initial phase of a larger research study investigating the feasibility of using automated dialog and artificial intelligence techniques to improve the usability and efficiency of PERSs for older adults during an emergency situation. In particular, this first phase focuses on demonstrating the possibility of using automatic speech recognition (ASR) with a microphone array and speech recognition software to enable communication and dialog as a means of interfacing with a PERS.

The new generation of ASR technology has achieved significant improvements in accuracy and commercial viability, as demonstrated by their presence in many fields, such as Interactive Voice Response (IVR) telephone systems, medical and business dictation, home and office speech-to-text computer software and others. ASR may be able to provide a simple, intuitive, and unobtrusive method of interacting directly with the PERS, giving the user more control by enabling him/her to chose the appropriate response to the detected alarm, such as dismissing a false alarm, connecting directly with a family member, or connecting with a call centre operator. The following is a description of the prototyping and preliminary testing of an ASR PERS interface, as well as a discussion of other areas within PERS where ASR could provide enhanced information about the state of the subscriber. Although the research described herein does not specifically test with older adult subjects, the results of the research are critical in setting the foundation for future prototype development and testing that will involve older adult subjects.

Methods

Development of a dialog-based PERS prototype

As shown in Figure 1, the development of the prototype occurred with two parallel stages of research. The left branch in Figure 1 (Stage 1) represents the analysis and definition of the dialog that occurs between users and a live call centre in a current, commercially available PERS to develop how the prototype should respond to a detected fall. This includes the selection of software used to run the ASR dialog. The right branch (Stage 2) represents the selection and evaluation of the hardware used Prototype development process for the prototype. The two branches were combined for the building and testing of the prototype (Stage 3).

Stage 1 -Definition of dialog and dialog implementation

To promote ease of use and compliance, a goal of this research was to design the automated dialog to be intuitive, effective, and friendly. Since current PERSs have included extensive research on how to interact politely, clearly and efficiently with a subscriber, the dialog for the prototype was based on the existing protocol for the Lifeline Systems Canada call centre. For example, Lifeline operators are instructed to initialise contact with a subscriber with a friendly introduction followed by the open ended question "How may I help you?". The dialog then flows freely until the operator and the subscriber determine together who, if anyone, should be summoned to help.

The need for a dialog is based on the inherent uncertainty about the state of the occupant and about what triggered the alarm. Therefore, the goal of the dialog between the occupant and the PERS is to determine if the alarm is genuine, and if so, the appropriate action to take. To arrive at this goal (i.e., deciding what action to take), the system navigates through a series of verbal interactions resulting in a dialog with the occupant. Different actions available to the prototype are listed in Table 1.

Actions are selected through a dialog exchange between the user and the system. The dialog structure for the prototype is depicted in Figure 2. Human factors experiments conducted on computer voice-based systems have demonstrated highest user satisfaction when automated dialog is modelled after live operators [16]. Thus, the prompts have been developed to emulate the familiar and friendly tone of PERS operators, for example, by the use of personal pronouns ("would you like me to call someone else to help you?"), and pre-recording the names of the occupant and responders.

At each dialog node in Figure 2, the corresponding prompt was played over a speaker, then the speech engine was activated to obtain the occupant's answer though a microphone. For these tests, close ended "yes"/"no" questions were selected to create a simple binary tree dialog structure. Transition from one state to the next depended solely on the best match of the user's response to an expression in the grammar (i.e. either 'yes' or 'no'). Each prompt was pre-recorded and saved as separate audio files by the researcher.

When defining the algorithms used to run the user/system dialog, the goal was to create an architecture that would be flexible and adaptable so that it could be easily modified as the project evolved. The modularity offered by modern programming practices and speech application programming interfaces (APIs) allows for flexible and scalable design, and requires minimal rewriting to integrate or remove components at any level. Java Speech API (JSAPI) is a set of abstract classes and interfaces that allow a programmer to interact with the underlying speech engine without having to know the implementation details of the engine itself. Moreover, the JSAPI allows the underlying ASR engine to be easily interchanged with any JSAPI compatible engine [17].

The prototype was tested using the Sphinx 4 speech engine, an ASR written in Java that employs a Hidden Markov Model (HMM) approach for word recognition [18]. The recognition rates for several tests using Sphinx 4 have demonstrated a low word error rate under a variety of testing conditions. Furthermore, this speech engine is open source thus making it easy to use and develop when this application is expanded in the future.

An XML parser was created using Jakarta Commons Digester [19] to load a file containing the dialog and action states (specified in XML format) at runtime. The XML files for the PERS application were built by modifying the Voice XML standard [20], which is generally used  for voice enabled web browsing and IVR applications. By implementing the dialogs in separate XML files, the program code does not need to be recompiled in order to change the dialog. This is beneficial for testing different dialogs easily and allows for seamless customization of the system: a dialog for a user in a nursing home (who might want to be prompted for the nursing desk first) could be different from a dialog for a user in the community (who would be asked if they needed an ambulance first). Likewise, the grammar files (in JSGF format) and the prompt files (in .wav file format) were also separated from the code itself to allow for easy modifications. The modular composition of the prototype enables grammars and prompts that take into account the accent or language preference of the user to be deployed on a per-user basis. Indeed, the system can be easily executed with any dialog specified in the XML format.

Stage 2 -Selection and validation of hardware

For a speech-based communication system, it is vital that the quality of the user's vocal response is sufficient to be correctly interpreted by the ASR. As such, the choice of microphone is very important. Wearing a wireless microphone is not an ideal solution because, just as with pushbuttons, the user must remember and choose to wear the microphone in order to interact with the PERS. Additionally, the user must remember to regularly change the batteries on the wireless device. Ideally an automated PERS should communicate with the user from a distance in a natural fashion, without requiring the user to carry any devices or learn new skills to enable interaction. For this study, the researchers decided that the best location for the microphone would be in the centre of the ceiling of the monitored room as this was out of the way, central to the room, would provide the best sound coverage and could not be easily obstructed.

The close talking microphones typically used for commercial voice recognition applications (e.g., headphones or computer desk microphones) were not appropriate for use in this PERS application since these types of microphones would not be able to capture the occupant's voice with enough strength or clarity. Additionally, single ceiling mounted microphones can suffer from reverberations, echoes in the room, and a variety of background noises (e.g., TVs, radios, dishwashers, etc.) [21,22]. Microphone arrays attempt to overcome such difficulties and have been designed for two purposes: 1) sound localization; and 2) speech enhancement through separation by extracting a target noise from ambient sounds.

The microphone array used in the prototype was custom designed and constructed by researchers at the Department of Computer and Systems Engineering at the University of Carleton in Ottawa, Canada. The array consisted of eight, Electret, unidirectional microphones suspended in an X-shaped configuration. The microphone signal-tonoise ratio was greater than 55 dB, sensitivity was -44 dB (+/-2 dB) and the frequency response ranged from 100-1000 Hz. A low noise, low-distortion instrumentation amplifier was also built into the array system. The microphone array was mounted on the ceiling in the center of a 16 × 20 ft (4.9 × 6.1 m) room. Four microphones were spaced 10 cm apart along each axis of the array, which was calculated by the researchers from Carleton to be the optimal distance for dimensions of the testing area.

The microphone array described above was designed to specialise in speech enhancement through localisation by implementing delay-and-sum beamforming to enhance audio signals coming from the user and destructively lower the impact of sounds coming from elsewhere [23].

In delay-and-sum beamforming a different delay is calculated for each microphone to account for the time the reference signal needs to travel from a given location to the array. Delay-and-sum beamforming was accomplished by passing the location (presumably known by the PERS) to a Motorola 68 k processor mounted on the array, which used this information to apply the appropriate delay to each microphone. For the prototype, the location of the user was input manually, although it is anticipated that this will be done automatically in a fully functioning PERS as it will be continually tracking the location of the user. This information about the location of the occupant could be used to direct the array to "listen" to the exact spot where the occupant is sitting or laying, making it easier to hear the occupant in both PERS-occupant and human call center operator-occupant dialogs.

Test 1 -Performance of a single microphone versus a microphone array with beamforming

The first experiment was designed to test the array in two modes: 1) using a single microphone from the array; and 2) using the array with the beamforming algorithm tuned into a zone of interest.

The AN4 speech database developed by Carnegie Mellon University was selected to test the system. This database has been used in several batch tests throughout the development and evolution of the Sphinx speech engines [24]. The AN4 database has voices from 21 female and 53 male speakers and consists of spoken words and letters. For these tests, only the spoken words were used for a total of 1846 utterances (with 79 unique words). Figure 3 illustrates the pattern of attenuation expected from the microphone array for sounds in the mid-range of human speech (1850 Hz) coming from zone 9. AN4 was played over a single computer speaker located on the laboratory floor in zone 9 for each test. Neither the speaker's location nor volume changed during the tests. For the single microphone test, only one microphone on the array was turned on. In the case of the beamforming tests, all the microphones were used and the researcher manually entered the location of the AN4 speaker. To create ambient noise interference, a pre-recorded audio track of a bubbling kettle (with a signal to noise ratio (SNR) of approximately 6.7 dB) was played over a separate speaker. The kettle noise was played from zone 17, the spot that caused the most destructive interference with the AN4 speaker. The Sphinx 4 ASR was used to analyse both sets of tests. The output from the ASR was compared with the known data to determine recognition rates.

Test 2 -Testing "yes"/"no" word recognition rate

While the results from the beam-forming tests were conducted with a large vocabulary, it is hypothesised that ASR recognition would improve significantly with a simple two-word vocabulary consisting of "yes" and "no". A convenience sample of nine subjects, 4 male and 5 female, was used for this experiment. The subjects ranged from 20 to 30 years of age. Each subject was asked to sit in the same spot as the AN4 speaker used in the previous tests (depicted as zone 9 in Figure 3). The subject was asked to speak at their normal volume and say the words 'yes' and 'no' twice for three conditions for a total of twelve utterances per subject (108 words in total). The three conditions were: 1) bubbling kettle interference played in the same location as previous tests (zone 17 in Figure 3 -area of the most attenuation of the human voice); 2) bubbling kettle interference played directly under the array (zone 13 in Figure 3 -intermediate attenuation); and 3) no noise interference.

Stage 3 -Prototyping the PERS interface

The dialog system developed in Stage 1 and microphone array selected and tested in Stage 2 were combined into the architecture depicted in Figure 4. The response planning module executes the dialog and actions outlined in Figure 2. Pre-recorded actions selected by the system were played over the speaker. In this system only audio files were played, however in a working system a call would also be placed to the appropriate party.

Test 3-Efficacy of the prototype dialog

This test examined the overall efficacy of the prototype automated PERS dialog interface. A convenience sample of four subjects (3 male and 1 female, healthy and between the ages of 20 and 30) each conducted a set of three scenarios with the system, for a total of 12 dialogs. Before each dialog, the subject was asked to envision a scenario read to them by the researcher and then asked to interact with the prototype to get the recommended assistance. The three scenarios were: 1) they were injured and needed an ambulance, 2) they had fallen, but only wanted their daughter to come and 3) a false alarm.

The Response Planning Module employed the dialog structure outlined in Figure 2, and the ASR matched the subjects' responses to either yes or no.

Attenuation pattern for frequencies of 1850 Hz originating in zone 9 Figure 3 Attenuation pattern for frequencies of 1850 Hz originating in zone 9. Table 2 presents the recognition results for a single microphone versus beamforming using the AN4 database (Test 1).

Results

As seen in Table 2, tests showed about a 20% improvement in accuracy when beamforming was used, demonstrating that a microphone array using basic delay-andsum beamforming provides improved recognition results over a single microphone in the presence of moderate volume interference noise. After obtaining these results, further tests were performed at a SNR of approximately 0dB and resulted in no recognition by either the single microphone or the array.

The results of the yes/no recognition test (Test 2) are summarised in Table 3. There were no errors in the no noise condition, six errors when the noise was directly under the microphone and four errors in the zone of previous tests. As the accuracy of this test was significantly higher than the AN4 test, it was decided that the prototype dialog questions would follow a closed-ended, "yes"/"no" format.

When the prototype dialogue was tested through the use of scenarios (Test 3), all 12 tests concluded with the system selecting the desired action, despite a word error rate of 21% (11 errors in 52 words spoken). The reason for this was because the system confirmed the user's selection before taking an action (see Figure 2). The errors consisted of three substitutions (yes for no or visa-versa) and eight deletions (missed words). Most of the deletions were missed by the ASR because users were speaking their response while the message was still being played by the system.

Discussion

The results from tests with the prototype are encouraging. During the array testing, simple delay-and-sum beamforming resulted in a considerable improvement (20%) in the word recognition rate of the array over a single microphone. This improvement might be greater with more complex microphone array algorithms [25,26] and prefilters [22]. Additionally, further experimentation with the Sphinx 4 configuration parameters may result in increased ASR performance [27].

The "yes"/"no" tests have twofold results. Firstly, unsurprisingly the location of noise interference has an impact on the ASR's ability to correctly identify words. This suggests that the system performance will be affected by the location and presence of unwanted noise. Secondly, the reduction of the users' response to either "yes" or "no"

Prototype Architecture Figure 4 Prototype Architecture.  greatly improves ASR recognition. In this case, overall recognition rates for the beam-former increased from about 50% to 90%. This increase is very likely the result of the significant simplification of possible matches the ASR had to choose from. However, it must be taken into consideration that the AN4 tests were conducted by playing the database over (high quality) speakers, while the 'yes'/'no' tests involved live humans.

The full prototype test conducted in Stage 3 (Test 3), resulted in several important insights. First, although all of the errors made in Test 3 were corrected by the confirmation-nature of the dialog, there is still the possibility (4.5% given a word error rate of 21%) that 2 errors could occur in sequence, resulting in the PERS making the wrong decision. This is an unacceptably high error rate as the occupant must always be able to get help when it is needed. As such, there needs to be a method (or methods) that the occupant can use to activate or re-activate the system whenever s/he wishes. One option is to enable a unique "activation phrase" that the user selects during system set-up. When the user utters this activation phrase, a dialog is initiated, regardless of whether or not an emergency has been detected. To further improve system accuracy, information from a vision system tracking the occupant could be used to reduce uncertainty about a situation. For example, if the user is lying still on the floor, this information could increase the weighting across possible answers that lead to emergency actions as opposed to false alarms. This type of intelligent, multi-sensor fusion can be achieved though a variety of planning and decision making methods such as partially observable Markov decision processes (POMDPs) [28]. Regardless, it is vital that in the case of doubt about a user's response (or lack thereof), the system should connect the user to a live operator, thus ensuring that the user's safety is maximised.

Secondly, the test subjects in Test 3 quickly became accustomed to how the system worked and would often start responding while the system was still "speaking". As the microphone was not activated until after the system finished playing a prompt (so as to avoid the system interpreting its' own prompt as a user response), these responses were missed and would have to be repeated, causing some confusion and frustration. This highlights the necessity for the user to be able to "barge-in" while a prompt is in progress. This is especially important in a system designed for emergency situations, where the user may be familiar enough with the system to anticipate the last few words in a system dialog and may be too panicked or in pain to wait. Most telephone voice systems today have taken this property of dialog into account, and allow users to speak before the system has completed its side of the dialog (i.e. barge-in), however the separation of the phone earpiece and receiver makes this approach easier to implement over the telephone than it would be for the type of PERS described here. Nevertheless, it is an important feature that will be investigated in future designs.

The literature has conflicting opinions on the comfort of seniors with recorded voices [10,29]. There is also a lack of evidence on whether an automated system would be appropriate for emergency situations where users may be under duress. Further research is needed to determine whether a recorded voice would quell or create confusion and/or discomfort and also whether occupants can attend to a series of directed questions while in a crisis. Additionally, tests with older adults would provide feedback in terms of usability and acceptability. As older adults represent the majority of targeted users of this technology, these questions must be well investigated and answered with the intended user population.

Finally, it must be stressed that although this paper presents promising preliminary research towards a new alterative to the current PERS techniques, more research is necessary to improve interactions with the user and to make the system more robust. While false positives (i.e., false alarms) can be annoying and costly, false negatives (i.e., missed events) must never occur as this could place the life of the occupant in jeopardy. Testing involving different software, hardware, and environment choices, using larger, more comprehensive groups of test subjects is needed. Only after such extensive testing with subjects in real-world settings will dialog interface technology be ready for the mass market.

Although the dialog program architecture for this prototype is fairly simple and deterministic, it was created with a modular architecture into which other algorithms could be easily applied. For instance, by using appropriate abstract classes and implementations, methods such as decision theoretic planning, such as a Markov decision process (MDP) [30] or POMDP [11] based approach, could be applied in the future to converge on dialogs that were most effective for each particular user.

In general, this prototype demonstrates the improved ability of a microphone array to remove noise from the environment compared to a single microphone. This enhances ASR accuracy and also allows for easier communication between a call centre representative and the occupant. Importantly, the successful recognition of most false alarms could significantly reduce false alarm call volumes in current PERS call centres, allowing operators to focus on real emergencies.

Limitations

Hearing loss is extremely common among seniors [31] and the loud volume settings on TVs and radios could lead to zero or even negative SNR. Therefore, before it can be implemented in a home environment, improvements in ASR performance will be needed to ensure the PERS interface is robust with smaller SNR, as well as non-uniform noise that contains human speech (e.g. TV, radio).

These tests were limited in the type of voice samples used.

The system was tested with users under calm, casual circumstances. It will be important to conduct tests on voices in emergency situations, either live or using recorded conversations from call centres, in order to ensure speech recognition performance is upheld when a person may be shaken by a fall or other crisis in the home. Secondly, these experiments were limited to a younger adult sample. It is important that tests be run with older adults on a system that has been trained using a database of older adult voices. The authors are currently working to build such a database. Limited work in comparing the success rate of ASR for various age groups indicates that differences may exist [32,33]. Finally, tests should also be conducted with people of different backgrounds who have strong accents to assess the affect on accuracy and determine the extent of customizations that would be needed [34].

Conclusion

Implementing ASR in the domain of PERS is a complex process of investigating and testing many tools and algorithms. The modularity of the code and of the components used in this study will facilitate the optimisation of the ASR and microphone array parameters, the addition of more complex dialog states, and the potential addition of statistical modelling methodologies, such as techniques involving planning and decision making.

Although the prototype did not perform perfectly, accuracy was significantly improved by limiting the vocabulary to 'yes' and 'no'. By including a confirmation for each action that the system was about to take, the prototype was able to overcome errors and successfully determine the proper action for all test cases. As such, the prototype designed and tested in this study demonstrates promising potential as a solution to several problems with existing systems. Notably, it provides a simple and intuitive method for the user to interact with PERS technology and get the type of assistance he/she needs. Having an automated, dialog-based system provides the occupant with more privacy and more control over decisions regarding one's own health. Additionally, the microphone array system proposed in this research requires only one device to be installed per room in the home or apartment. If coupled with automatic event detection, such as a computer vision-based system, this would be much simpler to install and maintain than other proposed automated PERSs, which generally use a multitude of sensors or RFID tags throughout the home. These advantages would likely translate into a significant reduction in non-compliance, as greater burden would be transferred from the user to the technology.

The next phase of research is currently underway and is focused on improving the robustness of the automated dialog-based and intelligent PERS specifically for older adults. An older adult speech corpus containing emergency type speech in Canadian English is being developed for this purpose. Once completed, this older adult speech corpus will be used to train the ASR component of the prototype PERS. We hypothesize that an ASR system trained with older adult speech in-context will be more effective than an ASR system trained with non-older adult speech out-of-context. In addition, older adult voices will be recorded in mock emergency situations and will be used to test the prototype PERS system. The decision making and dialogue capability of the automated PERS will also be further refined and tested possibly with a slightly larger vocabulary (e.g., help, ambulance), a probabilistic decision-making model, and/or a more complex language model. To enhance system flexibility, the ability to bargein at any time is also being explored. Once the system is operational, quantitative and qualitative system and usability testing with older adult subjects will be conducted.

Figure 1
1Prototype development process. Stage 1 -Definition of dialog and dialog implementation; Stage 2 -Selection and validation of hardware; Stage 3 -Prototyping the PERS interface.

Flow diagram of system dialog Figure 2
2Flow diagram of system dialog.

Table 1 :
1Actions available to the PERS prototypeEMSA call is placed to Emergency Medical Services (EMS).Responder 1A contact person from a list that is pre-defined by the user. When compiling this list, the nominated responder is notified and must give consent to respond to emergency calls. Responders can include neighbours, friends, and family.OperatorConnect to a live operator. This option can be accessed by the user. It is also the default action the system takes if it does not detect a response from the user or cannot determine which response the user wishes to initialise.Action Name
Action Description

False Alarm
Accidental alarm -no action needed.

Responder 2
See description for Responder 1.

Table 2 :
2Results of AN4 batch tests at SNR of ~6.7 dB

Single Microphone
Beamforming

Words Played
1846
1846

Total Errors
1302
924

Substitutions
401
371

Insertions
16
7

Deletions
885
546

Accuracy
29.5%
49.9%

Table 3 :
3ASR Yes/No vocabulary recognition results

Scenario 1 Scenario 2 Scenario 3 Overall

Words read
36
36
36
108

Total Errors
4
6
0
10

Accuracy
89%
83%
100%
93%

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AcknowledgementsThe authors would like to acknowledge the support of Lifeline Systems Canada, for contributing their time, resources and expertise in the area of PERSs.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsMH carried out the experiments, background research, analysis and interpretation of the results and drafting of the article. AM conceived of the study and participated in the concept development, testing and literature survey. VY participated in the background research, drafting of the article and is performing the next phase of the research. JB assisted with the system design and testing, data analysis, and drafting the article. All authors have read and approved the final manuscript.
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Identification of evolutionarily meaningful information within the mammalian RNA editing landscape
2014

Yiannis A Savva
Department of Molecular Biology, Cell Biology and Biochemistry
Brown University
185 Meeting St02912ProvidenceRIUSA

Robert A Reenan firstname.lastname@example.com
Department of Molecular Biology, Cell Biology and Biochemistry
Brown University
185 Meeting St02912ProvidenceRIUSA

Identification of evolutionarily meaningful information within the mammalian RNA editing landscape

Genome Biology
151032014R E S E A R C H H I G H L I G H T See related research by Pinto et al., http://genomebiology.com/2014/15/1/R5 * Correspondence: article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A large comparative genomic sequence study has determined the extent of conservation between RNA editing sites within the mammalian evolutionary tree.Expansion of the RNA editing universe

Generating cellular proteomes relies on the faithful decoding of genetic information. A complex network of cellular machines transcribes DNA into matured processed mRNA that is then translated into protein products, which are used by the cells to carry out basic biological functions. It is widely accepted that organismal complexity arises via the expansion of the genetic information potential by post-transcriptional modifications, such as alternative splicing and RNA editing. The latter is mediated in metazoans by a highly conserved protein family known as adenosine deaminase acting on RNA (ADAR) [1]. These enzymes hydrolytically deaminate adenosines to inosines (A-to-I) in double-stranded RNA (dsRNA) substrates. Ato-I RNA editing generates subtly different protein products by altering the primary sequence of target genes, since upon translation the ribosomal machinery interprets inosines as guanosines, leading to A → G substitutions ( Figure 1a). Therefore, electropherograms derived from edited cDNAs include A/G mixed peaks, which are considered to be a hallmark of A-to-I RNA editing. A decade ago, only few editing sites had been known to exist due to their accidental discovery by comparison of cDNA to genomic DNA sequences. However, a comparative genomics approach in Drosophila melanogaster uncovered a phylogenetic signature of RNA editing [2]. Since ADARmediated editing ensues through the formation of highly structured and frequently complex dsRNA substrates, necessary cis-regulatory elements should be highly conserved across Drosophila species. Indeed, cis-elements that promote imperfect dsRNA formation in pre-mRNA, also known as editing complementary sequences (ECS), usually found in introns, are highly conserved (Figure 1a). It is generally thought that the nature of the structural imperfections in these dsRNAs lend the specificity in determining which adenosines are edited by ADAR. In addition, sequence conservation is higher in exonic sequences near editing sites when compared with adjacent exons due to the functional constraints imposed by RNA structure. Using this pattern of evolutionary conservation led to the discovery of approximately 50 new editing sites in 16 different genes. Intriguingly, the conserved editing sites were found to be present in genes encoding proteins that are involved in electrical and chemical neurotransmission, including synaptic release proteins and voltage-gated and ligand-gated ion channels. To further understand the biological significance of RNA editing, contemporary studies use deep sequencing technologies to identify novel RNA editing sites. During the last decade, deep sequencing analysis rapidly expanded the RNA editing landscapes in various organisms, including humans, mouse and Drosophila. However, the extent of evolutionary conservation between the numerous mammalian RNA editing sites across the evolutionary tree is currently unknown.

The RNA editing enigma RNA editing sites are scattered within the human, mouse and Drosophila transcriptomes. Geographically, editing sites are found in both coding regions (exons) and in noncoding regions (5′ UTRs, 3′ UTRs, introns and intergenic) throughout genomes. Another theme from the deep-sequencing era is that much of the informational content of genomes is transcribed into non-coding RNA,  Figure 1 An overview of RNA editing. (a) Specific RNA editing occurring in a pre-mRNA. The nascent transcript folds into a complex dsRNA structure, pairing coding sequences (blue) with highly conserved intronic sequences. Structural features (for example, bulges and loops) in the duplex region focus ADAR's deaminase activity on a few or one adenosine residue. (b) Promiscuous editing of long repeat dsRNAs. Shown here is an inverted repeat of Alu elements whose transcription produces a long nearly perfect dsRNA. Numerous ADAR editing events can occur in such a substrate, altering its structure, and potentially interfering with downstream processes (for example, Dicer processing into endo-siRNAs). (c) A hypothetical scheme for conserved versus less-conserved RNA editing events. All RNA molecules can potentially form secondary structures, and thus potentially bind and be acted upon by ADAR. Those that are minimally structured will be edited poorly or not at all. The vast majority of RNAs will fall into this category, and be well below the action of serving as a variant incipient adaptation acted upon by natural selection (below dashed green line). Certain RNAs will more readily serve as ADAR targets, and will as a consequence also possess more dsRNA character. Such events can be acted upon by natural selection and serve as sources of variation in the expression of RNAs (for example, mRNAs, long non-coding dsRNA, miRNA precursors). Natural selection will preserve certain structural features, such as those in pre-mRNA and miRNA precursors, to ensure highly evolved edited structures. Other long dsRNAs, such as inverted repeat hairpin dsRNAs, will be edited as part of the regulation of host defenses to viruses and selfish genetic elements. ADAR, adenosine deaminase acting on RNA; dsRNA, double-stranded RNA; miRNA, microRNA, siRNA, small interfering RNA. whose functions largely remain to be determined. Comparison of RNA editing landscapes between different genetic model organisms has uncovered diverse ADAR substrates and revealed discrepancies within RNA editing systems. While the number of exonic editing sites that lead to non-synonymous amino acid substitutions (genomic recoding) varies significantly across a broad range of organisms, a common theme seems to be emerging. The majority of RNA editing sites are located in non-coding regions within genomes. For example, in the human genome, RNA editing sites are highly over-represented in Alu elements restricted within introns of transcribed genes [3]. Alu elements are lineage-specific repeat genomic sequences, which participate in dsRNA template formation acting as ADAR substrates (Figure 1b). Unlike mRNA targets of ADAR, such more perfect and extensive dsRNA substrates lend themselves to more extensive deamination, with up to 40% of adenosines in the duplex region undergoing modification. Similarly, within the mouse genome the majority of RNA editing sites are found in B1 short interspersed element repeats. RNA editing in non-coding regions of a transcript can have several functional consequences such as: creation or elimination of splicing signals, exonization of repeat elements, nuclear retention, regulation of microRNA (miRNA) biogenesis and function, cellular defense, and regulation of RNA interference [4]. It is thought that the collection of RNA editing sites in an organism's transcriptome contributes equally to the appropriate functioning of the nervous system, as exemplified from the generation of ADAR deficiencies in various genetic models [5]. In Drosophila, deletion of the adar locus results in severe neurological phenotypes, including extreme uncoordination, seizures and neurodegeneration. Furthermore, mice homozygous for ADAR1 null mutations die during early development due to severe apoptosis. In addition, ADAR2 null mutant mice experience repeated seizure episodes and die soon after birth. Interestingly, the lethality phenotype of the ADAR2 null mice is rescued by the introduction of the edited allele of a single RNA editing site in the glutamate receptor channel, GluR-B Q/R site [6]. This observation suggests that certain RNA editing sites are more physiologically critical compared with others existing in the same genome. Thus, a general enigma in ADAR-mediated editing is exactly how to determine which, of many, RNA editing sites are functionally important, and which may have no discernable function.

A unique set of RNA editing sites

In order to identify functionally important RNA editing sites from a vast RNA editing landscape, a recent study by Pinto et al. [7] used evolution as a key discriminator to delineate highly conserved sites in mammalian lineages. Taking advantage of enormous RNA-seq datasets of both human and mouse transcriptomes, the authors applied a standard BLAST alignment tool to compare 40 base pairs upstream and downstream of human genomic sequences surrounding an RNA editing site to the mouse genome. A set of basic filters was applied to the datasets to retain only RNA editing sites located at the same exact position in both human and mouse genomes. Surprisingly, this simple procedure identified 59 highly conserved editing sites. This set of RNA editing sites, which were termed evolutionary selected sites (ESS), represents 0.004% of the known human editing sites to date. Furthermore, the authors demonstrated that the percentage of ESS sites does not increase as RNA-seq data accumulate. Using a small fraction of the available RNA-seq data sets from 15 different mouse strains, the authors were able to retrieve approximately 95% of the ESS sites in any random choice of two mouse strains. While the ESS sites were found across all the mouse strains tested, the non-conserved sites were not consistently detected, suggesting that the ESS set is exquisitely specific. In addition, evidence for the presence of ESS sites can be found in RNA-seq data from an additional four genomes within the mammalian evolutionary tree: rat, cow, opossum and platypus. The presence of ESS sites across large evolutionary distances suggests a functionally important role in mammalian biology for these sites, despite the fact that the set is surprisingly small.

The nature of functionally important RNA editing sites

Due to the degeneracy of the genetic code, RNA editing can cause both synonymous and non-synonymous changes. In Drosophila, the majority of highly conserved RNA editing sites lead to non-synonymous amino acid changes in functionally important and highly conserved residues within proteins. Similarly, the majority of the mammalian ESS editing sites lead to amino acid recoding. Specifically, 37 out of 59 ESS editing sites are found in coding regions of the genome and 35 of them lead to non-synonymous amino acid substitutions (94%). In addition, most of the non-coding ESS editing sites (22/ 59) occur in transcripts of genes that are also edited elsewhere in their coding sequence. Recent studies in Drosophila identified editing sites in ECS non-coding genomic elements [8,9]. Not surprisingly, using structural RNA prediction software (mfold), Pinto et al. showed that most of the ESS editing sites in non-coding regions are located in potential ECS elements. Furthermore, two of the ESS editing sites are found in miRNAs in agreement with the previously described regulation of miRNA biogenesis and function through RNA editing. Further analysis revealed certain features of the ESS editing set. First, the ESS editing sites display higher levels of expression when compared with the non-conserved editing sites set. Second, the ESS editing set exhibits higher levels of editing and, more importantly, these levels of editing display striking conservation across 15 mice strains and between human and mouse. These observations indicate that the editing levels of the conserved mammalian RNA editing sites are set within the evolutionary tree and that the precise ratios of edited/ non-edited repertoires of protein products may contribute to the optimization of cellular physiology. Lastly, similar to the highly conserved RNA editing sites reported in Drosophila, the ESS editing sites are overrepresented in genes that play a pivotal role in nervous system functions such as synaptic release and ion transport. This observation suggests that natural selection acts through RNA editing to evolve RNA structures that are acted upon by ADARs to genetically recode the proteome associated with neurotransmission and thereby fine-tune brain physiology.

Unweaving the roles of RNA editing

Abnormalities in the RNA editing pathway are associated with multiple nervous system disorders including schizophrenia, epilepsy, suicidal depression and amyotrophic lateral sclerosis [10]. The conserved RNA editing sites within the mammalian evolutionary tree reported by Pinto et al. [7] have the potential to contribute to a better understanding of the link between the RNA editing process and various neurological diseases. With the rapid advent of genetic engineering techniques, specific RNA editing sites could be precisely examined in vivo in various animal models, thus uncovering functions of ESS single RNA editing events. Furthermore, the specific characteristics of the non-conserved set of RNA editing sites prompted Pinto et al. to propose that these events are simply a consequence of overactivity of RNA editing enzymes with no apparent evolutionary value. Certainly, particular specific RNA editing events are under intense selective pressure, yet all RNAs are structured to some degree due to the single-stranded nature of RNA. Many RNAs, from all classes, probably serve as poor ADAR substrates (Figure 1c). Low-level editing of barely structured RNAs is not likely to be under intense scrutiny by natural selection, but sequence variants that become more structured, or obtain more stable structures under altered environmental conditions, may be better ADAR substrates, and then be vetted by natural selection for their adaptive consequences. Further sequence drift, under selective conditions, could shape RNAs into efficient ADAR substrates over generations. Other targets, for instance long dsRNA transcribed from recent duplication or transposition events, may immediately be hyperedited, leading to intersection between RNA editing and small RNA processing.

Multiple reports suggest that the RNA editing pathway is highly sensitive to external and internal stimuli such as temperature and inflammation. Therefore, future studies should aim to investigate how these two different sets of mammalian RNA editing sites respond to alterations of environmental stimuli. Non-conserved RNA editing events within mammalian lineages could represent variations in how RNA editing reshapes a specific transcriptome/proteome in response to external or internal changes in the environment. Such editing sites could represent derived characters, as such, which could then be interpreted as molecular adaptations in cellular functions. Studies such as that by Pinto et al. open the doorway for identifying both the conserved and, perhaps equally interesting, non-conserved species-specific RNA editing events that have shaped, and been shaped by, evolution.

Abbreviations ADAR: Adenosine deaminase acting on RNA; A-to-I: Adenosine to inosine; cDNA: complementary DNA; dsRNA: double-stranded RNA; ECS: Editing complementary sequence; ESS: Evolutionary selected sites; miRNA: microRNA.
http://genomebiology.com/2014/15/1/103
Competing interestsThe authors declare that they have no competing interests.Published: 28 January 2014
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