Médéric Blestel
email: mblestel@insa-rennes.fr

Mickaël Raulet
email: mraulet@insa-rennes.fr

Open SVC Decoder: a Flexible SVC Library

Keywords: D.2.0 [Software Engineering]: General Algorithms, Performance Scalable Video Coding, mplayer, TCPMP, Joint Video Team, Joint Scalable Video Model

This paper describes the Open SVC Decoder project, an open source library which implements the Scalable Video Coding (SVC) standard, the latest standardized by the Joint Video Team (JVT). This library has been integrated into open source players The Core Pocket Media Player (TCPMP) and mplayer, in order to be deployed over different platforms with different operating systems.

INTRODUCTION

In October 2007, the Joint Video Team (JVT), composed of the ITU-T Video Coding Experts Group (VCEG) and the ISO/IEC Moving Picture Experts Group (MPEG) has standardized a Scalable Video Coding (SVC) [START_REF] Schwarz | Overview of the Scalable Extension of the H.264 / AVC Video Coding Standard[END_REF] extension of the H.264/AVC standard [START_REF]Advanced Video Coding for Generic Audio Visual services, Amendment 3: Scalable Video Coding[END_REF]. The two groups have also developed a reference software, named the Joint Scalable Video Model (JSVM) [START_REF]Reference software[END_REF] which implements this standard.

The SVC standard extends the AVC standard with scalability features allowing easy adaptation of the bit-stream to network and terminal constraints. SVC provides a high degree of flexibility in terms of scalability dimensions supporting various temporal or spatial resolutions and quality levels.

The Open SVC Decoder [START_REF] Blestel | Open SVC Decoder Web site[END_REF] [START_REF] Blestel | Open source code of an svc decoder[END_REF], an open source library, aims to implement this new standard. It has been developed using a data flow methodology and tested over differ-ent platforms like x86 platform, Personal Data Assistant, PlayStation 3 and Digital Signal Processor.

In this paper, a brief description of the SVC standard is done, followed by a presentation of the Open SVC Decoder (OSD) and its installation procedure.

SVC OVERVIEW

Scalable Video Coding (SVC), the new scalable codec based on H.264/AVC standard, has been developed to broadcast a video to multiple users with multiple displays and connected through multiple networks using a single bit-stream. Thanks to this standard, it is possible to partially transmit or decode a video bit-stream resulting in various video qualities.

In the SVC standard, the video compression is performed by generating a unique hierarchical bit-stream structured in several layers of information, consisting of a base layer and several enhancement layers. The base layer provides basic quality while the enhancement layers provide improved quality at increased computational cost. The particularity of the bit-stream is that the enhancement layers can be removed without compromising the decoding process of the resulting bit-stream. Each layer E(dependency id; quality id), can be easily identified thanks to two parameters, the "DQId" (derived by: (dependency id << 4) + quality id) and the "temporal id". These parameters refer to the different scalabilities present in the layer among the three types of scalability specified in the standard:

• Temporal : The temporal scalability which was already present in H.264/AVC, has been improved by partitioning the hierarchical B and P frames in different temporal layers. The temporal scalability of each frame can be determined thanks to the "temporal id" parameter.

• Spatial : This type of scalability tries to increase coding efficiency by exploiting the redundant information between layers. In addition of the basic prediction mode defined in H.264/AVC, a new macroblock coding mode has been defined to predict from a base layer, macroblock's information thanks to upsampling mechanisms. Each spatial enhancement should have a different "dependency id".

• Quality: The quality scalability is very similar to the spatial scalability but without changing of resolution between layers. The same inter-layer predictions are used except the up sampling mechanisms. The quality enhancement can be referred either by the quality id or by the dependency id following the SNR scalability chosen.

In the SVC amendment [START_REF]Advanced Video Coding for Generic Audio Visual services, Amendment 3: Scalable Video Coding[END_REF], temporal and quality scalabilities should be supported by decoders without any restrictions. Only the spatial scalability is limited according to the profile defined. There is three profiles in the SVC amendment:

• The Scalable Baseline profile: In this profile, the base layer must conform to H.264 / AVC Baseline profile.

Resolution ratios between successive spatial layers in both horizontal and vertical direction must be 1.5 or 2.

• The Scalable High profile: In this profile, the base layer must conform to H.264 / AVC High profile. No restrictions have been defined for the enhancement layers.

• The Scalable High Intra profile: Only intra pictures in all layers are authorized. As the previous profile, the base layer should be conforming to H.264 / AVC High profile.

OPEN SVC DECODER

IETR is developing since July 2006 the Open SVC Decoder, a C language Scalable Baseline profile library supporting all tools to deal with spatial, temporal and fidelity scalabilities. It is based on a fully compliant H.264 / AVC Baseline library with most of Main profile tools.

In this section, the library features and its conformance are presented.

Open SVC Decoder features

Contrary to the JSVM which decodes only the layer with the highest scalability, i.e the enhancement layer with the highest spatial, temporal and quality scalability, the Open SVC Decoder can decode partially the bit-stream until a specific layer with a specific temporal scalability. This particularity provides an adaptability of the decoder over different platforms by selecting the right layer in order to have a real-time decoding.

The library contains also several mechanisms to switch of layer during the decoding process which allows the user to select the layer to display by specifying commands. However, the decoder is also able to change of layer by itself when a missing enhancement occurs due to transmission errors.

In the case of a partial decoding of a bit-stream, the decoder will dismiss discardable layer. Figure 2 shows the data flow graph of the decoding process when the top layer of a four layers stream is not decoded. Variable Length Coding and Texture Decoding are processes for the first three layers but not for the fourth.

OSD conformance and benchmarks

The Open SVC Decoder has been compared to the JSVM 9.19 to benchmark and to test the conformance of the library using conformance sequences which can be found on the JVT site [START_REF]Conformance testing[END_REF]. A list of the conformance sequences in which Open SVC Decoder is compatible with, is available on the web site [START_REF] Blestel | Open SVC Decoder Conformance[END_REF].

Table 1 shows the results of the comparison between both decoders on several conformance sequences. The benchmarks were executed on a PC with Intel Core 2 Duo CPU at 2.4GHz. These benchmarks show the speeding up between the Open SVC Decoder and the JSVM decoder on several conformance sequences with different configurations. Indeed, the performance of the library is up to 50 times faster than the JSVM decoder.

OSD INSTALLATION AND EXECUTION

The library has been built into two open source players, TCPMP and mplayer which were using ffmpeg video codec [8]. This codec has been removed and replaced by the Open SVC Decoder in order to decode AVC and SVC bit-streams.

In this section, only the installation and execution of mplayer is presented. Others installation procedures are presented on the project web site [START_REF] Blestel | Open SVC Decoder Web site[END_REF].

Installation

We have decided to only present mplayer installation which is simplest than the TCPMP one. Moreover, this player is compatible with all major operating systems, including Linux and other Unix-like systems, Microsoft Windows and Mac OS X, and has been tested over different platforms.

The mplayer version proposed in this project is based on the 31411th revision of the mplayer SVN repository [9]. No major changes have been done except for the interfacing of the library into the mplayer.

The installation proceeds in several steps:

• Download the sources: The first step consists in downloading the source of the project [START_REF] Blestel | Open SVC Decoder download page[END_REF]. The latest release, 1 08 should be downloaded. The package is organized in three different directories: the library sources (Libs), mplayer directory and TCPMP directory.

• Download a MinGW package: This step is necessary only if the operating system is Windows. Indeed, mplayer under Windows, is only compatible with MinGW build environment which can be downloaded on this page [START_REF]Mplayer for win32 web site[END_REF]. The compilation with CygWin or others built environments is not working.

• Download SDL library: This step is necessary only if the operating system is different from Windows. The SDL library [START_REF]Simple Direct Media Layer[END_REF] is used to manage the layer to display.

• Configure the player : Once all packages downloaded, the next step consists in configuring the player by using the following the command line "./configure -enablesvc" in a console (MinGW if the operating system is Windows) at the root of the mplayer directory. The option "-enable-svc" allows the player to be configured with the SVC library located in the "Libs" directory. Without specifying this option, mplayer will be configured with the ffmpeg library and only the base layer will be decoded in case of a SVC bit-stream.

• Start the compilation: The compilation of all sources can be started using the command line: "make". Once the compilation done, the program mplayer is ready for use.

Execution

Once the installation finished, the program can be executed. Contrary to TCPMP which can only read multimedia file formats, mplayer can also read raw streams. The command line to execute mplayer is quite simple: "./mplayer file name".

However, to decode SVC raw streams like conformance sequences from the JVT site, the option "-fps" followed by the frame rate (25 as default) has to be specified in the command line. Moreover, if the operating system is Mac OS X, the option "-vo sdl" should be added in order to use SDL library to correctly display the output video.

As default, the decoding process starts by displaying the enhancement layer with the highest scalability. Options can be added to the command line to select a specific layer to decode with a specific temporal scalability.

For instance, the option "-setlayer" followed by a DQId value, allows to select the layer with the DQId specified present in the bit-stream. To select the temporal level to decode, you can specify the option "-settemporalid" followed by the temporal id wanted.

For example, the following command line "./mplayer -fps 25 mystream.264 -setlayer 16 -settemporalid 2 -vo sdl" allows to decode all layers necessaries to display the layer with the DQId equals to 16, of the bit-stream named "mystream.264". The decoder will display at 25 frames per second and using the SDL library, all frames of this layer with a "temporal id" inferior or equals to 2.

The configuration of the DQId and the temporal scalability can be changed during the decoding process thanks to hot-keys:

• "l": To select a layer with a lowest spatial or quality scalability if the layer currently displayed has a DQId different from 0.

• "b": To select a layer with a higher spatial or quality scalability if the currently displayed layer has not the maximum value of DQId present in the bit-stream.

• ";": To switch down of temporal scalability. The frame rate will not change, so the bit-stream will be decoded faster.

• ",": To switch up of temporal scalability.

Using this library, the user can change of temporal layer at any time whereas he can change of spatial and quality layer only on frames set as IDR (Instantaneous Decoding Refresh). This type of frame occurs occasionally in the sequence from the JVT site, that's why video bit-streams with multiple IDR frames are available on the project download page [START_REF] Blestel | Open SVC Decoder download page[END_REF]. These sequences allow to regularly switch between layers.

AUDIENCE

The Open SVC Decoder has been developed in the framework of Scalim@ges [START_REF]Scalim@ges project[END_REF] project in a modular manner [START_REF] Pelcat | From AVC decoder to SVC: Minor impact on a data flow graph description[END_REF]. This project aimed to promote SVC standard in order to reduce the number of formats manipulated in production, distribution, and use of video compatible with existing solutions. Partners of this project had actively contributed to the standardization of the SVC standard and its transport stream protocol [START_REF]Transport of scalable video over Rec[END_REF].

Currently, others French and international projects like SVC4QoE [START_REF] Barkowsy | Overview of the svc4qoe project[END_REF] and ScalNet [START_REF] Ransburg | Scalable Video Coding Impact on Networks[END_REF] are using Open SVC Decoder. ScalNet tries to focus on designing a streaming system based on the SVC standard. The system is designed to cope with streaming scenarios that can be classified in four use cases: session handover, network congestion, receiver heterogeneity and user driven adaptation.

The SVC4QoE project aims at associating Scalable Video Coding and Quality of Experience (QoE) evaluation techniques in order to maximize the user experience when receiving audiovisual content over broadcast networks. The purpose of the project is to explore and demonstrate how to optimize the broadcast network infrastructure in various receiving conditions by lowering the necessary bandwidth, while providing the best quality of the signal to a wide range of portable and hand-held receivers.

The Open SVC Decoder is likewise used as a starting point in the development of a new SVC library in the framework of MPEG-Reconfigurable Video Coding [START_REF] Mattavelli | The Reconfigurable Video Coding standard [Standards in a Nutshell[END_REF].

CONCLUSION

Since May 2009 when this project had been uploaded on sourceforge web site, Open SVC Decoder has been downloaded 7,100 times and the SVN repository has next to 2500 read transactions. These results show the interest of the community into this video codec and open source code.

The web site has also permitted us to meet and work with foreign teams in order to enhance the library. Optimized algorithms are regularly added to the Open SVC Decoder source code.

The speeding up's library compared to the JSVM, and its portability over different platforms make the Open SVC Decoder a relevant candidate for research projects

Figure 1 :

 1 Figure 1: Evolution of layers parameters

Figure 2 :

 2 Figure 2: Open SVC Decoder data flow graph

Table 1 :

 1 Open SVC Decoder Benchmark

	Sequence	Decoding time (s) Speed up JSVM OSD
	SVCBST-1	31.2	0.87	35
	SVCBST-2	23.3	0.87	26
	SVCBST-14	137	2.69	50
	SVCBST-15	50	2.11	23

ACKNOWLEDGMENTS

The authors would like to thank the numerous people having contributed code to this SVC library.

In particular, we would like to offer our most sincere thanks for Vincent Bottreau from Scalim@ges, Myllyniemi Mikko from ScalNet and all contributors from the project SVC4QoE who have supported Open SVC Decoder.

We also would like to take this opportunity to extend a warm thank you to Fernando Pescador and his team from the Electronic and Microelectronic Design Group (GDEM-UPM) from Madrid for their contributions to this work in particular to the deployment [19] of the library over digital signal processors (DSP).

The authors would like to thank the DGCIS (French Ministry for Industry), Région "Bretagne" and Région "Pays de la Loire" (regional councils) for partially funding the SVC4QoE project.


Keywords: Chronic hepatitis, Antivirals, Drug resistance, entecavir, tenofovir, interferon Chronic hepatitis B therapy

Chronic HBV infections remain a major public health problem worldwide. According to WHO estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma. Major progress in the treatment of chronic hepatitis B has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is a critical factor in determining the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleoside analogues has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multi-drug resistance. The selection of a potent antiviral with a high barrier to resistance as a first line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, the pharmacological barrier, viral fitness, the mechanisms of action and cross-resistance. Furthermore, because of specific viral kinetics, prolonged treatment with nucleoside analogues does not result in clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as prevent drug resistance and its complications in the long-term.

 1 7Hepatitis B virus resistance to antiviral drugs: where are we going? Fabien Zoulim 1 2 *

Service d h patologie et de gastroent rologie 1

The ultimate goals of therapy for chronic hepatitis B (CHB) are to prevent disease progression and to prolong patient survival (

). 1 -3

These goals can be achieved as long as HBV replication can be suppressed and sustained. Major clinical studies have demonstrated the role of viral replication in the pathogenesis and progression CHB. A large prospective cohort study from Taiwan has shown that elevated HBV DNA ( 10 copies/mL) and its persistence significantly increase the risk of cirrhosis, hepatocellular carcinoma (HCC) and death, ≥ 4 regardless of HBeAg status or baseline ALT levels( ). These data have been supported by several other similarly designed studies. [START_REF] Cj | Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[END_REF] Furthermore, one randomized controlled clinical trial of lamivudine in CHB patients with advanced fibrosis or cirrhosis showed the benefit of antiviral therapy on disease progression ( ). However, the clinical benefit of reducing disease progression was limited in patients who 5 developed lamivudine resistance ( ). Histological improvement has been observed during treatment with lamivudine, adefovir, tenofovir 5

and entecavir, although the development of resistance had a negative impact on the histological improvement observed with lamivudine ( 6).

-9

Thus, a maintained long-term response to therapy or a sustained off-treatment response are necessary to prevent liver damage and hepatic decompensation and to delay the onset of the long-term complications of CHB such as hepatocellular carcinoma (HCC).

Recent advances in antiviral treatment of CHB

Seven drugs have received approval for the treatment of CHB, including interferon-alpha, pegylated interferon-alpha and the nucleoside analogs (NUCs), which belong to one of three structural groups: L-nucleosides (lamivudine and telbivudine), alkyl phosphonates (adefovir dipivoxil and tenofovir disoproxil fumarate) or D-cyclopentanes (entecavir).

The antiviral efficacy of the currently approved therapies, in terms of viral suppression, has been assessed in several registration studies and recently reviewed ( ). Comparisons between studies are limited due to differences in patient characteristics, baseline HBV 1 -3 DNA levels, study design and methodologies used to quantify HBV DNA. Without head-to-head comparisons it is currently not possible to rank relative efficacy, but the results of these studies and clinical experience have shown that entecavir, telbivudine and tenofovir are the most potent of the currently available NUCs.

The interferons both have direct antiviral activity and immune-stimulatory properties. In clinical trials, pegylated interferon-alpha induced higher rates of sustained response during the 24-week off-treatment follow-up period despite a lower level of viral suppression compared to lamivudine following 1 year of therapy( , ). Furthermore, pegylated interferon administration has been associated with 10 11 improved serological responses such as hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion during long-term follow-up. Interferon administration has been shown to reduce resistance to NUCs when combined with lamivudine ( , ). 10 11 However, interferon therapy is associated with side effects and its efficacy is limited to a small proportion of highly selected patients ( ).

3

Resistance to NUCs

Resistance to NUCs is a major issue affecting long-term therapy with some of these agents. The clinical consequences of developing resistance to NUCs have been well documented. Patients treated with lamivudine or adefovir who develop virological breakthrough due to the presence of resistance mutations frequently experience acute exacerbations of disease (ALT elevations) and more rapid progression to acute liver failure, liver transplant and higher risk of HCC and death ( , , , ). 5 14 18 19 Another important consequence of drug resistance and the subsequent need for rescue therapy is the increased risk of development of multi-drug resistant HBV by sequential accumulation of resistance mutations on the same viral genome (

). This risk is particularly 20 -22 high for drugs with low barriers to resistance and with overlapping resistance profiles. In a second or third-line treatment setting, studies have demonstrated that entecavir is effective in patients with adefovir resistance and patients with prior lamivudine treatment who had not developed resistance, but not in patients with proven lamivudine resistance ( ). This emphasizes the impact of cross resistance (in this 23 case, between lamivudine and entecavir) on the outcome of rescue therapy. Tenofovir has also been shown to be effective in patients with lamivudine-resistance and an incomplete response to adefovir, but not necessarily in all patients with adefovir resistance ( ). Thus, these 24 studies demonstrate that inadequate management of resistant patients increases the risk of developing multi-drug resistance. It has also been shown that variant strains with single point mutations may also exhibit a multi-drug resistant phenotype ( ). 25

Treatment guidelines and resistance management

Improvement in the availability of better therapies and virological monitoring tools have led to a progressive change in treatment guideline recommendations. Besides lowering HBV DNA and ALT thresholds for treatment indications, international guidelines recommend that therapy be initiated with a potent antiviral with a high barrier to resistance, such as entecavir or tenofovir, to reach undetectable HBV DNA as a primary endpoint thus minimizing the risk of selecting resistant variants ( , ) ( ).

3 Figure

Avoid unnecessary treatment

To further minimize the risk of resistance, unnecessary treatment should be avoided and HBV DNA should be carefully monitored to check for primary non-response (<1 log drop in HBV DNA at week 12) as well as partial response (detectable HBV DNA at week 24). [START_REF] Marcellin | Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B[END_REF] Treatment decisions for patients with partial response may be influenced by drug potency and barrier to resistance ( ). In patients treated 2 with lamivudine, adefovir or telbivudine with a partial response at week 24, treatment should be adapted with a switch to a more potent drug or the addition of a second drug with a non-overlapping cross-resistance profile. In patients treated with entecavir or tenofovir who have a partial response at week 48, some experts suggest adding the other drug ( ). Alternatively, as long as the decrease in viral load 2 continues, monotherapy can be continued because of the very low resistance rates. However, if there is no progressive continuous decline in viral load levels and a subsequent plateau occurs, then the regimen should be adapted, preferably with an add-on strategy. With such a strategy, the development of resistance can be prevented in most cases.

Avoid sequential monotherapy

Recommendations for the management of patients who develop antiviral resistance are consistent among treatment guidelines ( , ,

. One key principle is that sequential monotherapy should be avoided in mostcases. If initial monotherapy fails, a second drug with a 26 non-overlapping resistance profile should be added or a switch should be made to a more potent combination of drugs ( ). Most patients 12 in treatment failure can be controlled with this rescue strategy.

Mechanism of antiviral drug resistance and barrier to resistance

Antiviral drug resistance is a result of adaptive mutations within the HBV genome and reduces the susceptibility of a virus to the inhibitory effects of a drug. The barrier to resistance can be defined as the difficulty with which these resistance mutants are selected ( ). 12 Mutations in the viral genome develop at a high frequency during viral replication, resulting in a diverse population of viral variants in infected individuals. Although HBV has a DNA-based genome, its replication cycle relies on an error-prone reverse transcription process, with mutations occurring at an estimated rate of 10 substitutions per base, per cycle ( ). Thus, drug resistance mutations may preexist 4 -27 in patients who have no previous exposure to antiviral therapy. However, the actual selection of resistance mutations, and hence a drug barrier to resistance, is also influenced by several factors related to the virus (the number of mutations required to confer resistance, and their effect on viral fitness), the drug (mainly its antiviral potency) and the patient (treatment compliance and pharmacodynamics of the drug).

Entecavir and tenofovir are the preferred first-line treatments

The low rates of resistance and reductions in resistance-associated complications are the major benefits of using nucleoside analogs with a high barrier to resistance. Furthermore, since most patients who initiate treatment for CHB therapy, especially HBeAg-negative patients, are likely to require long-term therapy, first-line therapies with a high barrier to resistance offer the greatest chance of successful long-term treatment. Highly potent CHB therapies with the lowest rates of resistance, such as entecavir or tenofovir, are therefore the preferred first-line NUC treatment options in recently updated guidelines ( , , ).

2 3 26

Alternative strategies for the prevention of resistance

A number of practical strategies for the prevention of drug resistance in clinical practice might be considered in view of the practice guidelines recommended by international liver societies ( ). Figure

Baseline evaluation

Before initiating therapy with a drug that has a low barrier to resistance (especially in countries where the other drugs are not yet available or affordable), an assessment of serum HBV DNA, ALT levels, prior treatment history and genotypic resistance may guide treatment selection in particular clinical situations. Baseline resistance testing may also be considered as drug resistance mutations have been detected in a number of treatment-na ve patients ( ). However, at present there is little data to demonstrate the clinical relevance of ï 28 resistance mutations that are present before treatment. Therefore, such results must be interpreted with caution when making treatment decisions. High levels of serum HBV DNA, ALT and elevated body-mass index have all been linked to increased rates of lamivudine resistance ( , ). Furthermore, as might be expected, prior treatment with NUCs has been shown to predict drug resistance ( ).

13 29 18 On-treatment monitoring and treatment adaptation: HBV DNA at week [START_REF] Van Bommel | Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues[END_REF] The roadmap concept includes an algorithm for monitoring HBV DNA levels at weeks 12 and 24, with strategies suggested for patient management based on virological responses at the time points and the genetic barrier of the drug being used ( , ). The roadmap 30 31 concept proposes that patients with a complete virological response at week 24 (undetectable HBV DNA by PCR) remain on treatment with regular monitoring while patients with an inadequate virological response ( 2,000 IU/mL at week 24) should receive additional ≥ therapy with a more potent drug. Treatment decisions in patients with a partial virological response ( 60 to <2,000 IU/mL at week 24), are ≥ based on potency and genetic barrier: patients receiving NUCs with a high genetic barrier can remain on treatment beyond 48 weeks, patients receiving a less potent NUC should continue treatment and be re-assessed at week 48, and patients receiving NUCs with a low genetic barrier should add on a more potent drug because of the high risk of resistance if treatment is not adapted ( ). In all cases patients 2 should be monitored regularly for virological breakthrough. The rationale for treatment decisions in the roadmap concept are based on predictors of response from studies of drugs with low resistance barriers (lamivudine, adefovir and telbivudine). These analyses demonstrate that patients with a profound early virological response during treatment with lamivudine ( ), adefovir, ( ) and telbivudine 32 8

( ) have a lower chance of developing resistance. However, because of the very low rates of resistance observed with entecavir and 16

tenofovir ( , ) it has not been possible to accurately assess predictors of resistance in these drugs. The main advantage of the roadmap 7 33 is that it provides a comprehensive guide to short-term monitoring in patients receiving first-line therapy with a drug that has a low barrier to resistance. However, the clinical outcomes associated with the roadmap concept have not been examined in a prospective study.

If this principle of treatment monitoring and adaptation is followed, most patients can be controlled, whether they start therapy with drugs with a high or low barrier to resistance.

Crucial role of treatment adherence

Poor adherence substantially reduces viral suppression and may increase resistance rates, as previously discussed. Good adherence to regimens with a low barrier to resistance is therefore absolutely necessary. Adherence may be monitored using patient reports, dispensed medication counts or HBV DNA testing. Adherence may be improved by educating patients on the importance of adherence and preventing resistance, providing assistance with treatment management (i.e. reassurance and advice regarding adverse events), by checking and reinforcing the importance of adherence at each appointment and by providing feedback on treatment progress.

Conclusions

Clinical studies have demonstrated that drugs with a high barrier to resistance, such as entecavir and potentially tenofovir, have significantly lower rates of resistance when compared to those with a low barrier to resistance such as lamivudine, adefovir or telbivudine.

The barrier to resistance of a drug can be defined as the difficulty with which antiviral resistance is selected during CHB therapy. This can be influenced by a number of factors including the drug s genetic barrier and intrinsic potency, the level of adherence to the treatment ' regimen, pharmacological barriers and the replication fitness of any drug-resistant variants that arise during viral replication.

Compelling evidence connects high levels of viral replication to an increased time to HBV DNA undetectability during treatment, and an increased incidence of cirrhosis, HCC and liver-related mortality. Thus, the correct choice of a first line potent therapy to achieve sustained long-term suppression of viral replication provides the best chance of achieving the goals of therapy, which are to prevent the progression of liver disease and to prolong survival. Most patients receiving treatment will require long-term therapy to meet these goals and the development of antiviral resistance is a major concern in these cases. Treatment with a potent drug that has a high barrier to resistance, such as entecavir or tenofovir, will minimize future resistance, preserve future treatment options, protect public health and maximize the chances of long-term treatment success. Furthermore, the correct choice of first-line therapy also provides the best chance of avoiding the need for salvage therapy, which can be significantly affected by NUC antagonism and cross-resistance. In recent years, results of studies and clinical experience have shown that major progress has been made in the management of antiviral drug resistance which has now become a manageable issue provided that adequate virological monitoring and treatment adaptation are performed. In developing countries where HBV infection is endemic programmes are needed for cost-effective delivery of the best drugs and virological monitoring, improving availability of antiviral treatment patient management and the prevention of resistance.

Perspectives

Although chronic HBV infection is not curable because of persistent viral cccDNA and integrated HBV genomes in infected cells, there are very few new drugs in the anti-HBV chemotherapy development pipeline. It is therefore important to continue research in this area to anticipate resistance issues in the vast population of patients who have not yet been treated worldwide. Several viral targets are of potential interest for the development of new drugs with more potent combination strategies to help enhance viral clearance and prevent resistance.

Inhibition of cell entry

The inhibition of virus cell entry is one of these main targets ( , ). Administration of pre-S1 peptides mimicking the envelope 34 35 protein domain involved in virus/cell membrane interaction resulted in the prevention of virus entry in the hepatocyte culture and the inhibition of viral infection and spread in a humanized SCID mouse model. Theoretically, the combination of this peptide with NUCs should prevent the infection of new cells while viral load is being suppressed by NUCs, thus increasing the rate of clearance of infected cells. More experimental studies are required for a proof of concept to test this hypothesis in clinical trials.

Targeting cccDNA

Targeting the formation and subsequent processing of viral cccDNA would be the ideal target but currently no candidate drug without cytotoxic effects is available for experimental studies. Epigenetic regulation of cccDNA transcriptional activity is another possible target which needs to be further investigated in experimental models ( ). 36

Capsid formation

Viral pregenome encapsidation and capsid formation represent potential targets. Phenylpropenamide derivatives and heteroaryl-pyrimidines (HAP) have been studied in hepatoma cell lines and been shown to inhibit replication of both wild type and in vitro amivudine resistant mutant genomes (

). Unfortunately the development of phenylpropenamides was not continued in the clinical 37 HBV infection to allow appropriately timed cessation of NUC administration.

Figure

Treatment guidelines for treatment of chronic hepatitis B with nucleoside analogues

- 40 setting

 40 because of toxicity. More recently AiCuris Pharmaceuticals has developed the HAP molecules as non-nucleoside inhibitors of HBV core protein dimerization, blocking nucleocapsid formation ( , ), and demonstrating efficacy in an animal model of HBV infection ( 39 40). 39Other targetsFinally, viral morphogenesis and egress represent another potential target for inhibition of the viral life cycle. In this respect, it was shown that Iminosugars which modulate the glycosylation status and conformation of envelope proteins may decrease the production of infectious particles ( ), resulting in an antiviral effect in the woodchuck model of hepadnavirus infection ( ). in vitro[START_REF] Lazar C | Treatment of hepatitis B virus-infected cells with alpha-glucosidase inhibitors results in production of virions with altered molecular composition and infectivity[END_REF] in vivo dendritic cells ( ) or the stimulation of the specific adaptive immune response ( ) to induce a sustained immunological control of 44 45 -47

  Cumulative annual incidences of resistance among nucleoside-na ve CHB patients are shown in the . The rate of drug resistance has decreased dramatically with the

		ï	Table
	development of the newer generation of NUCs ( ). Lamivudine resistance occurs frequently and is observed in up to 80 of patients 12 %
	treated for 5 years ( , 13 14	). Among adefovir-treated patients, the cumulative incidence of resistance over 5 years has been reported to be
	29 in HBeAg-negative patients and 42 in HBeAg-positive patients ( , % % 8 15	). Telbivudine resistance is slower to emerge; however, rates
	are substantial with 25 of HBeAg-positive and 11 of HBeAg-negative patients experiencing virological breakthrough due to resistance % %
	after 2 years of treatment ( ). Long-term studies of entecavir monotherapy in nucleoside-na ve patients have demonstrated that resistance 16 ï
	remains low (1.2 ) after 6 years of therapy at ( ). No tenofovir resistance has been observed after 3 years of treatment in the registration % 17
	studies ( ). 7
	Thus, the agents that have demonstrated the highest barrier to resistance in clinical studies in NUC na ve patients are entecavir and

ï tenofovir.

[START_REF] Marcellin | Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[END_REF] Other targets needing further experimental investigations are the modulation of the innate response of infected hepatocytes ( ) and


Tove Faber Frandsen

Jeppe Nicolaisen

Praise the Bridge that Carries You Over: Testing the Flattery Citations Hypothesis

Flattery citations of editors, potential referees, etc. has been claimed to be a common strategy among academic authors. From a sociology of science perspective, as well as from a citation analytical perspective, it is both an interesting claim and a consequential one. The paper presents a citation analysis of the editorial board members entering American Economic Review from 1984 to 2004 using a citation window of 11 years. In order to test the flattery citations hypothesis further we have conducted a study applying the difference-in-difference estimator. We analyse the number of times the editors and

INTRODUCTION

Scientific tradition requires that scientists, when documenting their research, refer to earlier works, which relate to the subject matter of their reported work. These bibliographic references are supposed to identify those earlier researchers whose concepts, theories, methods, equipment, etc. inspired or were used by the author in the process of conducting and presenting his or her research [START_REF] Weinstock | Citation indexes[END_REF].

Bibliographic references may, however, be exploited for other purposes. One of the alleged purposes that have been brought up repeatedly is flattery. P.O. Seglen has often claimed that flattery citations of editors, potential referees, etc. is a common strategy among academic authors -at least common enough to be mentioned time and again (e.g., [START_REF] Seglen | The skewness of science[END_REF]1997;1998). This is an interesting claim, and one, which if true, seem to have great consequences for various theories about the sociology of science, and of course for the practical use of citation analysis. But is it really true? Seglen himself makes no attempts to back it up by examples, by empirical evidence, nor by references to others. It is, however, a claim that can be investigated empirically. One way to do this would be to investigate whether editors, members of editorial boards and/or referees at certain journals are frequently over-cited in those journals compared to their citation rates in comparable journals. A positive result could at least indicate that the flattery citations hypothesis had something going for it. A negative result would, on the other hand, seem to falsify it right away. Currently, only two studies have tested the flattery citations hypothesis.

The first is a small-scale study of the quality control of a single journal in the field of Economics (Laband, Tollison & Karahan, 2002). The other study is a larger study that tests the flattery citations hypothesis in four Library and Information Science (LIS) journals [START_REF] Frandsen | A lucrative seat at the table: Are editorial board members generally over-cited in their own journals?[END_REF].

Laband, Tollison and Karahan (2002) investigate the citations to editors and board members of the American Economic Review (AER) by articles appearing in the AER. These results are then compared with the rate of citations to the same editors and board members in a control group of articles appearing in two comparable Economics journals. The comparisons of citation rates in 1985-1995 are mixed, and no general pattern of over-citation can be found. The final year analysed, 2000, is however, remarkable as it shows a four times greater rate of citations from AER articles than from articles in the control group. Laband, Tollison and Karahan (2002: 326-327) use the increased citations to calculate the value of being a member of editorial board: "[A]ssume that members of the AER editorial board receive approximately 2.5 additional references in the AER than these same individuals receive in the other top general interest journals. Assume further that the level of rent seeking that occurred in 2000 continues at a constant level (although the trend is upwards). In this case an individual serving a 5-year term on the AER"s board would pick up 12-13 cites in the AER over and above what (s)he could be expected to accrue otherwise. By itself, this surely creates a salary premium, 3 probably on the order of 10-20 percent in base salary, especially since AER citations are more valuable than most other citations to an economist. Assume the following scenario.

There is a 10 percent earnings effect. The individual editor has a base salary of $100.000, started to work on the editorial board at age 45, and served a 5-year term. At age 50 let the returns from marginal references kick in. The individual works until age 66 and then collects a pension worth half his salary. Applying a discount rate of 2.5 percent (equal to the rate of inflation so that these two cancel out) and letting the individual live to age 80, the cumulative value of the marginal references in this case is $ 240.000. At a 5 percent premium the additional references are worth $20.000."

The calculation of the value of references would preferably include a discussion of whether flattery citations are of equal value to regular citations but leaving that a side for the moment, Laband, Tollison and Karahan (2002) conclude that being an editor or member of board is of great value for the individual scholar also financially. The authors stress that there are other avenues for rent seeking behavior by authors and that rent seeking motives seem to play a relatively small role in the quality control process in economics.

The second study by [START_REF] Frandsen | A lucrative seat at the table: Are editorial board members generally over-cited in their own journals?[END_REF] The results do not unambiguously show a tendency to give flattery citations to editors and members of editorial boards in these four journals. Furthermore, any potential effect is found to be irrelevant as the difference in citations is negligible.

Both studies are highly dependent on the choice of journals as reference samples. It is important that the selected journals are representative for their discipline in order to be able to generalise the results. Furthermore, it is crucial that the journals are general as highly specialised journals cannot be expected to cite each other frequently.

The development of reliable estimates of the potential citation benefit from being an editor or member of editorial board begins with the specification of a causal hypothesis or hypotheses. As is the case with any study analysing the effect of a treatment or experiment, [START_REF] Greenstone | Quasi-experimental and experimental approaches to environmental economics[END_REF] argue that the key features of a causal hypothesis are that it contains a manipulable treatment that can be applied to a subject and an outcome that may or may not respond to the treatment. For a causal hypothesis to have any significance it is necessary to be able to expose it to a meaningful test. Such tests require that all other determinants of the outcome can be kept constant so that the effect of the treatment can be isolated. Ideally it would be possible to simultaneously observe the same ""subject"" receiving the treatment as well as not receiving the treatment. This will ensure that everything else is held constant. Of course, it is impossible to observe the same subject in both states simultaneously. We cannot observe the citation rates of a specific scholar being an editorial board member and at the same point in time not being a member of board. However, we can apply a quasi-experimental design that will enable us to test the hypothesis meaningfully. More specifically, we can analyze the citation data for each member of the board before and after entering the board. Using reference samples and applying a difference-indifferences estimator we can identify general tendencies in citation rates as well as tendencies specific to the journal investigated. The difference-in-differences estimator is an estimator that arises in policy analysis with data for two time periods. One version of the estimator applies to independently pooled cross sections and another to panel data sets [START_REF] Wooldridge | Introductory econometrics: a modern approach[END_REF]. For further illumination of the methods and their use the reader is referred to [START_REF] Wooldridge | Econometric Analysis of Cross Section and Panel Data[END_REF].

In order to test the flattery citations hypothesis further we have conducted a study applying the difference-in-difference estimator. The specific method is outlined below. It is followed by a results section, and a discussion and conclusion section in which we discuss the results in relation to various theories about the sociology of science and citation analysis in general.

METHODS

Since only Laband, Tollison and Karahan (2002) find a positive effect on membership of the editorial board, we proceed to test the hypothesis based on the journals included in their study. Laband, Tollison and Karahan (2002) analyse the editorial screening process in Economics with the objective of "ascertaining how well the process has functioned over time with respect to filtering "bad" papers and selecting "good" papers" (Laband, Tollison and Karahan, 2002: 315). They count the number of times the editors and editorial board members of the American Economic Review were cited in articles published in the journal itself as well as in a pool of documents comprising of articles from Journal of Political Economy and Quarterly Journal of Economics. They report the results from five year intervals from 1985 to 2000 with a one year lag (P326) implying that they have four observations for AER and four for the reference sample.

In this study we analyse the number of times the editors and editorial board members of the American Economic Review were cited in articles published in the journal itself as well as in a pool of documents comprising of articles from Journal of Political Economy and Quarterly Journal of Economics. We have chosen to analyze citation data five years before membership, the year he or she becomes a member and five years later. In other words years -5 to +5, leading to a period of 11 years. The first year included in our data is 1984 as is the case in the study by Laband, Tollison and Karahan (2002). However, we expand the publication years included in the study to every board member entering from 1984 to 2004.

We cannot include more recent publications than 2004 due to the length of the citation window. In the case of 2004 citations are analysed from 1999 to 2009.

Information on the composition of the board was found in the printed versions of the journal. Using the first issue of each publication year, any new names were registered on the basis of a comparison with the list from the previous year and attributed to year during which they entered. In some cases the role of the scholar in the journal changed from e.g. co-editor to board member. In these cases we only registered the first time he or she entered and not the change of role. This approach resulted in a dataset consisting of 167 editors and editorial board members of which a few had to be excluded as they could not be unambiguously identified in the Social Sciences Citation Index 1 . For cited scholars with common names and several publications, searches brought up hundreds of citations and it was not always possible to distinguish every single citation to confirm whether it was authored by the required author or another with the same last name and initial. The cited author field is not controlled, and consequently attention must be paid to the different forms of names. In these cases, it is possible that some citations were erroneously included or excluded. All citations included in the analysis are delineated to a specific journal and consequently, to a specific discipline and therefore, where there was doubt, the preference was for inclusion rather than exclusion. Hence, citations for these scholars are more likely to have been overestimated than underestimated. However, in a few cases scholars with common names had to be excluded as other scholars with the same last name and initial were found to be cited in the journals included in the study. This procedure resulted in a final data set consisting of 158 editors and board members. In a few cases an individual entered the editorial board more than once during the years observed, and in these cases the individual appears twice in the data set. Appendix 1 provides lists of the editors and editorial boards.

Editors and co-editors are assigned with a dummy variable (Editor=1 if co-editor or editor; otherwise editor=0). This variable is added to the data set to enable us to analyse any potential effect for editors or co-editors not found for regular members of board or perhaps of a different magnitude. In some cases an individual enters the board as regular member and subsequently becomes a co-editor. In the present study an individual is assigned 1 in the variable if he or she becomes editor or co-editor within the 11 year time period used to analyse the development in citation rates of the individual. Consequently, an individual appearing twice in the data set may be characterised as co-editor or editor in one of the entries and not in the other.

The citations received by each member need to be normalised as journals publish varying numbers of publications each year. Citations to all publications were included in the numerator, however, only the following publication types were included in the denominator: article, review, letter, note. Due to the indexing policy of the citation indexes, citations to all publication types are included in the numerator.

During the 31-year-period included in the data set American Economic Review published an average of 182 publications per year (defined as articles, reviews, letters and notes), Journal of Political Economy 54 publications and Quarterly Journal of Economics 48 publications.

The data in the study consists of observations in three groups. One of the groups is exposed to a treatment or experiment in the second period but not in the first period (entering editorial board in the middle of the time period analysed). The second and third group are not exposed to the treatment during either period. In the case where the same units within a group are observed in each time period, the average gain in the control groups is subtracted from the average gain in the treatment group. This removes biases in second period comparisons between the treatment and control groups that could be the result from permanent differences between those groups, as well as biases from comparisons over time in the treatment group that could be the result of trends. All this is integrated into the statistical analysis by introducing the difference-in-differences estimator. Since the work by [START_REF] Ashenfelter | Using the longitudinal structure of earnings to estimate the effect of training programs[END_REF], the use of difference-in-differences methods has become widespread in economics as well as in other fields working with social experiments [START_REF] Cook | Social Experimentssome developments over the past 15 years[END_REF][START_REF] Meyer | Natural and quasi-experiments in economics[END_REF]Imbens & Woolridge, 2009).

RESULTS

When interpreting the data, one should bear in mind that the difference-in-difference approach requires the identification of a specific intervention against which one should compare the difference in outcomes before and after intervention for a treatment and a control group. A source of spatial and temporal policy variation is necessary to estimate this effect. However, the effect of board membership cannot be expected to be exactly identifiable from year 0 or 1 due to publication lags. Publication lags are generally considerable in economics journals, and the lag can occur in various stages of the process [START_REF] Yohe | Current Publication Lags in Economics Journals[END_REF][START_REF] Trivedi | An Analysis of Publication Lags in Econometrics[END_REF][START_REF] Ellison | The Slowdown of the Economics Publishing Process. The Slowdown of the Economics Publishing Process[END_REF][START_REF] Azar | The slowdown in first-response times of economics journals: can it be beneficial?[END_REF]. In 1987 the publication lag was reported to be 65 to 90 weeks on average from submission to publication. Publications in the 1987 issues were consequently submitted in 1985 and 1986 [START_REF] Ashenfelter | Report of the Editor American Economic Review[END_REF]. In 2004 the publication lag was reported to be 83 weeks on average indicating that publications in 2004 were submitted in 2002 or 2003 [START_REF] Moffitt | Report of the Editor: American Economic Review[END_REF]. Thus, any flattery citations to an entering board member or editor cannot be expected to be seen before at least 1 to 2 years after entry.

Before analysing the data statistically we present a figure illustrating the average number of citations received by an editor or board member in a publication is these three journals during the years before and after entry. The data has been pooled regardless of the year entering board.

[ FIGURE 1] Figure 1 Average number of citations per publication to an entering board member (year 0 is the entering year).

First of all we notice that citations to scholars entering the American Economic Review tends to be lower than the number of citations received by these scholars in Journal of Political Economy and Quarterly Journal of Economics. Furthermore, the members of board tend to receive more citations during the entire period and not only in the years after entering the board. Consequently, the increase in citations over time seems to be a general trend.

However, the trends illustrated in this figure are highly dependent on the number of references in the journal. By pure chance, an individual is much more likely to receive 1 out of 100 citations than to receive 1 out of 1000. Consequently, the next figure depicts the average number of citations per reference to an entering board member.

[FIGURE 2]

Figure 2. Average number of citations per reference to an entering board member (year 0 is the entering year).

Figure 2 does seem to indicate a slight increase in citations to board members in American Economic

Review whereas such an increase is more difficult to determine for the two control journals, and consequently the difference between figures 1 and 2 could very well be a general increase in the number of references. The mean number of citations received in American Economic Review is generally lower than the two reference samples implying that there is a lower number of references per publication in American Economic Review compared to the two other journals.

The results are reported first in the form of descriptive statistics. Appendix 2 illustrates the differences in the number of citations received in the present study. It is evident that American Economic Review receives noticeably more citations than the two control journals. Consequently, normalisation is necessary. Normalisation is typically calculated using publications as is the case with the journal impact factor. However, alternatives exist that may provide a different picture of impact (see e.g. [START_REF] Nicolaisen | The Reference Return Ratio[END_REF]Opthof & Leydesdorff, 2010;[START_REF] Van Raan | Rivals for the crown: Reply to Opthof and Leydesdorff[END_REF]Leydesdorff & Opthof, 2010;[START_REF] Leydesdorff | How fractional counting affects the Impact Factor: Normalization in terms of differences in citation potentials among fields of science[END_REF]. Appendix 3 contains a table with the number publications and references in the three journals during the observed period. It is evident from the table clearly that the three journals have extremely different levels of annual publications as well as references.

Consequently, the two different methods of normalisation are included in the statistical analyses below.

The results of the statistical analyses are available in the following table. The table provides an overview of the various models.

[ Table 1] In order to be able to compare the number of citations in the three different journals we have to use some sort of normalisation, since otherwise any measured effect may be driven purely by different citation patterns or the different number of publications in the journals. Therefore, the citations are normalised using two different approaches. In the first approach, we normalize by the number of publications published in the relevant journal in the relevant year, and in the second approach, we normalize by the total number of citations given in the journal in that year, i.e. the resulting number is the share of citations given to a particular individual that year. As can be seen from Table 1 the results of the two analyses are fundamentally the same and consequently, we report both analyses simultaneously.

These two variations of the normalisation of citations differ according to entering person dummies, i.e. controlling for characteristics of specific persons in the data set. Consequently, two different regressions are being computed: One with person dummies and one without. Again, the results of the now four different analyses are the same and we report both simultaneously.

First of all, the number of citations received in Journal of Political Economy and Quarterly Journal of Economics are lower than the number received in American Economic Review. This is the case both before and after entering board of American Economic Review implying that is not an effect caused by entering board. Secondly, we find no effect of being an editor or co-editor compared to being an ordinary member of board when controlling for individual characteristics, but in the regressions with no person dummies this variable is highly significant reflecting the fact that editors and co-editors of American Economic Review are highly cited regardless of year or journal. Finally and perhaps most importantly, we cannot detect a citation effect of entering board of American Economic Review in any of the specifications, meaning that the present study must reject the hypothesis of flattery citations. 2In our search for evidence of the flattery citation effect one might argue that the effect may not exist for regular members of board, but may be measurable for editors and co-editors. Their roles make them more likely to receive flattery citations as their potential influence on the fate of a particular submission is expected to be much greater. Therefore we proceed by testing the flattery citations hypothesis specifically for editors and co-editors and consequently, we select out the subpopulation of our data containing only editors and co-editors of American Economic Review. Appendix 4 illustrates the development in total sums of citations received by board members excluding editors and co-editors.

greater increase in the citations received by the latter group compared to former but on the other hand the increase predates entering board. We test the citation flattery effect for editors and co-editors statistically. We use the same four models as previously (excluding the binary editor variable) and the results of the statistical analyses are available in Table 2.

[Table 2] The results of these regressions confirm the overall picture from Table 1, namely that no flattery effect can be found. Surprisingly, the results indicate that editors and co-editors not are cited to a larger extent in American Economic Review than in the other two journals as was the case for the entire population of editorial board members. However, the editors and co-editors of American Economic Review do receive a larger share of citations in their own journal than in Quarterly Journal of Economics.

DISCUSSION AND CONCLUSIONS

In the early days of science studies it was generally accepted among those who studied the sociology of science that scientific research is governed by a set of rules that are supposed to establish trust in, and guarantee the reliability of, the knowledge created in the research process. This scientific ethos was given its most concise and powerful formulation by the American sociologist Robert King Merton (1910-2003) who defined it in terms of four basic norms known as the CUDOS norms [START_REF] Merton | The normative structure of science[END_REF] 1973). 3 3 Communism (later termed "communality") expresses the norm that because all scientific inquiry relies on prior scientists" efforts to some degree, scientific advancements should be added to the pool of communal knowledge. Property rights should be kept to a minimum, and the members of a community must exchange the scientists" claims to intellectual property for recognition and esteem.

Universalism is the principle that truth claims should be subjected to pre-established, impersonal justification criteria that exclude consideration of particularistic criteria such as a scientist"s race, nationality, class, or religion.

Disinterestedness conveys the idea that scientists should seek truth objectively, without considering their individual interests.

Organized Skepticism captures the norm that before results should be deemed valid, the scientific community at large should examine their reliability. Norman Kaplan"s article The Norms of Citation Behaviour from 1965 is generally accepted as being the first explicit account of citing as normative behavior (e.g. [START_REF] Small | Citations and consilience in science[END_REF]. [START_REF] Kaplan | The norms of citation behavior: Prolegomena to the footnote[END_REF] held that "footnoting practices" are passed on by word of mouth from professor to student and by an examination of the varying practices of different journals. The major function of footnoting or citing is, according to Kaplan, the reaffirmation of the underlying norms of scientific behavior. About the same time as [START_REF] Kaplan | The norms of citation behavior: Prolegomena to the footnote[END_REF] issued his belief in citation practices being governed by an implied set of rules, Eugene Garfield (1965: 85) published a list consisting of fifteen reasons why authors cite. The list describes scientists as essentially faithful disciples of the CUDOS norms. Melvin Weinstock, in his article on citation indexes in Encyclopedia of Library and Information Science, offers the exact same list of reasons why authors cite. Weinstock"s introduction to the fifteen reasons is interesting as it precisely discloses the most basic assumption of the normative theory of citing: "Scientific tradition requires that when a reputable scientist or technologist publishes an article, he should refer to earlier articles which relate to his theme. These references are supposed to identify those earlier researchers whose concepts, methods, apparatus, etc. inspired or were used by the author in developing his own article (Weinstock, 1971: 19).

According to the normative theory, failure to give credit where credit is due only rarely occurs. Cole and Cole (1972: 370), for example, state that "sometimes […] a crucial intellectual forebear to a paper is not cited. The omission is rarely due to direct malice on the part of the author but more often to oversight or lack of awareness […]. We can assume that omitted citations to less influential work are random in nature […]". Garfield (1977: 7) agrees declaring that "the vast majority of citations are accurate and the vast majority of papers do properly cite the earlier literature". However, in the next sentence, Garfield admits that this assertion had not been empirically substantiated: "Unfortunately, there has never been a definitive study of this assertion".

The basic assumption of the normative theory of citing was not tested before the 1980"s. The pioneers of this work were not adherents of the normative theory, but a group of skeptics including among others the two biologists Michael H. MacRoberts and Barbara R. MacRoberts and the information scientist Terrence A. Brooks. These skeptics challenged the basic assumption that scientists cite their influences (e.g. [START_REF] Macroberts | Rejoinder[END_REF][START_REF] Macroberts | The negational reference: Or the art of dissembling[END_REF]1986;1987a;1987b;1988;1989a;1989b;1996;2010;[START_REF] Brooks | Private acts and public objects: An investigation of citer motivations[END_REF]. Moreover, new lists of citer motives began to surface -lists with motives far from those ideally prescribed by the CUDOS norms (e.g., [START_REF] Thorne | The citation index: Another case of spurious validity[END_REF]MacRoberts & MacRoberts, 1989a;[START_REF] Seglen | The skewness of science[END_REF]1997;1998). These lists portray the citing scientist as basically egoistic, selfinterested, particularistic, and prejudicedmore or less the opposite of the citer characteristics prescribed by the CUDOS norms. This quote from Seglen (1992: 636) is a telling example when compared to the Weinstock quote above: "Citations are not issued as an entirely fair and objective record of influence, but reflect both the needs and the idiosyncrasies of the citer, including such factors as utility, quality, availability, advertising (self-citation), collaboration or comraderie (in-house citations), chauvinism, mentoring, personal sympathies and antipathies, competition, neglect, obliteration by incorporation, argumentation, flattery, convention, reference copying, reviewing, and secondary referencing".

That an author sometimes cites to flatter a superior, a potential referee, or the editor of the journal s/he is about to submit an article to has been known and recognized long before P.O. Seglen began to write about it. Garfield has long ago admitted that flattery citations are a real phenomenon: "In some cases, without doubt, citations may be used for all those sullied purposes that supposedly demean its usefulness for information retrieval: flattery, padding, borrowed distinction, etc." Garfield (1974: 5) However, contrary to Seglen, Garfield (1974: 5) maintains that such cases are "the trivial exceptions".

The results of our study of four selected LIS journals confirm this [START_REF] Frandsen | A lucrative seat at the table: Are editorial board members generally over-cited in their own journals?[END_REF]).

Although we were not able to unambiguously determine whether flattery citations are actual or not, our results clearly show that any effect of such citations are at best minimal. We therefore concluded that the flattery citation effect appears to be inconsequential for citation analyses made on larger datasets. Yet, our study only concerned four journals representing one discipline. The flattery effect could be bigger and thus more consequential in other journals and disciplines. In order to test the flattery citations hypothesis further, we turned to the field of Economics. In this study we have analysed the number of times the editors and editorial board members of the American Economic Review were cited in articles published in the journal itself as well as in a pool of documents comprising of articles from Journal of Political Economy and Quarterly Journal of Economics. Results of the present study support the findings and conclusions of our last study. We find no support for a flattery citation effect in this analysis.

There are probably many good reasons why flattery citations are non-existent or very low in numbers.

One of the main reasons is perhaps that the risk of getting exposed as a toady sets a limit to the amount of flattery citations one can possibly bear to put in a scholarly paper. Scholarly papers have (potential) readers. Nevertheless, as discussed by Nicolaisen (2007: 625-629), this is regretfully often neglected by those who argue that citations are mostly given by the author for egoistic and self-promoting reasons.

The scholarly paper has been around for about 350 years and is apparently still doing very well. It is read, quoted, and used by men and women in a great many professions and societies. Would that be the case if the scholarly paper was just a fraud -If citations were mainly given for egoistic and selfpromoting reasons (e.g., flattery)? It is almost impossible to imagine that the scholarly paper could have survived for so long and with such success if that was the case. Scientists would long ago have stopped reading, quoting, and using it. In other words, it would have lead to the collapse of that communication channel. What our results seem to suggest is that flattery citations are non-existent or very low in numbers in the field of Economics, and thus only leave a small and insignificant toll on the scholarly communication system in that discipline. Although these results are in accordance with the results of our study of flattery citations in LIS [START_REF] Frandsen | A lucrative seat at the table: Are editorial board members generally over-cited in their own journals?[END_REF], more studies are obviously needed in order to investigate whether our conclusions are valid for all disciplines.

  tests the flattery citations hypothesis in four selected LIS journals (Journal of Documentation; Journal of Information Science; Journal of the American Society for Information Science (and Technology); Library & Information Science research).

The citations are found using Social Sciences Citation Index. Additional citation indexes are superfluous as we only need the publications of the journals in the analysis to be indexed.

There is a significant publication lag in economics, so one could argue that any flattery effect should not be observed earlier than 1-3 years after entry into the editorial board. For this reason different specifications of the regressions with flattery effect being measured only from year 2 and

after entry have been carried out. However, these regressions yield qualitatively identical results to the ones reported in Table1.

Acknowledgements

This paper is in part an extension and continuation of a paper presented at the ASIS&T Annual Meeting in Pittsburgh, PA (2010). The authors gratefully acknowledge the kind advice received in the reviewing process as well as the constructive feedback and suggestions from the audience.

GROUPS [APPENDIX 2] APPENDIX 3. PUBLICATIONS AND REFERENCES IN TREATMENT AND CONTROL GROUPS

Publications References


Dr Xandra W Van Den Tweel
email: x.w.vandentweel@amc.nl

PhD Johanna H Van Der Lee

PhD Harriët Heijboer

PhD Marjolein Peters

PhD Karin Fijnvandraat

Development and validation of a pediatric severity index for sickle cell patients

Keywords: Sickle cell disease, Pediatric hematology/oncology sickle cell anemia, severity index, morbidity 20-07-2010

Introduction. There is no instrument to measure severity of sickle cell disease (SCD) in pediatric patients that is generally accepted. The aim of this study was to develop and validate a severity index for SCD in children.

Methods. We developed an index consisting of 12 items and tested its validity of the index using data from 92 children. We tested whether different scores were obtained for patients classified by severity both subjectively and objectively by a partially validated existing index. Furthermore, we tested whether the index could differentiate patients classified according to genotype or the number of alpha-gene deletions and evaluated whether the score on the index was correlated with the average number and days of hospitalizations/year, age and a risk of death score.

Results. We explored the effect of three different weighting systems (score A, B and C) to summarize these items. All weightings demonstrated a significant difference between the scores of mild, moderate and severely affected patients, as classified by a subjective rating or with an existing index (p<0.01). The index clearly differentiated patients by genotype (p<0.01) or alpha-gene deletions (p<0.01). The correlation with hospitalization was moderate. Age and the risk of death score were weakly associated with the pediatric severity index for SCD.

Conclusion. This is the first pediatric SCD severity index that was developed and validated using modern clinimetric methodology. The validity and reliability of this index should be further evaluated in a prospective study including a larger cohort, preferably diagnosed at birth.

Introduction

Although sickle cell disease (SCD) is caused by a single missense mutation in the βglobin gene, the clinical picture in SCD patients is heterogeneous. Patients with a severe clinical course suffer from recurrent painful vaso-occlusive crises, develop irreversible organ damage at an early age and may die prematurely [START_REF] Platt | Mortality in sickle cell disease. Life expectancy and risk factors for early death[END_REF]. At the other end of the spectrum, there are patients who have normal life expectancy with relatively few complications [2;3].

The phenotype in patients with SCD is determined by the interaction of both genetic and environmental factors, of which some have been identified [1;4-6]. It is important to increase our understanding of factors that contribute to a severe clinical course.

Knowledge of these determinants may help to unravel the pathophysiological mechanisms underlying the disease process, identify novel targets for therapeutic interventions, and enhance patient care.

Studies of determinants of disease severity may be performed efficiently if patients can already be classified as having mild or severe disease during childhood, thereby limiting follow-up time. Early classification is based on the assumption that disease severity is a characteristic of the individual that is relatively constant over time. Since children rarely manifest irreversible organ damage, a severity index that is specifically aimed at this population is needed. At present such an index does not exist.

A systematic literature review of all disease severity assessment instruments (indices) for SCD revealed that only four of the 30 identified indices were partially validated [START_REF] Cameron | Evaluation of clinical severity in sickle cell disease[END_REF][START_REF] Day | Development and evaluation of a sickle cell assessment instrument[END_REF][START_REF] Pearson | Autonomic reactivity and clinical severity in children with sickle cell disease[END_REF].

No fully validated indices for a pediatric age range were found. The aim of this study was to develop and validate a severity assessment instrument for SCD in children. We define the concept of severity as "the rate and extent of reversible and irreversible damage to organs brought on by the SCD process, resulting in impairment requiring medical intervention". The ultimate goal is to develop and reach international consensus on an instrument which will serve as an outcome measure in etiological studies of SCD severity in children.

Methods

Development of a severity score

Item selection was based on a pool of 51 items retrieved from a systematic review of all disease severity assessment instruments for SCD (unpublished work). Items from this pool were rejected if the item was not applicable to children, non-specific for SCD or confounded. An example of a confounded item is the age at diagnosis, which is determined by several other factors beside the disease severity, such as the presence of a neonatal screening program and accessibility of medical care. The final index consists of 12 items, with 6 items regarding cumulative lifetime incidence of organ damage, 2 items concerning the number of recurrences of SCD related complications over a period of two years and 4 laboratory items (Table I).

Definition of the items

Cumulative lifetime incidence

1. Bone necrosis (avascular) of the hip and/or shoulder: Pain in hip and/or shoulder and abnormalities of the hip and/or shoulder confirmed by X-ray or MRI.

Cerebral infarcts or vasculopathy

Cerebral infarcts: Acute reduction or cessation of the cerebral blood flow, observed by MRI or CTscan, resulting in focal neurological impairment lasting more than 24 hours or without focal neurological impairment (so-called "silent infarcts"). 5. Priapism: Sustained, painful, and unwanted erection of the penis that is the result of either increased arterial inflow (ie, high flow) or, more commonly, the failure of venous outflow (ie, low flow), resulting in blood trapping within the erectile bodies [START_REF] Nolan | Hemolysis-associated priapism in sickle cell disease[END_REF] for which intervention in the hospital was necessary.

6. Splenic sequestration (acute): Acute reduction of hemoglobin > 3.2 g/dl compared to hemoglobin values in the stable situation, combined with acute enlargement of the spleen.

Cumulative incidence over a period of two years

7. Acute chest syndrome: Presence of a new pulmonary infiltrate on chest X-ray film and/or a defect on radionuclide imaging of the chest or abnormalities on spiral CT-scan, combined with acute respiratory illness [8;11]. 8. Painful crisis: Pain in the arms and legs, back, abdomen, chest or skull that lasts for at least two hours, leading to hospital admission and attributable to SCD [START_REF] Day | Development and evaluation of a sickle cell assessment instrument[END_REF].

Weighting of the items

Three different weighting systems to summarize the items of the severity index were used (Table I). First, all items were summed with an equal weight of 1, leading to score A. Secondly, acute life-threatening events and neurological complications were assigned more weight, receiving a score of 10, with all other items assigned a score of 1 (score B). events or complications associated with major sequelae (i.e. pneumococcal septicemia and/or meningitis, acute hepatic sequestration, acute splenic sequestration, cerebral infarction or vasculopathy). Although avascular bone necrosis and priapism are considered to be severe complications as well, they do not lead immediately to acute life threatening events. We therefore did not assign the maximum score of 10 for the presence of each of these items. Five points were attributed to laboratory values.

In score C the frequency was taken into account by attributing a higher score to episodes of acute chest syndrome and painful crisis that occurred more than once over a period of two years. As recurrent episodes of acute chest syndrome are associated with sickle cell chronic lung disease and increased mortality [12;13], a larger weight was attributed to this complication. Cut-off values to define abnormal laboratory parameters were obtained by using the upper tenth percentile (leucocytes, LDH) or lower tenth percentile (Hemoglobin, HbF) of the values obtained in this study population.

Study population, management, and data collection

The data used to validate the index were derived from patients aged 0-18 years who were born and diagnosed with SCD (HbSS, HbSC or HbS-β-thalassemia) in the Netherlands, were seen at least twice a year at the outpatient clinic of the study center (tertiary referral hospital) and had been followed for a period of more than two years.

Patients born outside the Netherlands were excluded to reduce potential information bias. Information on "lifetime cumulative incidence" is more likely to be missing in this group. In the study center all patients receive penicillin prophylaxis until the age of 12 years in combination with five-yearly pneumococcal vaccination. Transcranial duplex ultrasound (TCD) is performed twice a year in children with HbSS/HbS-β 0 -thalassemia and HbS-β + -thalassemia from the age of 4 to 12 years and once every year in older Data on the cumulative incidence of organ damage and the number of recurrences of SCD related complications were retrieved from patient records over life-time and entered into a database. The number of recurrences of SCD related complications was documented over the last two observation years or over a period of two years before the start of hydroxyurea therapy or regular blood transfusions. Laboratory values were taken from the outpatient clinic, when patients were in a stable phase, not using hydroxyurea and at least four months after the last blood transfusion. The percentage of fetal hemoglobin was assessed after the age of two years. If more than one laboratory value was available during a stable phase over a period of one year, the average of these values was taken.

All patients in the study were classified according to severity by a subjective expert classification and by the "SCD Assessment Instrument" (SCDAI) described by Day [START_REF] Day | Development and evaluation of a sickle cell assessment instrument[END_REF] and we calculated the risk of death score published by Sebastiani [START_REF] Sebastiani | A network model to predict the risk of death in sickle cell disease[END_REF].

The subjective expert classification was performed by two experienced pediatric hematologists (HH and MP), who independently classified all patients into three categories (mild, moderate, severe) based on their experience with these patients and information from the patient files before the current index was made. Any disagreement between the two experts was discussed and consensus was reached on final classification of the patient. The "SCD Assessment Instrument" (SCDAI) consists of the number of painful episodes and the number of acute chest syndrome episodes over a period of two years. Its content validity, inter-rater reliability and test-retest reliability were found to be sufficient [START_REF] Day | Development and evaluation of a sickle cell assessment instrument[END_REF]. We collected data on the number and days of all hospitalizations for SCD related complications from the first visit to the hospital for SCD until the day of entering these data into a database and divided these by the number of observation years. The risk of death score consists of 16 items (both clinical events and laboratory tests) predicting the risk of death within 5 years. The predictive value of the death risk score was validated in two unrelated sets of patients [START_REF] Sebastiani | A network model to predict the risk of death in sickle cell disease[END_REF].

Score validity

We assessed the validity of our index according to generally accepted criteria [START_REF] Terwee | Quality criteria were proposed for measurement properties of health status questionnaires[END_REF]. In order to assess if the scores A, B and C relate to other measures of the same concept, we formulated eight hypotheses. First, we expected the scores to be incrementally different for the three patient groups (mild, moderate and severe) that were identified by the experts, with the highest score for the severe patient group. Secondly, we expected the scores to be incrementally different in accordance with the SCDAI score [START_REF] Day | Development and evaluation of a sickle cell assessment instrument[END_REF]. The third and fourth hypothesis specified that the scores would distinguish disease severity based on genotype (patients with HbSS/HbS-β 0 -thalassemia having higher scores than those with HbSC/HbS-β + -thalassemia) and/or number of alpha-gene deletions (lower scores in patients with one or more alpha-gene deletions), respectively. For all hypotheses, a p-value <0.01 was expected. The fifth and sixth hypotheses stated that there would be a positive correlation between the scores and the average number of hospital admission days for sickle cell related complications per year and between the scores and the average number of hospitalizations for sickle cell related complications per year (Spearman's ρ > 0.4). Only hospital admissions for sickle cell related complications, as described in our index, were included in the analysis. The seventh and eight hypotheses stated that there would be a positive correlation between the scores and age, between the scores and the risk of death score (Spearman's ρ > 0.4)

Statistics

The inter-rater agreement of the experts was assessed by weighted kappa (K). The higher the K value, the stronger the agreement of the experts [START_REF] Altman | Practical statistics for medical research[END_REF]. The Kruskal-Wallis test was used to test differences between the scores of the groups as classified by the experts. The Mann-Whitney-U test was used for differences between the scores for groups as classified by the SCDAI, distinction between genotype and number of alphagene deletions, respectively. The fifth (higher scores in children with a larger number of hospital admission days/year), the sixth (higher scores in children with a larger number of hospitalizations/year), the seventh (higher scores in older children) and the eighth hypothesis (higher scores in children with a greater risk of death within 5 years) were tested by Spearman's correlation coefficient.

Results

Patient characteristics

This study population consisted of 92 patients (68 HbSS/HbS-β 0 -thalassemia, 24 HbSC/HbS-β + -thalassemia). The median age at the time of data assembly was 9.7 years (range 2.7-18.6 years); 58% was male.

Twenty-nine (32%) patients scored "0" on all three severity indices. There was no difference in age between this group (mean age 9.1 ± 3.5 years) and the patients who scored 1 or higher on the severity indices (mean age 10.4 ± 4.7 years). II). Seven (8%) patients only scored on laboratory values. Painful crisis was the most common complication. The following complications occurred only in HbSS/HbS-β 0 -thalassemia patients: acute hepatic and splenic sequestration, central nervous system abnormalities, priapism and acute chest syndrome.

Validity

Table III shows the scores A, B and C for the entire study population and for different subgroups classified in four ways. The patients were classified according to severity by experts and according to the SCDAI. The weighted K value for inter-rater reliability of the severity classification by the two experts (pediatric hematologists) was 0.52, which indicates moderate agreement [START_REF] Altman | Practical statistics for medical research[END_REF]. Furthermore, patients were classified based on their genotype and on the deletion of alpha-genes.

The scores A, B and C were significantly different for the three severity categories classified by the experts (p<0.01, Figure 1) and for the two severity categories of the SCDAI (p<0.01). There was a significant difference in scores A, B and C for subgroups of patients classified according to genotype (p<0.01). Patients with the severe genotype (HbSS/HbS-β 0 -thalassemia) scored higher than patients with the mild genotype (HbSC/HbS-β + -thalassemia) on scores A, B and C (Figure 2). Patients with one or two alpha-gene deletions scored lower than those without alpha-gene deletions on scores A, B and C. The correlation between scores A, B and C and the number of hospital admission days/year and the number of hospitalizations/year was moderate and statistically significant (Spearman's correlation coefficient for number of hospital admission days/year of 0.51 (p<0.01), 0.53 (p<0.01) and 0.55 (p<0.01, respectively (Figure 3) and for the number of hospitalizations/year of 0.40 (p<0.01), 0.49 (p<0.01) F o r P e e r R e v i e w and 0.51 (p<0.01), respectively). There was no significant correlation between scores A, B and C and age (Spearman's correlation coefficient of 0.16, 0.18 and 0.19, respectively). The correlation between scores A, B and C and the risk of death score was significant but weak (Spearman's correlation coefficient of 0.31 (p<0.01), 0.29 (p<0.01) and 0.26 (p<0.05), respectively) (Figure 4). Of the 3 different weighting systems, score C distinguished best among patient groups, as is evident from Figure 1 and 2.

Discussion

This is the first SCD severity index, exclusively aimed at children, that was developed using a transparent methodology. The index adequately differentiated between patient groups classified for severity by experts and by an existing index (SCDAI). Moreover, the index differentiated between patients classified by genotype (HbSS/HbS-β 0 -thalassemia versus HbSC/HbS-β + -thalassemia) or by the number of alpha-gene deletions. There was a moderate correlation between the scores and the number of hospital admission days/year and the number of hospitalizations/year. There was no significant correlation between the scores from the index and age and the correlation with the risk of death score was very weak. Score C, calculated with the most refined weighting system differentiating between items according to severity and the frequency of occurrence of complications, discriminated best between patient groups.

Contrary to our expectation we did not find a higher severity score in older children. This lack of association between age and severity has also been observed by Cameron et al., who reported no correlation between their severity index and age in a cross-sectional study [START_REF] Cameron | Evaluation of clinical severity in sickle cell disease[END_REF]. This should be interpreted as an indication of the heterogeneity in phenotype.

Only a longitudinal study, following patients from early youth into adolescence can Since death rates in children with SCD are much lower than in adults, even severely affected children may not have a high risk of death within 5 years. Secondly, the observation period for acute chest syndrome and painful crisis in our study was restricted to a period of two years in contrast to the dataset used in the model predicting death, which assessed these complications over an undefined, probably longer period. Therefore, our patients may score lower on the death risk score. Third, in the death risk score sepsis was an important predictor of death. Our index attributed few points to sepsis, as the most important causes of sepsis in children with SCD can be prevented with penicillin prophylaxis and vaccination. Four of the patients in our dataset were scored as "severe" by the death risk score. All four patients had a history of sepsis. One of these patients died as result of pneumococcal sepsis due to non-compliance of penicillin prophylaxis.

There are some limitations in the selection of the sample of patients that was used for validation of our index. At the time this study was performed there was no neonatal screening program in the area of our center. Children with a severe course leading to mortality at an early age may well have been missed, resulting in selection of patients with a milder phenotype. Although every effort has been made to obtain information on previous treatment at other hospitals, missing information on the period preceding treatment at the study center cannot be completely ruled out. A history of e.g. symptomatic gall stones or priapism could therefore be missed, which could lead to an underestimation of these complications. In conclusion, we developed a SCD severity index by a transparent and rigorous process. Further validation is of this index is needed, e.g. in a large prospective cohort study of patients diagnosed by neonatal screening. After further refinement and adaptation of this index, it may form a base from which international consensus can be reached on outcome assessment in etiological studies of pediatric patients. It is important to use uniform outcome measures since this enhances the comparability of results across studies and enables statistical pooling in meta-analyses.

List of abbreviations

5

 5 Cerebral vasculopathy: Stenosis or occlusion of the cerebral arteries documented by MRA. MRA was performed in children with a velocity of > 200 cm/s measured by transcranial duplex ultrasound (TCD).

3 .

 3 Hepatic sequestration (acute): Acute reduction of hemoglobin > 3.2 g/dl compared to hemoglobin values in the stable situation, combined with acute enlargement of the liver.[START_REF] Miller | Prediction of adverse outcomes in children with sickle cell disease[END_REF]. Pneumococcal septicemia and/or meningitis: Pneumococcal septicemia and/or meningitis confirmed by respectively culture of blood and/or cerebral spinal fluid.

Finally, items were

  weighted according to the severity of the different complications and the frequency of occurrence, ranging from 5-50 points (score C). Both scores B and C attributed the highest score (respectively 10 and 50 points) to acute life threatening

  the age of 15 years onwards all patients are screened by cardiac ultrasound and ophthalmologic examination.

  complications had occurred in 56 (60%) patients (Table

  in severity with age. Our severity index did not correlate well with the risk of death score by Sebastiani et al. This may be due to several reasons. First, our severity index was not intended to predict death but to measure clinical disease severity.

13 Central

 13 nervous system abnormalities may be underestimated in the HbSC group, since patients with HbSS and HbS-β-thalassemia are frequently screened for elevated cerebral blood flow by TCD in contrast to children with HbSC. This may introduce information bias concerning asymptomatic cerebral infarction. Since MRI/MRA is only performed in children with abnormal TCDs (>200 cm/s), children with HbSC will not undergo MRI/MRA unless they are symptomatic.

Figure 1 .

 1 Figure 1. Results of index A, B and C for patients of three severity categories classified by experts (Hypothesis 1)

Figure 2 .Figure 3 .

 23 Figure 2. Association between Scores A, B and C and genotype (Hypothesis 3)

Figure 4 .

 4 Figure 4. Correlation between Scores A, B and C and the death risk score (Hypothesis 8)

Table I . The items of the severity index with different weighting systems

 I

	American Journal of Hematology			Page 16 of 22
	Items	Classification	Score A	Score B	Score C
	Lifetime cumulative incidence		Points	Points	Points
			(max 20)	(max 47)	(max 285)
	SCD TCD SCDAI 1. Bone necrosis (avascular) SCD Transcranial Duplex Ultrasound F o r P e e r R e v i e w F o r P e e F o r P if present 1 2. Cerebral infarcts or vasculopathy if present 1 3. Hepatic sequestration (acute) if present 1 4. Pneumococcal meningitis/septicemia if present 1 5. Priapism if present 1 6. Splenic sequestration (acute) if present 1 Number of recurrences over past two years 7. Acute chest syndrome absent; present OR ≥ 2 over a period of 2 years 0; 1 8. Painful crisis absent; present OR ≥ 2 over a period of 2 years 0; 1 Laboratory values 9. Hemoglobin (g/dl) If ≤ 6.6 g/dl 1 F o r P e e r R e v i e w 1 10 10 50 10 50 10 50 1 10 10 50 0; 1 0; 10; 20 0; 1 0; 5; 10 1 5 e r 10. HbF (%) If ≤ 3.0 % 1 1 5 e r 11. LDH If > 700 U/l 1 1 5 12. Leucocytes (10E9/l) If ≥ 15.2 x 10E9/l 1 1 5 R e R v e i e w v i e SCD Assessment Instrument w	2
		John Wiley & Sons			1

Table II . Occurrence of complications in 92 patients

 II

	Page 17 of 22		American Journal of Hematology
		No of	No of	HbSS/HbS-β	0 -thalassemia (n=68)	HbSC/HbS-β	+ -thalassemia (n=24)
		patients	complications	No of		% of patients with	No of	% of patients with
				complications	complication	complications	complication
	Number of organ damage complications (lifetime cumulative incidence) Bone necrosis (avascular) Cerebral infarction (asymptomatic) Cerebral infarction (symptomatic) Cerebral vasculopathy (stenosis/occlusion) Hepatic sequestration (acute) Pneumococcal meningitis/septicemia Priapism Splenic sequestration (acute) Patients with ≥ 1 organ damage complications 36 Number of other SCD related complications (cumulative incidence over the last 2 years) 1 3 2 6 2 4 1 5 57 Acute chest syndrome 8 11 Painful crisis 24 35 Patients with ≥ 1 other SCD related complications 32 51 F o r P e e r R e v i e w 0 0 3 4 2 3 6 9 2 3 3 4 1 2 5 7 28 41 8 12 20 29 28 41	1 0 0 0 0 1 0 0 8 0 4 4	4 0 0 0 0 4 0 0 33 0 17 17
	Patients with ≥ 1 organ damage and/or	56	108	45		66	11	46
	other SCD related complications
			John Wiley & Sons				3

Table III . Scores of indices A, B and C for patients classified in four ways: 1) according to severity by experts, 2) according to severity by an existing score (SCDAI), 3) by genotype (β-globin gene mutation) and 4) by the presence or absence of an alpha-gene deletion

 III

		Number of	Score A		Score B			Score C
		patients	Median score (range)	Median score (range)	Median score (range)
	Total group	92	1 (0-7)		1 (0-23)			5 (0-130)
			Median	IQR	Median	IQR	Median	IQR	p
	Classification according to severity by experts*
	-mild	58
	-moderate	22
	-severe	12

American Journal of Hematology