The exploratory behaviour of rats in the hole-board apparatus : Is head-dipping a valid measure of neophilia ? The exploratory behaviour of laboratory rodents is of interest within a number of areas of behavioural pharmacology . However , how best to measure exploratory behaviour in rodents remains a contentious issue . Many unconditioned tests , such as the open field , potentially confound general locomotor activity with exploration . The hole-board apparatus appears to avoid this confound , as head-dipping into holes in the floor is assumed to be a valid measure of the subject 's attraction towards novelty -LRB- neophilia -RRB- . This study aimed to investigate whether head-dipping should be considered a valid measure of neophilia by comparing performance of adult male and female Lister hooded rats on the hole-board task -LRB- a -RRB- over repeated sessions and -LRB- b -RRB- when novel objects were absent or present underneath the holes . The results show that head-dipping initially decreased across repeated exposures , while time spent in the aversive central area increased . No change in head-dipping was seen in response to objects being placed underneath the holes . Rather than being a measure of neophilia , these results support the hypothesis that head-dipping represents an escape response , which declines as the subject becomes less fearful . These results are compared with previous studies of repeated exposure to other novel environments . 1 Introduction When faced with an unfamiliar environment or object , animals often exhibit behaviour patterns that broadly can be termed exploration , such as locomoting around the environment , orientating towards novelty , and touching or sniffing novel objects -LRB- Berlyne , 1950 , 1960 ; Glickman and Sroges , 1966 ; Welker , 1957 -RRB- . Exploration potentially provides an animal with new information about food sources , shelters or mating opportunities . However , by entering a new environment or attending to a novel stimulus , an animal might also increase it 's risk of predation , aggression from conspecifics or other hazards . Whether an animal investigates or avoids novelty has been described as the outcome of an approach -- avoidance conflict -LRB- Montgomery , 1954 , 1955 ; Montgomery and Monkman , 1955 -RRB- or as a balance between neophilic and neophobic tendencies -LRB- Greenberg , 2003 -RRB- . In motivational terms , neophilia can be defined as the attraction that an animal displays towards an object or place simply because it is novel , while neophobia is the aversion that an animal shows towards approaching a novel object or place -LRB- Greenberg , 2003 -RRB- . In behavioural terms , neophilia and neophobia can be considered respectively as curiosity-based approach to , and fear-based avoidance of , a novel stimulus -LRB- Hughes , 2007 -RRB- . The exploratory behaviour of rodents has gained recent interest within a number of areas of behavioural pharmacology . For instance , researchers studying drug addiction are interested in the neural mechanisms underlying neophilia due to the apparent overlap with the neural mechanisms involved in the rewarding effects of drug-taking -LRB- Bardo et al. , 1996 -RRB- . However , considerable controversy still surrounds the question of how best to measure neophilic and neophobic responses in laboratory animals . One of the most commonly used behavioural tests for laboratory rodents is known as the open field . Originally , the open field apparatus consisted of a flat , raised platform -LRB- Hall , 1934 , 1936 -RRB- , although the term open field is now commonly used to refer to any enclosed arena that can range in size from a small box to a large playing field -LRB- Crawley , 1985 ; Whishaw et al. , 2006 -RRB- . In such an arena , the overall level of locomotion and time spent in the centre of the arena -LRB- which is assumed to be aversive to rodents -RRB- are often interpreted as measures of exploratory behaviour . However , some researchers have argued that forcing an animal to be in an enclosed area , or on an open platform , does not allow the animal to exhibit its ` motivation ' to explore an unknown environment , as the task evokes a strong fear response -LRB- Birke and Sadler , 1986 ; Denenberg , 1969 ; Renner , 1990 ; Walsh and Cummins , 1976 -RRB- . Corticosterone levels have been found to rise in rodents on exposure to a novel open field environment -LRB- e.g. Marin et al. , 2007 ; Matzel et al. , 2006 ; Rees et al. , 2006 -RRB- , and open field behaviour is influenced by some anxiolytic -LRB- anxiety-reducing -RRB- substances -LRB- Prut and Belzung , 2003 -RRB- . In particular , benzodiazepines and serotonin receptor agonists , which have anxiolytic effects in human beings , generally increase the proportion of entries into the centre of the open field in rodents -LRB- Prut and Belzung , 2003 -RRB- . Together , these data suggest that the open field may provide valid behavioural measures of fearfulness , but may have limited value for researchers interested in measuring neophilia . Another common concern with interpreting open field tests is that differences in the performance of animals in the open field may result simply from differences in overall locomotor activity , which could be unrelated to differences in exploratory behaviour -LRB- Berlyne , 1960 ; Birke and Archer , 1983 -RRB- . In the 1970s , researchers began to use the hole-board apparatus , which consists of an enclosed arena with holes in the floor into which an animal can poke it 's head , referred to as head-dipping -LRB- e.g. File and Wardill , 1975a , b ; Nolan and Parkes , 1973 -RRB- . The frequency and duration of head-dipping are assumed to provide measures of neophilia -LRB- or directed exploration -RRB- that are independent from the general locomotor activity of the animal -LRB- File and Wardill , 1975a ; Ljungberg and Ungerstedt , 1976 -RRB- . This apparatus has been argued , therefore , to avoid the difficulties of interpreting general locomotion that prove problematic in the open field , and a number of studies have shown that head-dipping and locomotion can vary independently of each other -LRB- e.g. Abel , 1995 ; Durcan and Lister , 1989 ; File , 1977 ; Lister , 1987 ; Rogers et al. , 1999 -RRB- . In general , high levels of head-dipping are interpreted as indicative of neophilia , while low levels are assumed to result from a lack of neophilia or are assumed to reflect a high anxiety-like state in the animal -LRB- Crawley , 1985 ; Takeda et al. , 1998 -RRB- . The hole-board task is currently being used as a test of neophilia in many areas of behavioural pharmacology -LRB- Kliethermes and Crabbe , 2006a -RRB- . Researchers have attempted to validate head-dipping as a measure of neophilia by administering different classes of drugs and by comparing different genetic strains of rodents in their performance on the hole-board task . For example , if head-dipping is a neophilic response that is suppressed by an anxiety-like response , treatment with anxiolytic agents is predicted to increase head-dipping . Such studies have produced conflicting evidence ; for instances , treatment of rodents with anxiolytic benzodiazepines has been reported to increase -LRB- rats : File , 1977 ; mice : Nolan and Parkes , 1973 ; Takeda et al. , 1998 -RRB- , decrease -LRB- rats : Pellow et al. , 1985 -RRB- or have no effect -LRB- rats : Sayin et al. , 1992 -RRB- on the frequency of head-dipping . A recent review has suggested that the effects of anxiolytic compounds on head-dipping behaviour are generally confounded by changes in overall locomotion , despite the claims that head-dipping is unrelated to locomotor activity -LRB- Kliethermes and Crabbe , 2006a -RRB- . Similarly , a study of several inbred mouse strains reported that head-dipping and locomotion are highly correlated -LRB- Kliethermes and Crabbe , 2006b -RRB- . Whether head-dipping can be interpreted as a valid measure of neophilia remains unresolved -LRB- Bilkei-Gorzó and Gyertyán , 1996 ; Renner , 1990 -RRB- . The aim of this study was to investigate whether head-dipping behaviour should be considered a valid measure of neophilia by comparing performance of rats on the hole-board task -LRB- a -RRB- over repeated sessions and -LRB- b -RRB- when objects are placed underneath the holes . Repeated exposure to a novel apparatus is expected to produce a reduction in exploration as the animal becomes familiar with the environment , a process commonly referred to as habituation -LRB- Leussis and Bolivar , 2006 -RRB- . If head-dipping behaviour is a measure of neophilia , the frequency of head-dipping is therefore predicted to decrease over repeated sessions . In early study by Nolan and Parkes -LRB- 1973 -RRB- , head-dipping by young mice -LRB- 21 -- 25 postnatal days -RRB- was reported to be lower on a second exposure to the hole-board apparatus compared to the first exposure . Two recent studies have also provided evidence that head-dipping by mice and rats decreases on repeated exposure to the hole-board apparatus -LRB- Gagliano et al. , 2008 ; Mayeux-Portas et al. , 2000 -RRB- . If this behaviour is a valid measure of neophilia , head-dipping is also predicted to be higher in the presence , than in the absence , of objects . Although an early study reported that rodents head-dip more frequently when objects are present -LRB- File and Wardill , 1975a -RRB- , this finding has not received recent replication . Given that male and female rodents are reported to exhibit behavioural differences on the hole-board task -LRB- e.g. Aguilar et al. , 2003 ; Ray and Hansen , 2004 -RRB- , subjects of both sexes were included . 2 Materials and methods 2.1 Subjects and housing The subjects of this experiment were eight male and eight female adult Lister Hooded rats -LRB- supplied by Harlan , U.K. -RRB- . The animals were housed in a single room , which was controlled for temperature and humidity and was maintained on a 12-h light : dark cycle -LRB- lights on at 07:00 -RRB- . The animals were housed in same-sex pairs in plastic and wire mesh home-cages -LRB- measuring 25 cm × 45 cm × 15 cm -RRB- with ad libitum access to rodent pellets and water . All guidelines and requirements set out in the Principles of Laboratory Animal Care -LRB- National Institutes of Health , U.S.A. , Publication No. 86-23 , revised 1985 -RRB- and the U.K. Animals -LRB- Scientific Procedures -RRB- Act 1986 were followed . 2.2 Apparatus and experimental design The hole-board apparatus consisted of a wooden , grey box , measuring 68 cm × 68 cm . The walls were 40 cm high , and the box was raised 28 cm above the ground on a metal stand . Four holes -LRB- 4 cm in diameter -RRB- were cut into the floor of the apparatus ; each hole was 28 cm from a corner of the box along the diagonal from the corner to the centre . The floor of the box was marked out into four outer areas and one central area using black masking tape . The central area was delineated by four lines of tape each 20 cm from one of the walls , while the four outer areas were marked out by diagonal lines of tape running from the corners of the floor to the corners of the central square . The four holes were thus located at the corners of the central square . The apparatus was located in a small testing room with dimmed white lighting . The stand of the apparatus was open on all sides , allowing the floor or objects to be dimly lit . Each subject was tested ten times in the hole-board apparatus , once per day during two sets of five consecutive days -LRB- Monday -- Friday and the following Monday -- Friday -RRB- . During the first set of five trials , no objects were present underneath the holes of the apparatus ; during the second set of five trials , an object was placed on the floor under each of the four holes prior to the start of the trial , approximately 20 cm below each hole . The objects were all distinct from each other but were similar in size -LRB- approximately 10 cm in length or diameter : a black-and-white rubber ball , a purple plastic star , a red-and-white rubber pet toy , and a yellow , rubber dumb-bell shaped pet toy -RRB- . All trials were carried out between 09:00 and 17:00 h , and trials on males and females were alternated throughout the day . At the beginning of each trial , a subject was placed in one corner of the apparatus -LRB- always the corner closest to the door of the room -RRB- , facing the centre of the arena . Each trial lasted 10 min . At the end of the trial , the subject was immediately placed into a carrying box and returned to the home cage . Between each trial , the floor and walls of the apparatus and the novel objects , if present , were cleaned with 70 % alcohol solution . 2.3 Behavioural measurements During each 10-min trial , behavioural data were recorded by the observer -LRB- C.N. -RRB- onto a spreadsheet that was divided into 60 10-s time blocks . Inter-observer reliability between two independent observers -LRB- C.N. and G.R.B. -RRB- was over 80 % . The following behaviour patterns were recorded : -LRB- i -RRB- enter a new area : the animal moves from one area of the open field to another -LRB- all four paws had to be placed on the floor of a new area -RRB- ; -LRB- ii -RRB- head-dip : the animal places it 's head into one of the holes , to a minimum depth such that the ears were level with the floor of the apparatus -LRB- a new bout of head-dipping was recorded if the animal raised it 's head fully out of the hole before resuming -RRB- ; -LRB- iii -RRB- rear : the animal is stationary on it 's backpaws and raises it 's forepaws off the ground , extending it 's body vertically . The data on entries into a new area were used to calculate the total amount of locomotion -LRB- number of entries into all areas summed together -RRB- and the percentage of entries that were in made into the central area . The location of the animal during each of the 10-s time intervals was used to estimate the percentage of time spent in the central area . 2.4 Statistical analyses The data were analysed using repeated-measure ANOVAs , with ` objects ' -LRB- with or without -RRB- as a within-subject variable , ` trial ' -LRB- trials 1 -- 5 -RRB- as a within-subject repeated measure and ` sex ' -LRB- male or female -RRB- as a between-subject variable . Significant interactions were analysed further using simple effects post hoc tests -LRB- Howell , 2007 -RRB- . 3 Results 3.1 Total locomotion The total amount of locomotion did not vary across trials -LRB- F4 ,56 = 0.096 , n.s. -RRB- or vary with the presence or absence of objects -LRB- F4 ,56 = 0.071 , n.s. -RRB- . Females locomoted more on average than males -LRB- F1 ,14 = 4.871 , p = 0.045 ; Table 1 -RRB- . There were no interactions between trial and sex -LRB- F4 ,56 = 1.433 , n.s. -RRB- , trial and object -LRB- F4 ,56 = 2.615 , n.s. -RRB- or object and sex -LRB- F4 ,56 = 0.559 , n.s. -RRB- , and the three-way interaction between these variables was not significant -LRB- F4 ,56 = 1.174 , n.s. -RRB- . 3.2 Locomotion into the central area The percentage of entries that were into the central area differed significantly across trials -LRB- F4 ,56 = 14.842 , p < 0.001 -RRB- and varied with the presence or absence of objects -LRB- F1 ,56 = 84.240 , p < 0.001 -RRB- . There was also a significant interaction between trials and the presence or absence of objects -LRB- F4 ,56 = 7.662 , p < 0.001 -RRB- . Post hoc analyses indicated that the proportion of entries into the centre increased over the first five trials and remained steady thereafter -LRB- Fig. 1a -RRB- . The percentage of entries into the central area varied between the sexes -LRB- F1 ,14 = 5.209 , p = 0.039 -RRB- , with females exhibiting an overall greater proportion of entries into the centre than males -LRB- Table 1 -RRB- . There were no interactions between trial and sex -LRB- F4 ,56 = 0.761 , n.s. -RRB- or object and sex -LRB- F4 ,56 = 1.956 , n.s. -RRB- , and the three-way interaction between these variables was not significant -LRB- F4 ,56 = 2.567 , n.s. -RRB- . 3.3 Time spent in the central area The percentage of time spent in the central area differed significantly across trials -LRB- F4 ,56 = 8.085 , p < 0.001 -RRB- and varied with the presence or absence of objects -LRB- F1 ,56 = 35.393 , p < 0.001 -RRB- . There was also a significant interactions between trials and the presence or absence of objects -LRB- F4 ,56 = 3.493 , p = 0.013 -RRB- . Further analyses indicated that the time spent in the centre increased over the first five trials and remained steady thereafter -LRB- Fig. 1b -RRB- . The percentage of time spent in the central area varied between the sexes -LRB- F1 ,14 = 5.032 , p = 0.042 -RRB- , with females exhibiting an overall greater percentage of time in the centre than males -LRB- Table 1 -RRB- . There were no interactions between trial and sex -LRB- F4 ,56 = 0.083 , n.s. -RRB- or object and sex -LRB- F4 ,56 = 0.076 , n.s. -RRB- , and the three-way interaction between these variables was not significant -LRB- F4 ,56 = 1.001 , n.s. -RRB- . 3.4 Frequency of head-dipping The frequency of head-dipping differed significantly across trials -LRB- F4 ,56 = 2.626 , p = 0.043 -RRB- , and there was a significant interaction between trials and the presence or absence of objects -LRB- F4 ,56 = 4.482 , p = 0.013 -RRB- . Further analyses indicate that head-dipping decreased over the first five trials and slightly increased towards the end of the experiment -LRB- Fig. 2 -RRB- . There was no main effect of the presence or absence of objects -LRB- F1 ,14 = 0.142 , n.s. -RRB- . The frequency of head-dipping varied significantly between the sexes -LRB- F1 ,14 = 15.401 , p = 0.002 -RRB- , with females exhibiting an overall greater frequency of head-dipping than males -LRB- Table 1 -RRB- . There were no interactions between trial and sex -LRB- F4 ,56 = 0.324 , n.s. -RRB- or object and sex -LRB- F4 ,56 = 0.553 , n.s. -RRB- , or a three-way interaction between these variables -LRB- F4 ,56 = 0.779 , n.s. -RRB- . 3.5 Frequency of rearing The frequency of rearing differed significantly across trials -LRB- F4 ,56 = 3.204 , p = 0.019 -RRB- , with frequency increasing slightly across sessions -LRB- Fig. 3 -RRB- . There was no main effect of the presence or absence of objects -LRB- F1 ,14 = 3.898 , n.s. -RRB- or sex -LRB- F1 ,14 = 1.332 , n.s. ; Table 1 -RRB- . There were no interactions between trials and the presence or absence of objects -LRB- F4 ,56 = 0.457 , n.s. -RRB- , between trial and sex -LRB- F4 ,56 = 0.111 , n.s. -RRB- or object and sex -LRB- F4 ,56 = 0.006 , n.s. -RRB- , or a three-way interaction between these variables -LRB- F4 ,56 = 1.708 , n.s. -RRB- . 4 Discussion The aim of this study was to investigate whether head-dipping behaviour should be considered a valid measure of neophilia by comparing performance on the hole-board task -LRB- a -RRB- over repeated sessions -LRB- trials 1 -- 10 -RRB- and -LRB- b -RRB- when no objects were present -LRB- trials 1 -- 5 -RRB- and when objects were placed underneath the holes -LRB- trials 6 -- 10 -RRB- . The results show that head-dipping was high during the first test , decreased over the following two trials and remained relatively stable during the rest of the experiment . The initial drop in head-dipping following the first trial could be interpreted in two ways . First , head-dipping could be indicative of a neophilic response that decreases as the animal becomes familiar with the apparatus , i.e. head-dipping represents directed exploratory behaviour that drops as the apparatus loses its novelty . If this interpretation is correct , we would also predict that head-dipping would be greater in the presence of objects ; however , there was no evidence of an increase in head-dipping behaviour when objects were present underneath the holes . These results do not support the hypothesis that head-dipping is a valid measure of neophilia . The second interpretation of the initial drop in head-dipping frequency is that head-dipping could represent a fearful , neophobic response , such that , on first exposure to the apparatus , the animal actively attempts to find an escape route -LRB- Renner , 1990 -RRB- . Adult male rats have been shown to exhibit an increase in circulating corticosteroid levels following a single exposure to the hole-board apparatus -LRB- Márquez et al. , 2005 , 2006 -RRB- , suggesting that testing in this apparatus is a stressful event . If this interpretation of head-dipping is correct , we would also predict that , as head-dipping behaviour declines , fearfulness would also decline . In favour of this interpretation , while head-dipping frequency declined over the first few tests , the amount of locomotion into the central area of the hole-board , and the time spent in the central area , greatly increased over these trials . Therefore , as fearfulness apparently decreased , head-dipping also decreased . If we assume that the fear experienced on exposure to a novel apparatus can be equated to normal or ` state ' anxiety -LRB- Belzung and Griebel , 2001 -RRB- , these results contradict the assumption that head-dipping behaviour is suppressed by an anxiety-like response , in which case we might have expected head-dipping to vary in the opposite direction to anxiety-like behaviour . A small number of previous studies on rodents have also presented evidence that the frequency of head-dipping decreases on second exposure to the hole-board apparatus -LRB- Gagliano et al. , 2008 ; Mayeux-Portas et al. , 2000 ; Nolan and Parkes , 1973 -RRB- . The early study by Nolan and Parkes -LRB- 1973 -RRB- investigated whether previous experience with the hole-board apparatus with a solid floor inserted would influence frequency of head-dipping on second exposure to the apparatus . The results indicated that prior exposure to the plain board reduced the frequency of head-dipping on subsequent exposure as much as prior exposure to the board with holes -LRB- Nolan and Parkes , 1973 -RRB- . Again , these results do not support the idea that head-dipping provides a valid measure of neophilia , rather than a neophobic response induced by an unfamiliar test situation . In our study , head-dipping did increase in frequency towards the end of the experiment , after eight or more exposures to the apparatus . Therefore , we can not reject the possibility that , as the subjects became very familiar with the apparatus , they engaged in a greater level of visual exploration through the holes . Rearing behaviour is also commonly interpreted as an activity by which an animal obtains information about distal environmental cues -LRB- Lever et al. , 2006 -RRB- . Given that rearing behaviour gradually increased in frequency across the sessions , as the subjects presumably became less fearful , the amount of visual assessment of the testing room , both above and below the apparatus , may have increased . This interpretation is supported by an experiment carried out by Bilkei-Gorzó and Gyertyán -LRB- 1996 -RRB- . This study reported that the effects of the anxiolytic benzodiazepine chlordiazepoxide on head-dipping behaviour in rats varied with the light intensity during testing , such that treatment decreased head-dipping in very bright light and increased head-dipping under normal light . The authors argued that head-dipping during the aversive testing condition -LRB- bright light -RRB- represents an attempt by the subject to find an escape route from the apparatus , while head-dipping in less aversive conditions represents visual exploration of the apparatus . Future studies could investigate whether head-dipping increases with extended familiarisation to the apparatus even in the absence of novel objects , and whether head-dipping increases when novel objects are brought closer to the holes , when new novel objects are placed under the holes for each test , or when objects are re-located beneath different holes . Our results show that repeated exposure of subjects to a novel hole-board apparatus greatly affects the behavioural response , and that the neophobic response experienced by subjects during the first exposure to an apparatus apparently declines over further exposures . Repeated exposure to another commonly used behavioural test , the elevated maze , has been reported to result in a decrease in total locomotion and a decrease in the amount of time spent on aversive open sections of the maze -LRB- e.g. Cook et al. , 2002 ; Dawson et al. , 1994 ; Rodgers et al. , 1996 -RRB- . In contrast , in our study , no change of overall locomotion was found on repeated exposure to the hole-board , and the amount of time spent in the aversive central area of the hole-board apparatus increased over sessions . The reason for the differences in the behavioural effects of repeated exposure to these two types of novel environments may be related to differences in the design of the two types of apparatus . Repeated exposure to an elevated maze , which consists of open areas and closed areas , may have resulted in the subjects retreating into the darker , closed arms once an initial investigation had found no potential escape routes from the apparatus ; such a response was not an option in the hole-board test . If a shelter were added to the hole-board apparatus , locomotion might be predicted to decrease over repeated exposure , with subjects choosing to remain under a shelter once potential escape routes had been investigated . In support of previous reports -LRB- e.g. Aguilar et al. , 2003 ; Ray and Hansen , 2004 -RRB- , our results indicate that female rats head-dip more frequently , locomote more and spend more time in the centre of the hole-board apparatus than males . These sex differences in behaviour were not affected by repeated exposure to the apparatus , or by the presence of novel objects . Given that the locomotor patterns of female rodents are influenced by the stage of the estrus cycle and by experimental manipulation of hormones such as estradiol -LRB- e.g. Garey et al. , 2001 ; Morgan and Pfaff , 2002 -RRB- , researchers have questioned whether gonadal hormones might influence general levels of arousal that might impact on how females respond to novelty compared to males -LRB- Morgan et al. , 2004 -RRB- . However , while reports of sex differences in hole-board performance have been interpreted as showing that females are more exploratory than males , females have been reported to locomote more than males in familiar , as well as novel , environments -LRB- e.g. Cortright et al. , 1997 ; Eckel and Moore , 2004 -RRB- , and , as discussed above , head-dipping may not represent neophilic behaviour . Therefore , the conclusion that females are more exploratory or neophilic than males should not be drawn from such data . The results of this study indicate that the assumption that head-dipping on the hole-board task represents a neophilic response is not necessarily accurate . At least on first exposure to the apparatus , head-dipping is likely to result from an attempt by the subject to find a potential escape routes . This issue highlights a more general problem with unconditioned behavioural tests of exploratory behaviour , in that high levels of locomotion around an environment should not immediately be interpreted as neophilia or a positively rewarded aspect of novelty-seeking -LRB- Welker , 1957 -RRB- . Any behaviour in a novel environment will be influenced by both neophilia and neophobia , such that a single behavioural measure is unlikely to be purely indicative of either neophilic or neophobic tendencies . Rather than being at polar ends of a continuum , neophilia and neophobia should be thought of as two orthogonal factors that can vary independently -LRB- Greenberg , 2003 -RRB- . For researchers interested in rodent exploration , simple measures , such as head-dipping , are unlikely to expose by themselves the complex interaction between these two factors .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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PubMatrix : a tool for multiplex literature mining Background Molecular experiments using multiplex strategies such as cDNA microarrays or proteomic approaches generate large datasets requiring biological interpretation . Text based data mining tools have recently been developed to query large biological datasets of this type of data . PubMatrix is a web-based tool that allows simple text based mining of the NCBI literature search service PubMed using any two lists of keywords terms , resulting in a frequency matrix of term co-occurrence . Background With the advent of high throughput genomic and proteomic approaches , the ability to generate data has outstripped the ability to assign biological relevance . Searching the MEDLINE literature database of greater than 14 million entries one-by-one makes establishing biological significance a daunting task . The basic PubMed search window contains a typical single search box for the input of simple keyword combinations . PubMed does allows complex searches using advanced search options , but this requires some knowledge of string search assembly , and an understanding of the PubMed Entrez programming utilities . These are still relatively obscure for many molecular biologists . Literature mining approaches have been developed to place multiplex biological datasets into context relative to published medical literature . Computational tools such as PubGene -LSB- 1 -RSB- , VxInsight -LSB- 2 -RSB- , MedMiner -LSB- 3 -RSB- , EASE -LSB- 4 -RSB- , MeshMap -LSB- 5 -RSB- , XPLORMED -LSB- 11 -RSB- , AbXtract -LSB- 12 -RSB- , and HAPI -LSB- 13 -RSB- are available which allow the user to query more complex gene name or keyword combinations , including multiplex proteomic or cDNA microarray results , versus literature citations in PubMed with defined types of output . These computational tools use different strategies in literature mining and in some cases produce statistical significance or graphical displays . Similarly , literature based annotation projects such as the GO project -LSB- 9 -RSB- have devised a complex hierarchical annotation system using expert annotators based on a defined controlled vocabulary . This is important due to significant problems with nomenclature in molecular biology . Although quite useful , the GO approach does not allow for flexibility , variable interpretation , or individual investigator input in the hierarchies assigned to individual genes . In this report , we describe a simple , freely accessible , web based application for basic literature mining of PubMed that performs automatic multiplex Boolean queries . This allows the naive user to assign biological relevance and annotate gene lists through PubMed . Implementation PubMatrix is a CGI front-end application , which submits queries consisting of search and modifier terms against NCBI 's PubMed database and presents the results as a matrix of document hits . Results are stored in a database for retrieval and are presented as hyperlinks to the user for rerunning individual queries of interest . The application runs on an Apache http server using the PERL programming language and a MySQL database for storing terms and results . Results PubMatrix is a simple intuitive multiplex comparison tool requiring no user understanding of algorithm design , perl , or scripting , and minimal instruction time . It allows automatic systematic searching of PubMed followed by a quick intuitive survey of results , and as such , dramatically reduces the investigator time needed to query PubMed as compared to a gene-by-gene approach . Moreover , it is systematic and objective . Unlike typical PubMed searches performed on an ad hoc basis , the 1st and the 1000th query are searched in an unbiased manner . This helps avoid becoming distracted with seemingly interesting comparisons early on in a traditional literature search session . It is flexible in the sense that any list of terms in almost any combination may be used . With PubMatrix , large lists of keywords can be compared and , when used with lists of gene names and function , may be used to analyze and annotate microarray gene lists and datasets . GO keywords may be used to annotate gene lists in a semi-automated fashion . Additionally , the ability to save searches in an archive allows sharing among collaborators and public accessibility of curated lists of useful search results and search terms . Figure 1 shows the web interface for PubMatrix . Data entry begins with creating two lists of keyword terms , -LRB- figure 1 -RRB- SEARCH TERMS and MODIFIER TERMS . These can be any simple words or strings of words . Typically official gene symbols -LRB- TP53 , CTLA4 , etc. -RRB- can be used for microarray or proteomic data . These lists can be pasted into the appropriate data entry boxes on the page or loaded as a text file through the browser . Essentially any search combination that can be loaded into the basic PubMed search window can be run in PubMatrix in matrix file format . This gives a broad search capability as compared to PubGene -LSB- 1 -RSB- , which is limited to gene identifiers only . Terms in either list can contain PubMed field limits -LRB- i.e. author , title , abstract , journal , publication date , etc. -RRB- subject to PubMed/Entrez formatting specifications -LSB- 10 -RSB- . Compound terms in either list can be used as well . Like PubMed , success in using PubMatrix is dependent upon the quality of the input terms . If terms are general , you may end up with general results , if they are too specific , you may limit the search inappropriately . As in PubMed , PubMatrix makes no provision for nomenclature curation and provides no measure of statistical significance . General terms may be appropriate for some searches while specific terms may be useful for others . If the terms used are inappropriate or non-specific , the search will return inappropriate and low quality results ; quisquiliarum ineo quisquiliarum egredior . Figure 1 The PubMatrix Data Input Page There is currently a 100 SEARCH TERM and 10 MODIFIER TERM limit on the search capability due to NLM automatic script searching restrictions . The size and speed of PubMatrix is largely determined by NLM restrictions . In unrestricted tests , PubMatrix rapidly returned results using term lists of over 10,000 terms . The size limit of 100 × 10 will generally accommodate a gene list from a published summary table of microarray results or genes from a cluster produced from a typical clustering program . After data entry , the PubMatrix program then performs pairwise comparisons of each SEARCH term against each MODIFIER term using the Boolean operator `` AND '' , capturing only the pairwise frequency counts found in PubMed . It does not capture the actual PubMed record . Relative frequencies are then presented in an html matrix table -LRB- Fig 2 -RRB- of control terms versus search terms . This table can then be surveyed or sorted for positive hits . Clicking on a single frequency number in the matrix table then performs a de-novo individual query for that single pairwise combination in PubMed . In this way the user can drill down or focus on specific interesting combinations . Figure 2 The report page from a simple search of gene names versus neural modifier terms . All reported numbers are hyperlinked and will initiate a de-novo search for that specific term combination . Productive searches using broadly useful control term lists have been assembled into an associated PubMatrix public archive . These previously used search term lists may be commonly useful and may aid other investigators in subsequent searches . Examples include , official gene symbols , functional descriptors , cytogenetic bands , or polymorphic markers . Likewise , non-molecular term lists have been used and archived which may be broadly useful , such as commonly prescribed drugs , common diseases , and meeting speakers , among others . For example , prior to a meeting , an attendee can rapidly search all the meeting speakers names against important keywords found in the meeting program to provide a one-page summary of speakers scientific interests . Archived term lists can be copied to initiate new searches with new modifier term combinations . Table 1 gives examples of categorical lists of terms used in PubMatrix . Searches using these term lists can be found in the PubMatrix : Public Results page . Table 1 Examples of categorical search lists Category Examples Official Gene Symbols APOB , ACE , BDNF , CD45 , ... Polymorphic markers D1S478 , D6S470 , D13S193 , ... DNA sites AAATTT , CAGCAG , TTTTTT , ... Chromosomal bands 1ter * , 1p36 * , 1p35 * ... Xq27 * , Xter * Countries sweden , canad * , mexic * , finland , ... Common Prescription drugs acetaminophen , acyclovir , albuterol , alprazolam , ... Common diseases atopic dermatitis , asthma , crohn 's , Celiac , Graves ' , ... Date of Publication 1973 -LSB- dp -RSB- , 1974 -LSB- dp -RSB- ... 2000 -LSB- dp -RSB- , 2001 -LSB- dp -RSB- , 2002 -LSB- dp -RSB- Meeting Speakers Weiss A , Pierce SK , Kupfer A , ... PubMatrix tables can be combined or processed further to provide visual displays or summaries of complete experiments or large datasets in the context of medical literature . Figure 3 shows a display of cDNA microarray results of an ovarian cancer cell line treated with the drug cisplatin . The literature results are displayed in the context of gene expression ratios -LRB- Z-ratios -RRB- . Similarly , Figure 4 shows a comprehensive term list of human cytogeneic bands covering the human genome -LRB- 1p36 * , 1p35 * , 1p34 * ... Xter * -RRB- versus the single term `` Autoimmune '' . When displayed by chromosome , major autoimmune loci are identified . These include the major histocompatibility complex , chromosome 2q -LRB- CTLA4 -RRB- , as well as APECED on 21q . Figures 3 and 4 were displayed in MS EXCEL using the 3-D chart view option . Moreover , PubMatrix tables can be pasted into spreadsheet programs and imported into other types of data visualization programs such as CLUSTER/TREEVIEW -LSB- 11 -RSB- or SPOTFIRE -LSB- 12 -RSB- for graphic display and manipulation . Figure 3 Gene expression results -LRB- Z-ratio -RRB- of cisplatin treatment of an ovarian tumor cell line versus keywords relevant to cisplatin resistance . This graph was constructed in MS EXCEL directly from a PubMatrix search result table using the 3D chart view option after adding gene expression values -LRB- Z-ratios -RRB- . Figure 4 Visual display of chromosomal-band term list versus the term . `` autoimmune '' . Search terms were 313 sequential human chromosomal bands -LRB- 1pter , 1p36 , 1p35 , 1p34 , etc. ... Xq26 , Xq27 , Xq28 , Xqter -RRB- versus the single modifier term `` autoimmune '' . This graph was constructed in MS EXCEL using 3D chart view option after separating individual chromosome results into individual columns . Conclusions PubMatrix allows a simple systematic approach to query the medical literature in PubMed with comparative keyword lists . It performs simple automatic queries and greatly reduces analysis time . In this way , increasingly large datasets generated by high-throughput multiplex assays such as proteomic or microarray assays can be mined , archived , displayed , and annotated for biological and disease relevance . Availability and requirements PubMatrix is available for free use at this URL : Authors ' contributions KGB and TJB conceived the approach and participated in early design and testing . DAH , GD , RAL , and CC participated in software design and testing . JE participated in web design , database development , and algorithm modification . All authors read and approved the final manuscript

O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

literature mining
microarray
proteomic
pubmed


Learning from the problems of problem-based learning Background The last decade has witnessed a rapid expansion of biomedical knowledge . Despite this , fashions in medical education over the same period have shifted away from factual -LRB- didactic -RRB- teaching and towards contextual , or problem-based , learning -LRB- PBL -RRB- . This paradigm shift has been justified by studies showing that PBL improves reasoning and communication while being associated with few if any detectable knowledge deficits . Background Many doctors have commented that their medical education began in earnest on the first day that they entered the hospital wards as a hands-on practitioner . Claims of this kind support the view that the apprenticeship model of professional learning -- which has been the backbone of training in the healing arts for thousands of years -LSB- 1 -RSB- -- remains as central to medical career development today as ever -LSB- 2 -RSB- . A perennial complaint of the medical apprentice-in-training is that there are too few structured teaching activities within the busy world of postgraduate work -LSB- 3 -RSB- , a concern which many institutions have addressed by developing formalised continuing education initiatives reminiscent of medical school courses -LSB- 4-6 -RSB- . Predictably , different complaints prevail at the pre-licensure phase of the training spectrum , where students often feel more motivated to acquire the -LRB- implicit -RRB- competence of the practising doctor -LSB- 7,8 -RSB- than to absorb large volumes of -LRB- explicit -RRB- scientific and/or humanistic theory -LSB- 9,10 -RSB- . Such feelings underlie an unresolved debate over the optimal balance between factual -LRB- ` teaching ' , or content-based -RRB- and practical -LRB- ` training ' , or performance-based -RRB- components of professional development -LSB- 11 -RSB- and , as such , could explain a recent drift away from the didactic emphasis of older biomedical educative approaches -LSB- 12 -RSB- and towards quasi-experiential , or problem-based , learning -LSB- 13,14 -RSB- -LRB- PBL ; Figure 1A -RRB- . This hypothesis can not fully account for the PBL-led transformation of medical teaching in the 1990s , however , overlooking as it does a powerful contrary trend : the explosive proliferation of biomedical knowledge -LSB- 15,16 -RSB- as epitomized by the completion of the Human Genome Project -LSB- 17 -RSB- . Although at first sight contradictory , this reciprocal relationship between knowledge growth and didactic teaching invites a unifying explanation : namely , that the switch of educational philosophy to non-didactic methods represents a strategy for teachers and students to cope with the expansile information environment -LSB- 18,19 -RSB- . Figure 1 Comparison of growth rates of PBL and biomedical knowledge . -LRB- A -RRB- , Relative growth of interest in PBL versus lecture-based teaching based on PubMed keyword frequencies between 1975 and 2000 . The Title fields of the journal database were searched each year for the strings `` problem-based learning '' -LRB- open squares -RRB- or `` lecture '' -LRB- open diamonds -RRB- ; the retrieved items were then scrutinized to determine those dealing with the subject of teaching style -LRB- e.g. , eponymous `` lectures '' were excluded -RRB- . -LRB- B -RRB- , Growth rates of journal articles dealing with subject matter relating to science , medicine and education . The strings `` gene '' -LRB- solid diamonds -RRB- , `` clinical '' -LRB- open squares -RRB- and `` medical education '' -LRB- solid triangles -RRB- are shown here , illustrative of the frequencies of many other keywords searched . There are many things which a fresh medical student , unburdened by factual knowledge , can begin to learn : basic surgical methods , resuscitation interventions , generic reasoning skills , and counselling techniques , to name a few . The pivotal question , then , is not whether such context-dependent -LRB- but sequence-independent -RRB- learning will prove effective -LSB- 20 -RSB- ; rather , it is why this reorientation of teaching philosophy has occurred at all , and at this time . Or to put the issue another way : what is the hard evidence indicating that the original educational system was broken and that the new system is likely to fix it ? A secondary issue , which has been a prime concern of PBL critics -LSB- 21 -RSB- , is whether there may prove to be long-term hidden costs payable for the clear short-term benefits afforded by the PBL teaching philosophy . Since there are major differences in the way that PBL is implemented between schools , evidence to confirm or refute such hypotheses may be impossible to assemble . By the same token , it is an oversimplification to view all PBL as having low fact-based content , just as it is to equate all older teaching methods with rote learning . Nonetheless , since PBL veers more to the active/contextual , and didactic teaching to the passive/factual , it is plausible that one bias occurs at the expense of the other . Discussion What is knowledge -- anyone know ? The traditional educational sequence involves theory preceding application , an accelerated model of which has long been satirized in clinical circles as `` watch one , do one , teach one '' . As noted above , however , some applications may be learned in the absence of theoretical knowledge , just as some subsets of theoretical knowledge may be unassociated with any obvious application . Is it possible , then , to define a minimum essential `` core knowledge '' spectrum for the student of biomedicine ? If so , should such knowledge expand in parallel with other biomedical information , or should any such expansion be restricted by its relevance to changes in clinical performance -LRB- the ` barefoot doctor ' model -RRB- ? In the latter case , how long can healthcare competence and credibility be maintained in the face of rising constraints on scientific core knowledge -LSB- 22 -RSB- ? If core knowledge is indeed expanding at a rate similar to that of non-core knowledge , then the strategy of solving the broad problem of knowledge expansion by defining a narrower core can only be a temporizing measure . On the other hand , if the quantum of core knowledge is deemed non-expansile -- arbitrarily defined , for example , to represent the amount of knowledge capable of being instilled in an average student by x teaching hours per week spread over y years -- then any expansion of non-core knowledge will cause the core to shrink as a proportion of total knowledge . In 1984 , for example , a list of two hundred drugs was hailed as a solution to information overload in the field of pharmacology -LSB- 23 -RSB- ; but by 2000 the overload problem in this discipline was perceived to have deteriorated despite both the embracement of PBL and relentless efforts to re-define a core curriculum -LSB- 24 -RSB- . A key difficulty in addressing this problem is that expansion of biomedical information is asymmetric -- different areas of knowledge grow at different rates which in turn vary -LRB- and are ascribed differing priorities -RRB- during different periods -LRB- Fig. 1B -RRB- . In practice , most curricula cope with differential knowledge growth by adding new core modules to cover areas of rapid growth -LSB- 25 -RSB- ; the problem with this approach is that the notion of `` core '' becomes fluid , invalidating the concept . Moreover , it is difficult to discard ageing core knowledge at the same rate as adding new information , since the credibility of newer information tends by its nature to be weaker than that of older content . Rigid conservation of the core leaves trainees selectively deficient in new knowledge areas , on the other hand , making them less competitive in the marketplace . Discrepancies emerging between planned -LRB- taught -RRB- and actual -LRB- learned -RRB- medical curricula -LSB- 26 -RSB- further weaken the practicability of paradigms based on core knowledge . The concept of core knowledge as a stand-alone solution to the problem of information inflation thus appears flawed -LSB- 27 -RSB- . Although at any one time certain knowledge subsets may be deemed dispensable for learning purposes , a continuous expansion of knowledge must imply a comparable expansion of knowledge essential for maintenance of professional competence -LSB- 28 -RSB- . Moreover , practicality should not be the sole criterion by which core knowledge is judged ; a medical training system can not succeed by simply cloning service-based doctors , but must also produce academics , researchers , visionaries and leaders able to develop the service infrastructure -LSB- 29 -RSB- . It is against the background of these diverse challenges that the recent growth of PBL should be appraised . The lure of the non-expert A traditional authoritative doctor who dares challenge the information explosion faces the same risk as the immovable object confronting the irresistible force . The outcome has been to shatter the image of the omniscient doctor , as well as to dent the plausibility of experts in all fields . This slide from grace of the specialist -- formerly a dominant figure in the medical educational pantheon , and a revered colleague in the battle against information overload -LSB- 30 -RSB- -- has paralleled the decline of the lecture as a teaching medium . These linked trends suggest that the internet-empowered medical customer of the 21st century -LRB- whether patient or student -RRB- now questions information promulgated by mere individuals , thus threatening clinical and teaching paradigms formerly assumed unassailable . This problem has created a niche for PBL , rejecting as it has the old curriculum 's reliance upon experts and specialists -LSB- 31 -RSB- . The reported disadvantages of non-expert biomedical teaching with respect to knowledge transmission -LSB- 32 -RSB- and disease understanding -LSB- 33 -RSB- have been parried by numerous studies showing no detectable information deficits in PBL-trained -LRB- compared to lecture-taught -RRB- students -LSB- 34-38 -RSB- . Such negative data may be of limited reassurance , however , given the insensitivity of the endpoints used to measure what is in practice a rather limited curricular divergence -LSB- 39 -RSB- . It is likewise arguable that endpoints such as knowledge acquisition and clinical skills are surrogates , and that the most critical deliverable of medical training -- namely , the quality of patient outcomes -- has not been measured in any controlled trial of PBL -LSB- 40 -RSB- . These points lend credence to criticisms that the present-day popularity of PBL has so far been driven more by individual enthusiasm and conjecture than by objective scientific evidence -LSB- 41 -RSB- . Who , then , stands to gain from PBL ? Medical teachers are perhaps the most immediate beneficiaries -LSB- 42 -RSB- . Reduced self-perceptions of fallibility may be one attraction for teachers , as new PBL supervisors find that their educational contributions are no longer falsifiable by their pupils . In addition , responsibility for providing a sufficient knowledge base can be passed from teacher to student under the PBL auspices of ` self-directed learning ' -LSB- 43 -RSB- . Yet another benefit relates to the lack of formal preparation required to initiate a PBL session -LSB- 44 -RSB- -- an advantage which suggests a gain in efficiency . But does this bear scrutiny -LSB- 45 -RSB- ? Things have changed Efficiency can be calculated by dividing -LRB- productivity -RRB- by -LRB- time and effort -RRB- . What do we mean in this context by productivity ? A half-century ago , the only responsibility of a medical school was to produce clinicians to serve the local community ; today , however , teaching activities incorporate postgraduate specialist education , continuing medical education , professional and career development , public and patient awareness programmes , education-related research , conference and workshop organization , national and international collaborative initiatives , professional accreditation and audit activities , development of electronic teaching resources , and so on . Hence , a modern faculty 's teaching productivity is not able to be gauged exclusively -LRB- or even predominantly -RRB- by the number and quality of its outgoing medical graduates , but rather must be judged by the sum total of its useful educational output . This raises short - and long-term issues as to the most efficient ways to utilize faculty time and effort : traditional teaching service activities -LRB- e.g. , tutorials , mentoring -RRB- must compete with more ambitious developmental activities -LRB- e.g. , production of journal articles , books , software or web resources -RRB- . Small-group tutorials are a time-honoured teaching modality , but the opportunity cost is high ; while there must surely remain a place for personalized teaching , it seems doubtful whether the modern academic system can tolerate the luxury of an accelerating trend in this direction -LSB- 46 -RSB- . In contrast , the traditional apprenticeship training approach seems cost-effective , relying as it does upon the learner assisting a professional in the execution of his/her paid duties . In this context it is worth noting that the development of PBL -- growth of which during the 1990s coincided with similar trends favouring noncognitive-based medical school admissions -LSB- 47-49 -RSB- and humanities-rich preclinical experience -LSB- 50-52 -RSB- -- was spawned a quarter of a century ago in a regional medical school in Canada -LSB- 53 -RSB- . One need scarcely point out that the 1975 academic environment responsible for this educational breakthrough bears little resemblance to the market-driven imperatives that preoccupy most medical faculty members today , both in Canada -LSB- 54-56 -RSB- and elsewhere -LSB- 57-62 -RSB- . A changing environment not only justifies , but mandates , adaptation ; if the 1990s trends do indeed represent a retreat from an information-dominated world , then the substitution of a PBL-dominated philosophy could be fraught with significant longterm perils . From words to actions Solutions lie in compromise . Such change is painful because it involves the abandonment of ideals formerly attainable ; the vision of a one-size-fits-all medical school becomes no longer practical , and ever more difficult decisions will be needed as to what style -LRB- s -RRB- of graduate is most urgent for a faculty to produce . This process of curricular differentiation has started , but the pace is set to quicken as medical markets emerge and diverge , and as competition for faculty survival sharpens . To what extent , though , should these divisive educational decisions be made by markets , faculties , students , patients or governments ? Contrary to popular thought , there will remain a strong need -- and possibly an enlarging one -- for a subset of highly-trained medical graduates from a knowledge-intensive learning environment who are capable of assimilating the complexities of science , informatics , humanities and logistics that comprise modern medicine . Since the proportion of individuals and faculties suitable for this leadership mission looks set to decline , however , a larger number will need to accept the equally daunting compromise of skills prioritization . Teachers can not teach without students , but students can learn without teachers . This belated insight has transformed the role of teachers into that of learning facilitators , akin to a culture of `` thinking apprenticeship '' . Paradoxically , in an age when even complex skills such as landing aircraft are learned using robotic simulators , the trend in medical education has switched back to labor-intensive small-group teaching under the guise of PBL . This at first seems all the more curious given the unprecedented availability of alternative technologies for teaching clinical reasoning , the increasing importance of an adequate knowledge base in an ever more sophisticated professional environment , the growing pressures on faculties to use limited fiscal resources in the most cost-effective manner , and the novel opportunities for commercializing educational activities and products via the development of software and web-based resources . The rise in PBL popularity over the 1990s thus suggests a retreat from the fallout of the biomedical information explosion . Although this response seems rational enough as a short-term adaptive measure , it should not be regarded as a solution to the problem of knowledge expansion . Just as PBL was originally pioneered as a reaction against complacency in traditional pedagogy , so must today 's medical schools reject expediency and confront the unresolved information-management challenges of 21st-century medical education . The formulation of more efficient techniques for imparting factual knowledge , a greater emphasis on directing limited resources to the production of reusable teaching tools -LSB- 63 -RSB- , and a willingness to experiment with differentiated medical curricula that prioritise graduate skill subsets , can all play a role in driving educational reform as a positive and ongoing adaptive process . Summary The knowledge explosion of the last two decades has been accompanied by a decreasing reliance on didactic teaching . This educational paradigm shift has been led by widespread embracement of PBL , the original rationale of which was to improve students ' ability to reason and communicate . In recent years , however , PBL has grown more rapidly in apparent response to information overload in medical school curricula , and may thus be viewed as a symptom of the problem of biomedical knowledge expansion . The challenge of defining the right balance between what is taught , what is learned , and what remains unlearned will not disappear . Although few knowledge deficits have been detected in today 's PBL-educated students , a decreasing concern with the adequacy of the professional knowledge base could yet erode the future credibility of the medical profession . By continuing to rely on popular PBL escape clauses such as ` self-directed learning ' and ` information management ' , today 's medical educators risk losing sight of this longterm threat . The era of active learning began thousands of years ago with the first apprentice . We now live in a new era with new challenges , one of which is exponential information expansion . PBL provides one way for faculty and students to cope with this challenge , but sidesteps deeper issues relating to the widening core of essential professional knowledge . Innovative curricular experiments using educational strategies complementary to PBL would therefore appear timely . Abbreviations PBL , problem-based learning Competing interests None declared . Pre-publication history The pre-publication history for this paper can be accessed here :

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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