Assessment of neuropsychological trajectories in longitudinal population-based studies of children

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1 1 Department of Environmental Health, Boston University Shool of Publi Health, Boston, Massahusetts, USA; 2 Department of Neurology, Boston University Shool of Mediine, Boston, Massahusetts, USA; 3 Community Health Program, Tufts University, Massahusetts, USA; 4 Battelle Memorial Institute, Columbus, Ohio, USA; 5 University of West Virginia, Morgantown, West Virginia, USA Correspondene to: Dr R F White, Department of Environmental Health, Boston University Shool of Publi Health, Boston, Massahusetts, USA; rwhite@bu.edu Aepted 23 Otober 2008 This paper is freely available online under the BMJ Journals unloked sheme, see jeh.bmj.om/info/unloked.dtl Assessment of neuropsyhologial trajetories in longitudinal population-based studies of hildren R F White, 1,2 R Campbell, 3 D Eheverria, 4 S S Knox, 5 P Janulewiz 1 ABSTRACT This paper provides a strategy for the assessment of brain funtion in longitudinal ohort studies of hildren. The proposed strategy invokes both domain-speifi and omnibus intelligene test approahes. In order to minimise testing burden and pratie effets, the ohort is divided into four groups with one-quarter tested at 6-monthly intervals in the 0 2-year age range (at ages 6 months, 1.0, 1.5 and 2.0 years) and at annual intervals from ages 3 20 (one-quarter of the hildren at age 3, another at age 4, et). This strategy allows investigation of ognitive development and of the relationship between environmental influenes and development at eah age. It also allows introdution of new domains of funtion when age-appropriate. As far as possible, tests are used that will provide a rih soure of both longitudinal and ross-setional data. The testing strategy allows the introdution of novel tests and new domains as well as piloting of tests when the test burden is relatively light. In addition to the reommended tests for eah age and domain, alternative tests are desribed. Assessment methodology and knowledge about hild ognitive development will hange over the next 20 years, and strategies are suggested for altering the proposed test shedule as appropriate. This paper summarises the proess of reviewing and seleting outome measures that assess ognitive abilities as indiators of the development of brain struture and funtion from the age of 6 months to 20 years and offers a strategy for their use in epidemiologial studies. This strategy applies measures that are appliable in prospetive designs and allow desription of the natural development of ognitive skills while monitoring potential environmental influenes (eg, diet, soial, media, hemials) on developmental trajetories. This assessment plan assumes a omprehensive evaluation of dimensions of intelletual development that enompasses both appropriate aspets of ognition and detetion of vulnerable domains of funtion at speifi stages of development. The strategy proposed is signifiantly influened by the neuroognitive and neuropsyhologial literature. It is espeially appropriate for interpreting developmental ognitive outome data with regard to brain-behaviour relationships. An initial assessment issue involves resolving the tension between testing general intelligene and assessing neuropsyhologial funtioning. In the former ase, an intelligene quotient (IQ) is omputed based on administration of standardised omnibus tests. In the latter, domain-speifi sores are omputed based on administration of speifi tests. This issue has reeived onsiderable attention in the developmental neurotoxiology literature. Supplement IQ tests have been used extensively in the study of ertain types of toxiant exposures (espeially lead and polyhlorinated biphenyls (PCBs)), and it has been argued that IQ tests are preferable to other kinds of tests for their publi health value. This belief posits that individuals besides psyhologists understand the meaning of suh tests, and the results are therefore more likely to be taken seriously and ated upon by the publi health ommunity and soiety at large. In ontrast, domain-speifi neuropsyhologial tests have reeived more attention in reent years in behavioural toxiology beause of their sensitivity to prenatal exposure to toxiants suh as methylmerury 1 and niotine. 2 In addition, it has been argued that these tests provide more insight into the underlying entral nervous system (CNS) damage that may be assoiated with exposures, sine there is a signifiant literature that links impaired performane within individual domains or patterns of impaired and intat performane aross domains to speifi types of brain damage (strutural, neural system, neurotransmitter). Epidemiologial designs an allow onsideration of both IQ and domain-speifi outomes at ritial stages of vulnerability during hild development. Suh an approah provides the advantages of both types of assessment approahes as well as the potential to re-evaluate the results of existing studies when new data are aquired. DOMAINS OF RESEARCH INTEREST Categorising the dimensions of ognition into omponent parts is hallenging even to ognitive psyhologists and neuropsyhologists, who often divide or subdivide these dimensions in different ways. It is even more diffiult to ategorise existing ognitive and behavioural tests sine few were designed to be pure tests of a speifi aspet of ognitive proessing or a single domain. For the purposes of developing a reommended battery, domains were identified using the labels ommonly applied in linial neuropsyhology. 34 In addition, areful onsideration was given to key aspets of proessing that should be assessed within eah domain. The following list identifies the domains seleted by the authors and assoiated defining harateristis. The definitions are not meant to be exhaustive but to give the reader an overview of the types of skills subsumed under eah domain and assessed by assoiated neuropsyhologial tasks. General intelligene/mental abilities/omnibus ognitive skills tests These tests onsist of subtests with various labels purported to measure aspets of ognitive funtion. i15

2 Supplement Subtest sores are summed in order to obtain overarhing measures suh as IQ, often aompanied by omnibus measures of verbal abilities (eg, Verbal IQ, Verbal Comprehension Index), visual-motor or visuospatial skills (eg, Performane IQ, Pereptual Organization Index), attention/working memory (eg, Working Memory Index, Attention Index) or speed of proessing (eg, Proessing Speed Index). Aademi skills This domain inludes skills suh as reading words or paragraphs, spelling and ompleting arithmeti problems. Attention This domain enompasses several proesses inluding the apaity to fous on and attend to stimuli over a period of time (sustained attention, often assessed by Continuous Performane Tests) and the apaity to take in and report bak stimuli immediately after presentation (eg, Forward Digit Span or Visual Pointing Span). Exeutive funtion/working memory This is a omplex domain that historially inludes the apaities to learn and manipulate stimuli (eg, Digit Span Bakward, Visual Pointing Span Bakward), to invoke strategies for manipulating novel stimuli (any task with a struture that enhanes task ompletion if reognised) or to solve novel problems (problem solving tests). This domain inludes skills suh as the ability to aquire the set of new tasks and to maintain the set of the task while ompleting it as well as the ability to flexibly swith from one set of task requirements to another. Inhibition of dominant or distrating stimuli in order to attend to ritial stimuli is also inluded in this domain. Language/verbal skills This domain inludes basi linguisti abilities suh as the apaity to produe phonemes, lexial development and prodution of words, speeh omprehension and linguisti aspets of writing and reading. Language skills are often divided into expressive and reeptive omponents. Applied verbal skills, suh as voabulary definitions, are sometimes inluded in this domain. Visuospatial abilities These non-verbal abilities generally invoke the proessing and manipulation of visual designs, the spatial or physial aspets of environmental objets or onstrutional skills. These abilities are assessed by tasks suh as drawing designs, reognising objets presented in degraded form or embedded in a more omplex visual array, or assembling puzzles or blok designs. Construtional tasks involve motor output, but there are visuospatial tasks that require simply the mental manipulation of spatial information (eg, identifying the orret outline of an objet presented in ut-up form, mathing faes, mathing angles). Learning and memory This domain enompasses several aspets of memory funtion. Delarative memory is generally divided into anterograde and retrograde memory funtion. Anterograde memory refers to the learning of new information, retention of information over shorter and longer delays, and the apaity for retrieval of information from memory stores. It an be assessed using both reall and reognition paradigms (reall paradigms get at the i16 individual s apaity to retrieve information at will while reognition paradigms are often better at assessing apaity for learning and retention when retrieval problems exist). Anterograde memory funtions are sometimes divided into verbal and visuospatial omponents, generally assoiated with dominant and non-dominant memory funtion, although visuospatial memory skills are also frequently affeted in individuals with basal ganglia and white matter dysfuntion. Anterograde memory is measured in many ways inluding the presentation of stories, lists of words, designs or objets for immediate learning, with delayed reall and reognition (multiple hoie) onditions. Retrograde memory refers to the apaity to remember events or information from earlier stages of the individual s life. It an be tested using famous faes, questions about historial events or fats, or questions about the individual s personal history. Proedural learning and memory refers to the individual s apaity to learn and remember a problem-solving sequene (eg, reading words in a mirror) or a motor skill (eg, driving a ar). Motor skills These abilities refer to the individual s apaity to arry out manual motor ativities. Using neuropsyhologial tests, they are generally assessed using the hands (manual motor dexterity), with evaluation of speed and auray. Tasks may be relatively simple (tapping a omputer key or finger tapping apparatus), omplex and requiring oordination as well as speed (pegboard tasks) or integrative (writing or typing symbols to math digits on a oding task). Other domains an be inluded if relevant or if standardised tests beome available. These inlude expressive and reeptive prosody, motivation/malingering and tatile/kinestheti funtion. Tasks assessing the above domains and onditions under whih they might be applied are disussed in this paper. METHODS The development of a reommended longitudinal ognitive assessment strategy onsisted of several steps. First, a deision was made to fous on quantitative measures that detet subtle prelinial ognitive dysfuntion. Seond, it was deided to expand riteria for test seletion beyond outomes that solely depend on linial diagnosis of neuropsyhiatri disorders, as this strategy ould miss more subtle dysfuntion in hildren at ritial ages and has little power to desribe ognitive development. Further, the list of ritial domains and the stages of development that should be evaluated required definition. Using this framework, the list of tests and test batteries that evaluate these domains was developed and the tests were then reviewed aording to a set of riteria. Throughout this proess, existing linial and sientifi knowledge about hild development was supplemented with literature on developmental neurotoxiology, whih desribes the relationships between exposure to ommon environmental hemials and their effets on brain funtion. Studies in this field have taken advantage of the power of ognitive developmental tests as measures of brain funtion and have thus produed important information on domains of ognitive funtion that are espeially vulnerable to the subtle effets of environmental influenes, ages at whih partiular vulnerabilities may appear in speifi funtional domains, effet sizes of subtle defiits attributable to environmental influenes and test instruments that are espeially useful to detet subtle ognitive defiits in hildren.

3 Based on a review of the literature and on speifi riteria developed for test seletion, a subset of tests was identified and further explored for inlusion in a proposed assessment battery. In addition, strategies for assessing hildren at ritial stages during development were onsidered. It should be noted that the development of a battery to be used over long periods of time relies on the state of the art in the field at present. Therefore, one must antiipate that tests and test strategies will be adjusted at intervals as long-term studies progress. Overview of tests and test batteries available Many ognitive and neuropsyhologial tests have been published that diretly or indiretly assess the domains desribed above. A ompendium that was too extensive to publish with this paper is available on the NICHD website ( Pages/Neuropsyhologial-Assessments-in-Children-from-a- Longitudinal-Perspetive-for-the-National-Children-s-Study.pdf). It inludes approximately 135 tests and sales that are listed by domains of researh interest and inlude appliable age ranges. Inluded in that table are five of the most ommonly used batteries that have been reommended for evaluating hildren and adults with suspeted or known exposure to hemial toxiants. The listings are not exhaustive but inlude all tests onsidered for inlusion in the reommended battery. Some other types of novel tasks and tests are mentioned in this paper even though they do not exist as published standardised tests. Criteria used in test review The tests listed in the ompendium were reviewed by RFW and a shorter list of tests was seleted as andidate sreening tasks. Criteria for test seletion are disussed below. Plae of test in hild development literature Tests were onsidered with regard to their plae in the field of developmental psyhology. Tests that have been in widespread use by liniians and researhers were given preferene. This was done for several reasons. First, suh tests are generally feasible with regard to administration. Seond, they are more interpretable beause they are assoiated with more published information onerning the relationship of test outomes to partiular types of developmental disorders (eg, attention, learning disabilities, speeh and language disorders, extremes in IQ, motor defiits), neurologial diseases (eg, epilepsy, brain tumours, traumati brain injury), neuropsyhiatri disorders (eg, autism, hildhood depression, personality disorders, posttraumati stress disorder, anxiety), mediations and medial onditions (eg, geneti disorders affeting ognition, metaboli disorders, respiratory diseases). Suh information ontributes to the apaity of the tests to assist in sreening (for triaging hildren on to other evaluations) at the same time they serve as outome measures. In addition, struture-funtion relationships have been desribed for many of the tests, relating impaired performane on ertain tests (or patterns of impaired and retained performane on groups of tests) to partiular strutures of the CNS. This knowledge is ritial in that it may allow investigators to form hypotheses onerning the strutural or funtional elements of the CNS that may be affeted by exposures. These hypotheses an serve as the basis for further investigations (eg, sophistiated neuroimaging). Supplement Plae of test in the neurotoxiant literature If tests had proven sensitivity to low level and subtle effets of hemial exposures, they were high on the andidate list for exploring exposure-outome relationships in a large epidemiologial sreening study where toxiant exposure is being measured. They also may have value in examining the subtle effets of other types of exposure (eg, stress, violene, mediations, drugs, stimulus deprivation or overstimulation, undernourishment/overnourishment/malnourishment). The website ited above inludes extensive tables that summarise the developmental neurotoxiology literature that inluded standardised test outomes. Construt validity Priority was given to tests that have demonstrated ability to assess speifi domains. In addition, an attempt was made to identify tests that ould reliably assess a speifi ognitive proess (or a set of proesses) within a domain, and it was also deemed neessary to balane the types of tests used within and aross domains at speifi ages. Demographis Preferene was given to tests for whih the effets of age (in months at the younger ages) and gender have been defined/ quantified. It was ritial to inlude tests with a wide age range sine longitudinal studies may follow individuals from birth to age 20. Effets of parental eduation and intelligene were also onsidered, if available. Culture/ethniity/language Available data on the relationships between ulture and language and test performane were also onsidered. Are there ethniity/ultural effets on test performane, and if so, what are they? Are there speial versions of the tests for hildren from speifi subultures? How ulture-fair is the test? Also onsidered were effets of primary languages and multilingualism on test performane, inluding availability of the tests in languages other than English. Information was not available on these variables for many of the tests, but tests with suh information reeived speial onsideration. Psyhometris Sensitivity to subtle effets of exposures requires tests that possess ertain psyhometri harateristis. These inlude a suffiient range of outome sores and variane to reliably identify exposure-outome relationships. They must also be reliable (espeially with regard to test-retest reliability), that is, result in similar sores in the same person when measured at repeated time points with no hange in exposure. It is also important that they have demonstrated validity with regard to the onstrut they are measuring as demonstrated by their relation to other known tests (see above). Priority was also given to tests that are well standardised. Availability of appropriate normative values for test performane at different ages and for other variables was onsidered to be important for ertain purposes (eg, haraterising ohort performane relative to the US population). However, for data analysis purposes, raw sores are usually the outome of hoie in epidemiologial studies. Other fators Other test harateristis that were onsidered important inlude ease of administration, aeptability to hildren, aeptability to parents, reasonable diffiulty levels without i17

4 Supplement extreme frustration for most hildren, effiieny and apaity of the test to ontribute to sreening/triaging. Partiipant burden is a major issue and even outstanding measures were disarded if it they are too time-onsuming to allow inlusion of other required measures. Finally, it must be stated that RFW s experiene using the tests in researh and linial settings played a role in the test review. Batteries were limited in administration time to h, depending on age. Battery design and testing strategy for prospetive developmental assessments The literature on exposure-outome relationships is inomplete with regard to data on age at exposure and age at whih exposure effets an be deteted. For example, the neurotoxiology literature suggests that lead exposure in early hildhood is assoiated with IQ hanges 5 and that prenatal methylmerury exposure is assoiated with domain-speifi neuropsyhologial effets at the age of 7 years. 6 However, systemati studies aross ages of exposure, ages at whih outomes are measured and speifi toxiants do not yet exist. It is therefore diffiult to pinpoint ritial ages at whih speifi types of neuropsyhologial outomes should be measured. Given the existing knowledge, it appears that the optimal strategy is to aquire outome data at as many ages as possible. Beause pratie effets are large and an overwhelm subtle exposure effets, it is not reommended that eah hild be tested every year. A strategy that would allow the olletion of data in yearly age inrements but prevent pratie effets is to divide a large ohort into groups of hildren. Testing eah hild every 4 years beginning at age 3 6 would result in neuropsyhologial outome data on a large group of hildren at eah age. Before age 3, it is reommended that the four groups of hildren be tested at 6 months, 1 year, 1.5 years or 2 years. This strategy is outlined in table 1, whih gives an age 6 domain 6 test representation of a reommended battery. Eah of the four subgroups of hildren is designated by the letters A, B, C and D. This strategy also allows repeat testing with ertain key tasks at widely divergent ages, failitating longitudinal follow-up on exposure-outome relationships. The testing strategy neessarily initiates testing of different domains at different ages. For example, exeutive funtion testing is not introdued until age 7. Testing of learning and memory is limited before age 7. These reommendations reflet the developmental urve of domain-speifi skills as well as the availability of tests appropriate for ertain ages. These fators are disussed in greater detail below. The testing strategy allows for the introdution of different tests that assess the speifi domains at different ages. Using this strategy, domain-speifi findings observed on one test an be evaluated somewhat later with a similar test from the same domain, allowing a hane to evaluate onvergent validity. It is also possible to examine more than one speifi aspet of ognitive proessing within eah domain. In designing the battery, attempts have been made to evaluate parallel aspets of ognitive proessing during eah age range and within eah domain. Consideration was given to using the neuropsyhologial outome measures as triggers prompting omplete diagnosti evaluations in hildren who may have speifi types of developmental disorders. Thus, the reommended battery inorporates the ages and riteria for using outome measures to triage hildren into sreening for mental retardation, disorders of attention and learning, motor oordination defiits, autism and neurologial disorders. i18 Finally, the views presented here are guided by personal experiene of RFW, whih inludes 30 years of work in researh and linial settings assessing individuals aross the lifespan. This work has inluded prospetive evaluation of hildren with environmental exposures during infany and early hildhood, ross-setional researh on environmental toxiant exposures in hildhood, oupational exposure studies with adults and the long-term evaluation of neurodegenerative disorders in elderly subjets. In all of this researh, neuropsyhologial test tehniques have been applied as a method for unovering the underlying neuropathologial mehanisms of ation for ognitive development. The battery desribed below is viewed as a starting point in planning ognitive and neuropsyhologial assessments of a large ohort at various ages. RESULTS Reommended neuropsyhologial outome battery and alternative tests Table 1 summarises the reommended test battery to be administered at eah age level for eah proposed domain. The age ranges over 2 years at the lowest level (with 6-month intervals for testing until age 2) and 4 years after that until age years (so that 25% of the ohort is tested at eah age). A suggested testing shedule in a large study ould therefore ontain four groups: Group A: hildren tested at ages 5, 3, 7, 11, 15 and 19 years of age ; Group B: hildren tested at ages 1, 4, 8, 12, 16 and 19 years of age; Group C: hildren tested at 1.5, 5, 9, 13, 17 and 20 years of age; Group D: hildren tested at 2, 6, 10, 14, 18 and 20 years of age. It is noteworthy that this approah an also be used with other testing strategies in mind. For example, if all study population hildren were to be tested at fixed ages, the set of tests reommended for eah designated age ould be administered. The reader is also referred to the NICHD website ( whih inludes other details about the tests desribed in this setion. The rationale for hoosing the tests for eah domain will be reviewed, along with a summary of the advantages and disadvantages of eah test for both reommended and alternative tests. A brief setion will follow desribing speial requirements of test administration during eah of the six proposed age ranges and sreening possibilities during some testing yles. Assessment domains by age omnibus intelligene (IQ) and abilities measures These measures assess potential exposure effets on omnibus measures of general mental abilities at ages that have proved to be ritial in previous studies (0 2 and 3 6 years), ages at whih suh measures are relatively stable and should reflet IQ aross hildhood (7 10 years), and at an age when long-term effets on IQ of earlier exposures an be evaluated (15 18 years). For age years, the Bayley Sales of Infant Development- II 7 are reommended. Although other sales exist (eg, Fagan test, Brazelton Sale), the Bayley Sale has the best standardisation and has been used extensively in previous exposure-outome researh. For example, it has been applied to assess the effets of lead, 8 12 PCBs, methylmerury and dihlorodiphenyldihloroethylene Although the Bayley Sale is a fairly blunt instrument that may not pik up subtle defiits assoiated with exposures and the items are rather diverse (ie, they do not easily lend themselves to domain-speifi analysis), it is the best option available. It is reommended that this test be given to the ohort subgroups at one time point eah (6 months, 1 year, 1.5 years or 2 years).

5 Table 1 Reommended test matrix for a ohort of hildren with 25% in eah of four age exposure groups (A, B, C, D) Age at testing Battery length (min) Group(s) to be tested 6 months 20 A Sreening domain: Bayley-II 1 year 20 B Sreening domain: Bayley-II 1.5 years 30 C Sreening domain: Bayley-II 2 years 30 D Sreening domain: Bayley-II 3 years 60 A IQ domain: WPPSI-III (blok design, matrix reasoning, voabulary subtests) Attention domain: Conners Rating Sale-R Language domain: EVT (naming subtest); PPVT-III Visuospatial domain: Beery Visual-Motor Integration Test-5 Motor domain: Revised Purdue Pegboard Novel/pilot tests (group C) 4 years 75 B IQ domain: WPPSI-III (blok design, matrix reasoning, voabulary subtests) Attention domain: Conners Rating Sale-R; Conners CPT-II Language domain: EVT (naming subtest); PPVT-III Visuospatial domain: Beery Visual-Motor Integration Test-5 Learning and memory domain: Coding reall (Wehsler test) Motor domain: Revised Purdue Pegboard; Coding subtest (Wehsler test) Novel/pilot tests (group D) 5 years 95 C IQ domain: WPPSI-III (blok design, matrix reasoning, voabulary subtests) Attention domain: Conners Rating Sale-R; Conners CPT-II Language domain: EVT (naming subtest); PPVT-III Visuospatial domain: Beery Visual-Motor Integration Test-5 Learning and memory domain: CVLT-Children s edition; WRAML-2 (stories subtest) Coding reall (Wehsler test) Motor domain: Revised Purdue Pegboard; Coding subtest (Wehsler test) Novel/pilot tests (group A) Tests 6 years 95 D IQ domain: WPPSI-III (blok design, matrix reasoning, voabulary subtests) Attention domain: Conners Rating Sale-R; Conners CPT-II Language domain: BNT; PPVT-III Visuospatial domain: Beery Visual-Motor Integration Test-5 Learning and memory domain: CVLT-Children s edition; WRAML-2 (stories subtest); Coding reall (Wehsler test) Motor domain: Revised Purdue Pegboard; Coding subtest (Wehsler test) Novel/pilot tests (group B) 7 years 8 years 9 years 10 years 11 years 12 years 13 years A B C D A B C Supplement IQ domain: WASI (blok design, matrix reasoning, voabulary, similarities subtests) Aademis: Wide Range Ahievement Test 3 (spelling, arithmeti, reading subtests) Attention domain: Conners Rating Sale-R; Conners CPT-II; Digit Span Forwards (Wehsler test) Exeutive funtion domain: WCST Language domain: BNT; PPVT-III Visuospatial domain: Bender Gestalt-II Learning and memory domain: Bender Gestalt-II (reall ondition); CVLT-Children s edition; WRAML-2 (stories subtest)* stimuli hanges at age 9; Coding reall (Wehsler test) Motor domain: Grooved Pegboard; Finger Tapping Test; Coding subtest (Wehsler test) Novel/pilot tests (7 years group C; 8 years group D; 9 years group A; 10 years group B) Attention domain: Conners CPT-II ; Digit Span Forwards (Wehsler test) Exeutive funtion domain: Digits Bakwards (Wehsler test); TMT Language domain: EVT; CELF-4 (sentene struture subtest) Visuospatial domain: HVOT; ROCF; Berry Visual Motor Integration Test-5 Learning and memory domain: ROCF (reall ondition); WRAML-2 (stories and verbal learning subtests); Coding reall (Wehsler test) Motor domain: Grooved Pegboard; Finger Tapping Test; Coding subtest (Wehsler test) Novel/pilot tests (11 years group C; 12 years group D; 13 years group A Continued i19

6 Supplement Table 1 Continued Age at testing Battery length (min) Group(s) to be tested Tests 14 years 120 D Attention domain: Conners Rating Sale-R; Conners CPT-II; Digit Span Forwards (Wehsler test) Exeutive funtion domain: Digits Bakwards (Wehsler test); TMT Language domain: EVT; CELF-3 (sentene struture subtest) Visuospatial domain: HVOT; RCOF; Berry Visual-Motor Integration Test-5 Learning and memory domain: ROCF (reall ondition); WRAML-2 (stories and verbal learning subtests); Coding reall (Wehsler test) Motor domain: Grooved Pegboard; Finger Tapping Test; Coding subtest (Wehsler test) Novel/pilot tests (group B) 15 years 16 years 17 years 18 years 19 years 20 years At ages 3 6 years an abbreviated version of the Wehsler Preshool and Primary Sale of Intelligene (WPPSI-III) 21 (Blok Designs, Matrix Reasoning and Voabulary) is reommended. The WPPSI-III was hosen over other possibilities for several reasons. The Wehsler sales have been the most extensively applied to IQ researh on this age range in the past and they dovetail niely with Wehsler subtests available at later ages. The subtests hosen will produe an IQ sore, have parallel versions available at later ages and an ontribute some information to domain-speifi funtion (although they are far from pure measures of speifi domains). The major disadvantage of the Wehsler Sales is that they have somewhat abbreviated ranges, meaning that at the lowest and highest age ranges the tests an be too diffiult or too simple and that persons with low IQs or those who are gifted may be out of range (ie, unable to meaningfully omplete subtests or able to orretly omplete all or virtually all items). A B C D A and B C and D IQ domain: WASI (blok design, matrix reasoning, voabulary, similarities subtests) Aademis: Wide Range Ahievement Test 4 (spelling, arithmeti, reading subtests) Attention domain: Conners Rating Sale-R; Conners CPT-II; Digit Span Forwards (Wehsler) Exeutive funtion domain: Digits Bakwards (Wehsler); WCST Language domain: BNT; PPVT-III Visuospatial domain: Bender Gestalt-II Learning and memory domain: Bender Gestalt-II (reall ondition); CVLT-II; WRAML-2 (stories subtest); Coding reall (Wehsler) Motor domain: Grooved Pegboard; Finger Tapping Test; Coding subtest (Wehsler) Novel/pilot tests (15 years group C; 16 years group D) IQ domain: WASI (blok design, matrix reasoning, voabulary, similarities subtests) Aademis: Wide Range Ahievement Test 4 (spelling, arithmeti, reading subtests) Attention domain: Conners Rating Sale-R (not at age 18); Conners CPT-II; Digit Span Forwards (Wehsler test) Exeutive funtion domain: Digits Bakwards (Wehsler test); WCST Language domain: BNT, PPVT-III Visuospatial domain: Bender Gestalt-II Learning and memory domain: Bender Gestalt-II (reall ondition); CVLT-II; Wehsler Memory Sale-III (logial memory subtest); Coding reall (Wehsler test) Motor domain: Grooved Pegboard; Finger Tapping Test; Coding subtest (Wehsler test) Novel/pilot tests (17 years group A; 18 years group B) Attention domain: Conners CPT-II Exeutive funtion domain: TMT Language domain: EVT; CELF-4 (sentene struture subtest) Visuospatial domain: HVOT; ROCF Learning and memory domain: ROCF (reall ondition); CVLT-II; Wehsler Memory Sale-III (logial memory subtest) Motor domain: Grooved Pegboard; Finger Tapping Test Novel/pilot tests (19 years group A and B; 20 years group C and D) BNT, Boston Naming Test; CELF, Clinial Evaluation of Language Fundamentals; CVLT, California Verbal Learning Test; CPT, Conners Continuous Performane Test; EVT, Expressive Voabulary Test; HVOT, Hooper Visual Organization Test; PPVT, Peabody Piture Voabulary Test; ROCF, Rey Osterrieth Complex Figure; TMT, Trail Making Test; WASI, Wehsler Abbreviated Sale of Intelligene; WCST, Wisonsin Card Sorting Test; WPPSI-III, Wehsler Preshool and Primary Sale of Intelligene; WRAML, Wide Range Assessment of Memory and Learning. Other tests that were onsidered for this age span inlude the MCarthy, 22 whih has also been used extensively in developmental researh. The major disadvantage of this test is the limited number and heterogeneity of items in speifi subsale areas. The Stanford Binet Intelligene Sale-V 23 was also onsidered. The major advantage of this test is that it an be given aross the lifespan, frequently using the same subtests. It is also exellent for measuring the higher and lower ends of intelligene. Disadvantages inlude limited use in developmental researh, less information on relationships between subtest performane and developmental outomes, and the fat that there is limited experiene with the most reent edition of the sale. The publishers have signifiantly altered the test; an important omission from the new version appears to be the opying test, whih proved to be very sensitive in several ultures at several ages to the effets of prenatal and hildhood exposure to methylmerury. Finally, the Kaufman sales (KABC-2, KBIT-2) were onsidered. These sales have also i20

7 been used less extensively in developmental researh and have reently undergone signifiant revision, raising questions about their omparability to previous versions of the tests. The Raven Progressive Matries Test 26 has been used in the past in toxiant exposure studies. This test has been suessfully applied in many ultures and appears to possess inherently less ultural and linguisti bias than other intelligene tests. However, the Raven test assesses intelligene in a one-dimensional fashion (a type of non-verbal exeutive funtion) and supportive psyhometri data for the test are limited with regard to norms, validity and reliability. At ages 7 10 and years the Wehsler Abbreviated Sale of Intelligene (WASI) 27 is reommended to assess the general abilities domain. This test has four subtests (Blok Designs, Matrix Reasoning, Similarities and Voabulary) that provide ontinuity with the WPPSI-III subtests reommended for hildren aged 3 6 years. In addition, the WASI an be used aross the lifespan after age 6 using the same subtests. Another possibility for hildren aged 7 10 years is the Wehsler Intelligene Sale for Children (WISC)-IV, 28 a revised version of the earlier WISC sales (WISC, WISC-R, WISC-III) whih have been used extensively in developmental researh. The WASI was reommended over the WISC-IV owing to its greater brevity and its ontinuity aross the developmental span. For the age range, inlusion of a full Wehsler assessment would require use of both the WISC-IV and the WAIS-III, swithing tests at age 16 or 17 years. This would produe less ontinuity in the age range testing, and both sales an be problemati for 16-year-old subjets (too easy or too hard). The NEPSY 29 was onsidered as an alternative test for both omnibus sores and domain-speifi assessment and is seen as an alternative instrument. The test seems to have a rather low eiling and subtest length is somewhat limited, restriting the utility of outome data. When disussing the neuropsyhologial domains below, subtests from the IQ tests and the NEPSY an always be onsidered to be possible alternative tasks. The pros and ons of these tests have been desribed above and will not be repeated. Aademi sreening A domain for brief aademi testing was inluded as an assist to sreening for learning disorders. This domain was not designed to serve as a full assessment of aademi abilities as outome measures, although the results an be used as a ursory evaluation of these outomes at the age ranges in whih they are inluded. In hildren aged 7 10 years, brief testing of basi aademi skills an be ombined with results of IQ and domainspeifi testing in order to identify those who may have disorders of learning. The test reommended for this domain is the Wide Range Ahievement Test-4 (WRAT-4), 30 whih assesses single-word reading, single-word spelling and arithmeti. This test was seleted for ease of administration, time effiieny and its aeptane in the field. It has seen limited use in exposure studies. Alternative tests inlude the Woodok- Johnson 31 whih was used in a study of methylmerury, the Kaufman Test of Individual Ahievement-2 and the Wehsler Individual Ahievement Test. 32 These tests are more omplex than the WRAT-4 and less suited to sreening. It is reommended that the WRAT-4 be repeated during the age testing in order to assess stability of any exposure-related hanges in basi aademi skills over time. Supplement Attention/onentration The ognitive proesses subsumed under this domain have been widely desribed and evaluated in the ognitive psyhology literature. Sine it is not possible to assess all aspets of the domain, this assessment strategy fouses on behaviour, sustained attention/reation time and spans of apprehension. Tests reommended for this domain among 3 6-year-old hildren inlude the Conners Rating Sale-Revised 33 and the Conners Continuous Performane Test (CPT)-II. 34 The Conners Rating Sale is used to assess behavioural harateristis that are assoiated with attention defiit hyperativity disorder (ADHD) as defined by the Diagnosti and Statistial Manual-IV (DSM- IV). Outomes inlude both a sore that an be used as a quantitative outome measure and assignment of a provisional diagnosis of ADHD based on ut-off riteria. Thus, the test an ontribute to sreening for ADHD in this age range. Testing with the Conners CPT-II begins at age 6, and the test allows evaluation of lapses in attention (omission errors), overresponding (false positives) and reation time. Reation times have proved to be sensitive indiators of exposures to toxiants and mediations. The Conners CPT-II was reommended beause of its widespread use in hild linial neuropsyhology. Span of apprehension testing (Wehsler Digit Span Forward) is not reommended for this age group owing to limited appliability at the age of 3 5 years. For hildren aged 7 10 years, it is reommended that the Conners Rating Sale-Revised be repeated in order to aquire a seond set of outome sores on attentional behaviours and to allow a seond hane to pik up possible ases of ADHD that were missed at previous testing. The Conners CPT-II is also reommended at all ages due to the sensitivity of reation time data to many types of exposures/insults/disorders. Finally, the Wehsler (WISC-IV) Digit Span Forward test is reommended as a span of apprehension task. This task provides data on the number of bits of information that the hild an automatially register and repeat bak. Suh data are important as outome measures (and have been related to speifi types of exposures during development). They an also be used to estimate appropriate expetations for performane on learning tests. Other possibilities inlude the Neurobehavioral Evaluation System (NES) letter or animal CPT, 35 whih has also been used extensively and effetively in deteting subtle toxiant effets in hildren and adults. The NES is less widely available and more diffiult to adapt to different testing situations than the Conners test. Normative and psyhometri data are also less extensive for it. A visual pointing span test is another alternative. For hildren aged years, it is reommended that the Conners CPT-II and the WISC-IV Digit Span Forward be repeated. At age 14 the Conners Rating Sale-R an be repeated to assess stability of sores and ut-offs for ADHD diagnosis riteria. At ages 15 18, it is reommended that the Conners CPT-II and Wehsler Digit Span Forward assessment be repeated (WISC-IV for ages 15 16; WAIS-III for ages 17 18). The Conners Rating Sale-R an be repeated at ages 15, 16 and 17 years. At ages the reommended attention test for the brief battery is the Conners CPT-II. Exeutive funtion/working memory This domain is a omplex one and related skills tend to develop somewhat later than those subsumed under other domains. Sine it would be impossible to evaluate all aspets of this i21

8 Supplement domain at every age level, testing is limited to sreening for a few skills at eah age level. The tests hosen for the age ranges between 3 and 18 years were seleted to inlude both visually and verbally mediated tasks. Proposed testing begins in the 7 10 year age range. The Wisonsin Card Sorting Test (WCST) 36 is a widely used task assessing this domain. It taps inferential reasoning, working memory, apaity to attain and swith sets flexibly, and ability to inhibit distrations and perseverative tendenies. Performane on this test has been related to a wide variety of neurologial and developmental disorders, neuropsyhiatri syndromes and exposures to hemial toxiants. A seond test, the WASI Similarities test, is administered as part of the general intelligene testing and also taps aspets of exeutive funtion. This task assesses abstrat reasoning and its performane sores have been related to aspets of normal and abnormal hild development. The Children s Categories Test 37 is an alternative test for the same domain. It has two levels (for ages 5 8 and 9 13 years), so the test stimuli are different for hildren tested at ages 7 and 8 years than for those tested at 9 and 10 years. A few of the items are slightly problemati. Other tests that assess this domain that an be onsidered as alternatives for use in the 7 10 year range inlude the Children s Color Trails Test 38 (age 8 10 years) and the Stroop Color Word Test. 39 The Color Trails Test appears to be relatively ulture fair but has (in RFW s experiene) been diffiult to administer (many hildren do not understand it initially). There is also muh less information about how performane on this test relates to other aspets of hildhood ognitive development than is available for other tests of exeutive funtion. The Stroop Test is ommonly used as an exeutive test and muh more is known about its relationship to other variables. However, performane on the test varies widely, affeting reliability and psyhometris of the test for data analysis purposes. The exeutive domain tests reommended in table 1 for the age group are Wehsler (WISC-IV) Digit Span Bakward, a working memory task requiring the registration and manipulation of verbal information, and the Trail Making Test (TMT) 40 whih requires the examinee to trak and onnet visual information (A ondition) and to alternate sets while traking and onneting visual stimuli (B ondition). Both tests have rih soures of sientifi and linial data to support their use and interpretation in a study suh as this. Drawbaks to the Digit Span Bakward inlude resistane to the task by examinees who feel they annot manipulate numbers as well as the need for onsiderable examinee ooperation in ompleting it. The TMT is a timed task and optimal performane is only eliited when the examinee is willing to work as quikly and aurately as possible. It also requires automati knowledge of the alphabet sequene and numbers. Alternative tests inlude the tests desribed above for examining this domain in hildren aged 7 10 years. For testing in the year age group, it is reommended that Wehsler Digit Span Bakward (WISC-IV for age years, WAIS-III for age years), the WCST and WASI Similarities be repeated. Other possibilities inlude the Children s Categories Test (Level 2), 37 Children s Color Trails 38 (1 17) and Color Trails 41 (age 18 years). Pros and ons of these tests have been noted above. Another alternative is the Paed Auditory Serial Addition Test (PASAT), 42 a rather diffiult task that was developed to demonstrate subtle brain damage assoiated with head injuries. A strength of this test is its sensitivity to subtle proessing defiits. However, beause it requires onsiderable examinee ooperation, performanes tend i22 to be rather variable. It is not as well represented in the general developmental ognitive literature as some of the other tests mentioned. The reommended exeutive domain task for the brief testing of subjets aged years is the TMT, repeated 7 8 years after initial presentation to the ohort. This is a highly sensitive and effiient test that is also well investigated and appropriate for young adults. Language/verbal skills Goals for assessment of this domain inlude examination of lexial knowledge, simple verbal omprehension and ability to define voabulary words while allowing preliminary sreening for speeh disorders and verbally-based learning disabilities at the younger ages. The group of tests reommended for eah age range inludes tasks assessing both expressive and reeptive aspets of language skills. During the assessment of hildren aged 3 6 years it is reommended that simple naming of objets be evaluated. Both tests reommended for the assessment of naming require the hild to name objets presented in drawings or pitures. The naming portion of the Expressive Voabulary Test (EVT) 43 is reommended for hildren aged 3 5 years. The EVT was hosen beause of its appliability for expressive language during hildhood and the partiular balane of naming/synonyms in assessment of language funtion over development. At 6 years of age a different naming test must be applied. The Boston Naming Test (BNT) 44 is reommended owing to its feasibility from the age of 6 years through adulthood and its known effetiveness in deteting subtle effets of prenatal exposure to toxiants suh as methylmerury. It has been applied in widely diverse ultures and subultures and translated into many languages. Another possible test that ould be used to evaluate naming in this age range is the WPPSI-III Naming Test whih an be administered at all four ages (3 6 years), although it does not have a parallel version for use at later ages. The Peabody Piture Voabulary Test-III (PPVT-III) 45 is reommended as a test of reeptive language or language omprehension for this age range. It has a number of advantages, inluding ease of administration, well-doumented reliability and validity, extensive norms, well-defined psyhometris and widespread use in the field. Similarly, the Token Test for Children 46 has normalised sores for ages 3 12 (in 6- month inrements). It was developed as a rapid sreening measure of language ompetene, partiularly for hildren with reeptive language dysfuntion that depresses language sores. Both tests are appropriate but the Token Test was seleted as an alternative to the preferred PPVT beause it is less proessspeifi in its task demands. It is reommended that assessment of ability to provide definitions of words be arried out with the WPPSI-III Voabulary Test, a test with the same advantages as PPVT- III. Another assessment, the Clinial Evaluation of Language Fundamentals-IV (CELF-4) 47 inludes both expressive and reeptive subtests, one of whih is also reommended for use at a later age level. However, most of the CELF-4 subtests appear to be less appropriate for sreening in the 3 6-year age group than those inluded in the reommended list. At ages 7 10 years the BNT is reommended as an assessment tool for expression/naming, the PPVT-III for omprehension/ reeptive speeh and the WASI Voabulary subtest for prodution of word definitions. Pros and ons of these tests and alternative tasks are noted above.

9 Reommended tests for the language domain in the year age group inlude two new tasks that allow examination of a slightly different aspet of expressive and reeptive proessing and thus redue pratie effets aross the age ranges. The EVT Synonyms task (requiring the examinee to produe words with the same meaning as those given orally by the examiner for a stimulus piture) and the CELF-4 Sentene Struture subtest (a reeptive task requiring reognition of words appropriate to sentenes) are reommended for this age range. These tasks are less well known than the language tests reommended for earlier age ranges but have been well standardised and normed and will provide information on more omplex aspets of expressive and reeptive language at this age level. For the language/verbal assessment at ages years, it is reommended that the BNT, PPVT-III and WASI Voabulary subtest be repeated. The reommended brief language domain assessment at ages years inludes repetition of the EVT (Synonyms) and CELF-4 Sentene Struture subtest. It is also possible to repeat the BNT or PPVT-III or to apply other language tasks. Visuospatial abilities The ritial proesses that must be evaluated in the assessment of visuospatial abilities have been less well defined than those of other domains, and there has been onsiderable overlap in the stimuli used aross visuospatial tasks designed for hildren. To aommodate potential individual differenes, it was deemed important to inlude both traditional onstrutional tasks (with a motor omponent suh as drawing or putting bloks or puzzle piees together) and motor-free tasks that involve visuospatial proessing and integration at a ognitive level only. The visuospatial tasks reommended for use at ages 3 6 years inlude the Visual Motor Integration Test (VMI-5). 48 This task is well embedded in the developmental literature and has reently been revised and renormed. It has been used in previous work involving environmental toxiant exposure and was hosen partially for its similarity to the Copying Test of the Stanford Binet-IV. 23 The latter task was highly feasible in several ultures and able to detet subtle effets of early exposures to methylmerury. The Copying Test was also valuable beause it ould be administered aross the lifespan, a property not assoiated with the VMI-5. However, the two tests have overlapping stimuli and test requirements. An alternative onstrutional test is the Bender Gestalt-II. 49 The original version of this test has been used extensively in both linial and researh situations and has deteted effets of toxiant exposures. However, for this age range the test ould only be administered at ages 5 and 6 years. The WPPSI-III 21 Blok Designs and Matrix Reasoning subtests are reommended for the 3 6-year age range. They provide a measure of visuospatial skills with a motor omponent (Blok Designs) and a test without motor requirements (Matrix Reasoning). Both have a strong exeutive omponent (as do many visuospatial tests). They also ontribute to the IQ sore reommended for this age group. The Blok Designs and Matrix Reasoning subtests of the WASI are reommended for the 7 10-year age range. Advantages and drawbaks are similar to those desribed for the subtests at ages 3 6 years, though the WASI subtests an be given aross the lifespan after age 6. A seond reommended visuospatial task for hildren aged 7 10 years is the Bender Gestalt-II, a visual onstrutional task similar to the initial version used in prior researh but with additional designs added for a better range of sores and diffiulty level. Experiene with Supplement the revised version is still somewhat limited. It has a reall ondition, an advantage that ontributes to the test s effiieny in a battery suh as that to be used for the National Children s Study. For hildren aged years, three tests are reommended. Repetition of the VMI-5 is suggested as a measure of visual onstrutions. The Hooper Visual Organization Test (HVOT) 50 is reommended as a motor-free task assessing visual integration. The test has a somewhat low eiling in adults, but is one of the few tests available that allows examination of visual organisation without drawing or assembling onrete objets. Finally, the Rey-Osterreith Complex Figure (ROCF) test 51 is reommended for use in this age range. The ROCF is a relatively diffiult onstrution that inreases the range of assessment of the visuospatial domain, an be given quikly, is well known to liniians and researhers in hild development and inludes memory onditions. Soring of the ROCF an be done simply, although omplex soring systems have been developed for it. This task also produes a wealth of qualitative information that may be useful for ertain kinds of data analysis. The visuospatial tasks reommended for the year age group assessments inlude the Bender Gestalt-II and two WASI subtests (Blok Designs and Matrix Reasoning). For the year age group the brief visuospatial battery reommended inludes the motor-free HVOT and the ROCF to assess onstrutional ability. Learning and memory As noted in the definitions above, learning and memory funtion involve several key ognitive proesses. Lukily, several tests of learning and memory have been developed that address all or most of these funtional proesses. For the reommended battery, this domain is foused on anterograde memory rather than retrograde memory or proedural learning. Beause hildren differ in their verbal and visuospatial abilities and beause the erebral strutures subserving the proessing of verbal and visual information are different, visual and verbal memory tests are inluded at eah age level. Similarly, within the verbal modality, learning lists of words or word-pairs an be differentiated on a neural system or neurofuntional basis from learning disourse or paragraph material. For this reason, both word list and disourse tasks were inluded as muh as possible at eah age level. The battery for this domain is relatively limited in the 3 6- year age range. Few tests are available and administration of these kinds of tests is diffiult for very young hildren. The reommended test battery takes advantage of the use of the WPPSI-III Coding Test at ages 4 6 years (see Motor domain below) to arry out inidental learning of the symbol-symbol pairs (visual memory task). At 5 6 years of age, administration of the California Verbal Learning Test (Children s version) (CVLT-C) 52 is reommended. This is a list-learning test devised to omprehensively assess learning and memory at several levels, with learning, immediate and delayed reall onditions as well as spontaneous and reognition test paradigms. It is thus a rih test that provides onsiderable information. It is somewhat time-onsuming and some individuals resist list-learning tests, but its advantages were judged to outweigh disadvantages. The Wide Range Assessment of Memory and Learning-2 (WRAML- 2) 53 Stories subtest is also reommended for hildren aged 5 6 years. The previous version of the WRAML has been used in researh of this type and appears to be solid with regard to psyhometris and standardisation. It was reently revised, but i23