Electronic records of children who received care in a large primary care network associated with a tertiary care children's hospital were evaluated retrospectively. HC measurements are routinely performed at well child visits until three years of age in the network.

All subjects were born before 31 January 2008 and had at least one HC recorded in the electronic medical record before 31 January 2009 while they were between 3 days and 3 years of age. The HC measurements for these children had previously been used to create new HC growth curves 5 . Subjects with known birth weight less than 1500 grams or gestational age below 33 weeks were excluded.

Although HC curves may also be used to monitor the head growth of children with known diagnoses, our goal in this study was to evaluate the performance of HC curves for the identification of children with previously undetected pathology. Therefore, subjects were excluded if they had evidence of neurosurgery or a diagnosis of pathology known to be associated with an abnormally large head size before the first HC for that subject was recorded in the electronic record, regardless of whether the HC percentile was high. Subjects with diagnoses associated with small head size before the first HC was recorded were also excluded in order to avoid downwardly skewing the HC distribution of the final sample. Subjects with diagnoses made on prenatal ultrasound, which is performed routinely in our population, were excluded.

The primary outcome of interest was the new diagnosis before three years of age of IEC or MGCM. The following were included as IEC: hydrocephalus (enlarged, not merely prominent, ventricles without evidence of brain volume loss); chronic subdural hematoma (with or without associated hydrocephalus); cyst (> 1 cm, causing mass effect or hydrocephalus); brain tumor (> 1 cm, causing mass effect or hydrocephalus) 4 . The following were considered MGCM: overgrowth syndromes (including acromegaly, Beckwith-Weidemann, Simpson-Golabi-Behmel Sotos, and Weaver syndromes), Alexander disease, cranial dysplasia, Canavan disease, Fragile X syndrome, galactosemia, gangliosidosis (GM₁ and GM₂), glutaric aciduria (type I and D-2-hydroxyglutaric aciduria), hemimegalencephaly, histiocytosis X, hypoadrenocorticism, hypoparathyroidism, Jacobsen syndrome, MASA syndrome, megalencephalic leukodystrophy, metachromatic leukodystrophy, mucopolysaccharidoses, neonatal progeroid syndrome, neurocutaneous syndromes (including neurofibromatosis type I, macrocephaly-capillary malformation, and multiple others), Noonan syndrome (and cardiofaciocutaneous, Costello, and Leopard syndromes), Opitz-Kaveggia syndrome, Peters-plus syndrome, peroxisomal disorders, progeroid form of Ehlers-Danlos, PTEN hamartoma syndromes (including Bannayan-Riley-Rubalcava and Cowden syndromes), Rett syndrome/X-linked MECP2 neurodevelopmental disorder, Robinow syndrome, sebaceous nevus of Jaddassohn, and Schwachman-Bodian-Diamond syndrome. The receipt of intervention for IEC or MGCM, including surgery, medication, special diet, or social services referral, was a secondary outcome 6 7 8 .

We performed a secondary analysis including benign enlargement of the subarachnoid spaces (BESS) in the outcome because the clinical significance of this condition is controversial. Although BESS, when diagnosed, is rarely treated and the fluid collections generally resolve without intervention, some studies have raised concerns about the possibility of an association with subdural hematoma and increased rates of developmental delay 9 10 11 12 13 14 15 16 17 .

In addition to demographic characteristics, independent variables included the HC percentiles and z-scores as determined by the Centers for Disease Control (CDC) 18 and World Health Organization (WHO) 2 growth curves as well as the primary care network (PCN) 5 curves derived from this cohort. The determination of HC z-scores and percentiles has been described previously. Efforts had previously been made to remove erroneous measurements 5 . During this evaluation we detected and excluded 3,439 additional measurements that were likely to be erroneous (1.3% of all measurements), primarily by identifying measurement pairs representing a decrease in HC.

Demographic data, visit and billing codes, and HC were obtained on all subjects between the beginning of electronic record collection at that practice and 31 January 2009.

In order to identify subjects with IEC or MGCM, subjects with any of the following indicators in the clinical databases were evaluated with chart review: an outpatient diagnostic code for pathology that can cause abnormal head size; an order or result for neuroimaging; a referral to or evaluation by a relevant specialist; chromosome or genome analysis; or billing or diagnostic codes for neurosurgery. Subjects whose only indicator was an evaluation that occurred after the third birthday were not evaluated further. Chart review was limited to neuroimaging results that did not contain identifying information when possible.

Because practices in the network began using the electronic medical record at variable times, and because we evaluated children born as late as one year before our data collection stop-date, we had variable amounts of information on our subjects. To assess whether inclusion of subjects with incomplete data affected our results, we performed a sensitivity analysis restricted to subjects whose first recorded HC was before 1 month of age and whose last recorded HC was after 24 months of age.

All analyses were performed using Stata 11.2. Test characteristics for thresholds of the 95^th, 97^th, and 99.6^th percentiles were evaluated; a subject with any HC-for-age percentile above the threshold criterion was considered to be test-positive. The threshold criterion of crossing 2 increasing major percentile lines (MPL: the 5^th, 10^th, 25^th, 50^th, 75^th, 90^th, and 95^th percentile lines) was evaluated; for analytic thoroughness, criteria of crossing 4 and 6 increasing MPL were also evaluated. To determine the number of increasing MPL crossed, each subject's highest head circumference-for-age percentile was compared with his or her first percentile.

The sensitivity, specificity, and positive and negative predictive values, likelihood ratios, number needed to test, and number needed to screen for these thresholds for identifying a) all subjects with IEC or MGCM and b) subjects with IEC or MGCM who received intervention were determined.

The study was reviewed and approved by the Institutional Review Board of the Children's Hospital of Philadelphia.

Eighty-five subjects were found to have new diagnoses of pathology before three years of age (Figure 1). Of the 85 subjects with IEC or MGCM, 43 subjects had no diagnostic or surgery code and were identified because of the presence of neuroradiology orders or results, or specialist referrals or evaluations.

Of the 85 subjects with the outcome, 56 had IEC: hydrocephalus (n = 24), chronic subdural hematoma (n = 15), cyst (n = 8), and tumor (n = 9). Twenty-nine had MGCM: neurofibromatosis (n = 8), tuberous sclerosis (n = 5), Beckwith-Wiedemann (n = 4), and 1 or 2 subjects each with the following diagnoses: glutaric aciduria type I, Sturge-Weber syndrome, Sotos syndrome, Fragile X syndrome, Noonan syndrome, Leopard syndrome, Bannayan-Riley-Ruvalcaba syndrome, hemimegalencephaly, X-linked MR associated with MECP2 duplication, and diffuse thickening of the skull with no known syndrome. None of the children with conditions classified as MGCM also had lesions large enough to be considered IEC.

There were 24 subjects who received specific intervention for pathology: 18 underwent surgery, 5 additional subjects did not receive surgery but were referred to social services because of concern for non-accidental trauma, and one was prescribed a special diet. Other subjects received variable degrees of further follow-up and evaluation, ranging from no follow-up for three subjects to multiple specialty evaluations and further neuroimaging.

New diagnoses of IEC or MGCM were found in 0.11% (85/74,428) of the entire study population, with 0.03% (24/74,428) who had pathology with subsequent intervention. The age at diagnosis ranged from 3 days to 1075 days (median, 200 days). Eight subjects were diagnosed before 1 month; eight were diagnosed after 24 months.

Subjects with IEC or MGCM had a wide range of head sizes, including some with HC below the 1^st percentile. The distributions of maximum HC percentile for subjects with pathology were different from the distribution for subjects without known pathology, but with a large amount of overlap (Figure 2).

The sensitivity, specificity, positive predictive value, positive and negative likelihood ratios, number needed to screen and number needed to test varied by threshold and curve source (Tables 2 and 3). The negative predictive value was 99.9% for each threshold. The threshold of crossing 6 major percentiles identified 490 (CDC), 556 (WHO) and 130 (PCN) children, but none of these subjects had pathology. Almost all of these children had a corresponding increase in weight and length z-scores of similar magnitude.

Crossing 2 increasing major percentile lines had the highest sensitivity but lowest positive predictive value, 0.1%-0.2% (diagnosis) and < 0.1%-0.1% (intervention). The only threshold with a number needed to test less than 100 for diagnosis of any new pathology was the 99.6^th percentile of the CDC curve (NNT = 55). The 99.6^th percentile of the PCN curve also had the highest likelihood ratio positive at 16.3 (diagnosis) and 22.0 (intervention), but had low sensitivity (15% diagnosis, 21% intervention).

The sensitivity analysis restricted to those 15,712 children with at least one evaluable HC recorded before 1 month and one after 24 months of age showed similar test characteristics. The cumulative incidence (0.19%) and positive predictive values for diagnosis for the 99.6^th percentiles were somewhat higher (CDC 1.5%, WHO 0.9%, PCN 3.4%), but the sensitivity of these criteria were low (CDC 27%, WHO 27%, PCN 23%).

When the 239 subjects diagnosed with BESS were included in the outcome (Table 4), the sensitivities (17%-75%), positive predictive values (0.7% - 9.7%) and likelihood ratios positive (1.4-24.6) were higher than for IEC and MGCM alone.

There were 46 subjects with pathology with IEC or MGCM whose head circumference was never above the CDC 95^th percentile, 13 of whom received intervention. The 25 subjects with IEC (7 with hydrocephalus, 5 with cysts, 9 with subdural hematomas, and 4 with tumors) were diagnosed because of increasing HC percentile, acute altered mental status that led to the diagnosis of underlying chronic subdural hematomas, or other neurologic signs. The 21 subjects with MGCM were primarily diagnosed because of characteristic signs unrelated to head size, such as macroglossia or café-au-lait spots.