Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013.

OBJECTIVE: To estimate cause-of-death distributions in the early (0-6 days of age) and late (7-27 days of age) neonatal periods, for 194 countries between 2000 and 2013. METHODS: For 65 countries with high-quality vital registration, we used each country's observed early and late neonatal proportional cause distributions. For the remaining 129 countries, we used multinomial logistic models to estimate these distributions. For countries with low child mortality we used vital registration data as inputs and for countries with high child mortality we used neonatal cause-of-death distribution data from studies in similar settings. We applied cause-specific proportions to neonatal death estimates from the United Nations Inter-agency Group for Child Mortality Estimation, by country and year, to estimate cause-specific risks and numbers of deaths. FINDINGS: Over time, neonatal deaths decreased for most causes. Of the 2.8 million neonatal deaths in 2013, 0.99 million deaths (uncertainty range: 0.70-1.31) were estimated to be caused by preterm birth complications, 0.64 million (uncertainty range: 0.46-0.84) by intrapartum complications and 0.43 million (uncertainty range: 0.22-0.66) by sepsis and other severe infections. Preterm birth (40.8%) and intrapartum complications (27.0%) accounted for most early neonatal deaths while infections caused nearly half of late neonatal deaths. Preterm birth complications were the leading cause of death in all regions of the world. CONCLUSION: The neonatal cause-of-death distribution differs between the early and late periods and varies with neonatal mortality rate level. To reduce neonatal deaths, effective interventions to address these causes must be incorporated into policy decisions.

Estimation of daily risk of neonatal death, including the day of birth, in 186 countries in 2013: a vital-registration and modelling-based study.

BACKGROUND: The days immediately after birth are the most risky for human survival, yet neonatal mortality risks are generally not reported by day. Early neonatal deaths are sometimes under-reported or might be misclassified by day of death or as stillbirths. We modelled daily neonatal mortality risk and estimated the proportion of deaths on the day of birth and in week 1 for 186 countries in 2013. METHODS: We reviewed data from vital registration (VR) and demographic and health surveys for information on the timing of neonatal deaths. For countries with high-quality VR we used the data as reported. For countries without high-quality VR data, we applied an exponential model to data from 206 surveys in 79 countries (n=50,396 deaths) to estimate the proportions of neonatal deaths per day and used bootstrap sampling to develop uncertainty estimates. FINDINGS: 57 countries (n=122,757 deaths) had high-quality VR, and modelled data were used for 129 countries. The proportion of deaths on the day of birth (day 0) and within week 1 varied little by neonatal mortality rate, income, or region. 1·00 million (36.3%) of all neonatal deaths occurred on day 0 (uncertainty range 0·94 million to 1·05 million), and 2·02 million (73.2%) in the first week (uncertainty range 1·99 million to 2·05 million). Sub-Saharan Africa had the highest risk of neonatal death and, therefore, had the highest risk of death on day 0 (11·2 per 1000 livebirths); the highest number of deaths on day 0 was seen in southern Asia (n=392,300). INTERPRETATION: The risk of early neonatal death is very high across a range of countries and contexts. Cost-effective and feasible interventions to improve neonatal and maternity care could save many lives. FUNDING: Save the Children's Saving Newborn Lives programme.

Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis.

BACKGROUND: Bacterial infections are a leading cause of the 2·9 million annual neonatal deaths. Treatment is usually based on clinical diagnosis of possible severe bacterial infection (pSBI). To guide programme planning, we have undertaken the first estimates of neonatal pSBI, by sex and by region, for sub-Saharan Africa, south Asia, and Latin America. METHODS: We included data for pSBI incidence in neonates of 32 weeks' gestation or more (or birthweight ≥1500 g) with livebirth denominator data, undertaking a systematic review and forming an investigator group to obtain unpublished data. We calculated pooled risk estimates for neonatal pSBI and case fatality risk, by sex and by region. We then applied these risk estimates to estimates of livebirths in sub-Saharan Africa, south Asia, and Latin America to estimate cases and associated deaths in 2012. FINDINGS: We included data from 22 studies, for 259 944 neonates and 20 196 pSBI cases, with most of the data (18 of the 22 studies) coming from the investigator group. The pooled estimate of pSBI incidence risk was 7·6% (95% CI 6·1-9·2%) and the case-fatality risk associated with pSBI was 9·8% (7·4-12·2). We estimated that in 2012 there were 6·9 million cases (uncertainty range 5·5 million-8·3 million) of pSBI in neonates needing treatment: 3·5 million (2·8 million-4·2 million) in south Asia, 2·6 million (2·1 million-3·1 million) in sub-Saharan Africa, and 0·8 million (0·7 million-1·0 million) in Latin America. The risk of pSBI was greater in boys (risk ratio 1·12, 95% CI 1·06-1·18) than girls. We estimated that there were 0·68 million (0·46 million-0·92 million) neonatal deaths associated with pSBI in 2012. INTERPRETATION: The need-to-treat population for pSBI in these three regions is high, with ten cases of pSBI diagnosed for each associated neonatal death. Deaths and disability can be reduced through improved prevention, detection, and case management. FUNDING: The Wellcome Trust and the Bill & Melinda Gates Foundation through grants to Child Health Epidemiology Reference Group (CHERG) and Save the Children's Saving Newborn Lives programme.

Every Newborn: progress, priorities, and potential beyond survival.

In this Series paper, we review trends since the 2005 Lancet Series on Neonatal Survival to inform acceleration of progress for newborn health post-2015. On the basis of multicountry analyses and multi-stakeholder consultations, we propose national targets for 2035 of no more than 10 stillbirths per 1000 total births, and no more than 10 neonatal deaths per 1000 livebirths, compatible with the under-5 mortality targets of no more than 20 per 1000 livebirths. We also give targets for 2030. Reduction of neonatal mortality has been slower than that for maternal and child (1-59 months) mortality, slowest in the highest burden countries, especially in Africa, and reduction is even slower for stillbirth rates. Birth is the time of highest risk, when more than 40% of maternal deaths (total about 290,000) and stillbirths or neonatal deaths (5·5 million) occur every year. These deaths happen rapidly, needing a rapid response by health-care workers. The 2·9 million annual neonatal deaths worldwide are attributable to three main causes: infections (0·6 million), intrapartum conditions (0·7 million), and preterm birth complications (1·0 million). Boys have a higher biological risk of neonatal death, but girls often have a higher social risk. Small size at birth--due to preterm birth or small-for-gestational-age (SGA), or both--is the biggest risk factor for more than 80% of neonatal deaths and increases risk of post-neonatal mortality, growth failure, and adult-onset non-communicable diseases. South Asia has the highest SGA rates and sub-Saharan Africa has the highest preterm birth rates. Babies who are term SGA low birthweight (10·4 million in these regions) are at risk of stunting and adult-onset metabolic conditions. 15 million preterm births, especially of those younger than 32 weeks' gestation, are at the highest risk of neonatal death, with ongoing post-neonatal mortality risk, and important risk of long-term neurodevelopmental impairment, stunting, and non-communicable conditions. 4 million neonates annually have other life-threatening or disabling conditions including intrapartum-related brain injury, severe bacterial infections, or pathological jaundice. Half of the world's newborn babies do not get a birth certificate, and most neonatal deaths and almost all stillbirths have no death certificate. To count deaths is crucial to change them. Failure to improve birth outcomes by 2035 will result in an estimated 116 million deaths, 99 million survivors with disability or lost development potential, and millions of adults at increased risk of non-communicable diseases after low birthweight. In the post-2015 era, improvements in child survival, development, and human capital depend on ensuring a healthy start for every newborn baby--the citizens and workforce of the future.

Neonatal severe bacterial infection impairment estimates in South Asia, sub-Saharan Africa, and Latin America for 2010.

BACKGROUND: Survivors of neonatal infections are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified and yet important for program priority setting. Systematic reviews and meta-analyses were undertaken and applied in a three-step compartmental model to estimate NDI cases after severe neonatal bacterial infection in South Asia, sub-Saharan Africa, and Latin America in neonates of >32 wk gestation (or >1,500 g). METHODS: We estimated cases of sepsis, meningitis, pneumonia, or no severe bacterial infection from among estimated cases of possible severe bacterial infection ((pSBI) step 1). We applied respective case fatality risks ((CFRs) step 2) and the NDI risk among survivors (step 3). For neonatal tetanus, incidence estimates were based on the estimated deaths, CFRs, and risk of subsequent NDI. RESULTS: For 2010, we estimated 1.7 million (uncertainty range: 1.1-2.4 million) cases of neonatal sepsis, 200,000 (21,000-350,000) cases of meningitis, 510,000 cases (150,000-930,000) of pneumonia, and 79,000 cases (70,000-930,000) of tetanus in neonates >32 wk gestation (or >1,500 g). Among the survivors, we estimated moderate to severe NDI after neonatal meningitis in 23% (95% confidence interval: 19-26%) of survivors, 18,000 (2,700-35,000) cases, and after neonatal tetanus in 16% (6-27%), 4,700 cases (1,700-8,900). CONCLUSION: Data are lacking for impairment after neonatal sepsis and pneumonia, especially among those of >32 wk gestation. Improved recognition and treatment of pSBI will reduce neonatal mortality. Lack of follow-up data for survivors of severe bacterial infections, particularly sepsis, was striking. Given the high incidence of sepsis, even minor NDI would be of major public health importance. Prevention of neonatal infection, improved case management, and support for children with NDI are all important strategies, currently receiving limited policy attention.

Using causal diagrams to guide analysis in missing data problems.

Estimating causal effects from incomplete data requires additional and inherently untestable assumptions regarding the mechanism giving rise to the missing data. We show that using causal diagrams to represent these additional assumptions both complements and clarifies some of the central issues in missing data theory, such as Rubin's classification of missingness mechanisms (as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR)) and the circumstances in which causal effects can be estimated without bias by analysing only the subjects with complete data. In doing so, we formally extend the back-door criterion of Pearl and others for use in incomplete data examples. These ideas are illustrated with an example drawn from an occupational cohort study of the effect of cosmic radiation on skin cancer incidence.

Adding fever to WHO criteria for diagnosing pneumonia enhances the ability to identify pneumonia cases among wheezing children.

OBJECTIVE: To examine the ability of the criteria proposed by the WHO to identify pneumonia among cases presenting with wheezing and the extent to which adding fever to the criteria alters their performance. DESIGN: Prospective classification of 390 children aged 2-59 months with lower respiratory tract disease into five diagnostic categories, including pneumonia. WHO criteria for the identification of pneumonia and a set of such criteria modified by adding fever were compared with radiographically diagnosed pneumonia as the gold standard. RESULTS: The sensitivity of the WHO criteria was 94% for children aged <24 months and 62% for those aged ≥24 months. The corresponding specificities were 20% and 16%. Adding fever to the WHO criteria improved specificity substantially (to 44% and 50%, respectively). The specificity of the WHO criteria was poor for children with wheezing (12%). Adding fever improved this substantially (to 42%). The addition of fever to the criteria apparently reduced their sensitivity only marginally (to 92% and 57%, respectively, in the two age groups). CONCLUSION: The authors' results reaffirm that the current WHO criteria can detect pneumonia with high sensitivity, particularly among younger children. They present evidence that the ability of these criteria to distinguish between children with pneumonia and those with wheezing diseases might be greatly enhanced by the addition of fever.

Variant Creutzfeldt-Jakob disease in the United Kingdom: a countrywide or local risk?

BACKGROUND: The aim of this study was to identify factors that may have augmented local risks for variant Creutzfeldt-Jakob disease (vCJD). METHODS: A descriptive study was conducted of local investigations of UK cases of vCJD, who had lived close together at some point since 1980. The main outcome measures were domestic, educational, occupational, healthcare associated, social and recreational links between cases; common dietary, iatrogenic and other possible routes of exposure to vCJD infection; and locally elevated vCJD risk. RESULTS: A cluster of five cases of vCJD in a rural area in North Leicestershire was investigated in 2000 (p=0.004). A further 12 investigations of geographically associated cases of vCJD have been undertaken in the UK. In nine of the 12 locations, some or all of the local cases had consumed beef purchased from the same local retail outlets or provided by a common supplier of school meals, or had some aspect of their medical-dental care in common. In only three of these locations were circumstances identified where the local risk of transmission might have been elevated. In none of the locations was there strong evidence to exclude chance as a likely explanation for the local occurrence of these vCJD cases. CONCLUSION: Although it is possible that in some parts of the UK local factors may have increased the risk of acquiring vCJD, most cases that were geographically close to each other are most likely due to the same factors that gave rise to the large majority of other vCJD cases in the UK.

Risk factors for sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Although surgical transmission of Creutzfeldt-Jakob disease (CJD) has been demonstrated, these iatrogenic cases account for only a small proportion of all CJD cases. The majority are sporadic CJD (sCJD) cases of unknown cause. This study investigated whether some cases classified as sCJD might have an unrecognized iatrogenic basis through surgical or other medical procedures METHODS: This study compared medical risk factors from 431 sCJD cases referred 1998 to 2006 with 454 population control subjects. Possible geographic and temporal links between neurological and gynecological operations in 857 sCJD cases referred from 1990 to 2006 were investigated RESULTS: A reported history of ever having undergone surgery was associated with increased risk for sCJD (odds ratio, 2.0; 95% confidence interval, 1.3-2.1; p = 0.003). Increased risk was not associated with surgical categories chosen a priori but was confined to the residual category "other surgery," in which the increase in risk appeared most marked for three subcategories: skin stitches, nose/throat operations, and removal of growths/cysts/moles. No convincing evidence was found of links (same hospital, within 2 years) between cases undergoing neurosurgery or gynecological surgery INTERPRETATION: It is unlikely that a high proportion of UK sCJD cases are the result of transmission during surgery, but we cannot exclude the possibility that such transmission occurs occasionally. A study based on accurate surgical histories obtained from medical records is required to determine whether the increased risk associated with reported surgical history reflects a causal association or recall bias.

Source of variant Creutzfeldt-Jakob disease outside United Kingdom.

We studied the occurrence of variant Creutzfeldt-Jakob disease (vCJD) outside the United Kingdom in relation to the incidence of indigenous bovine spongiform encephalopathy (BSE) and to the level of live bovines and bovine products imported from the UK during the 1980s and the first half of the 1990s. Our study provides evidence that a country's number of vCJD cases correlates with the number of live bovines it imported from the UK from 1980 to 1990 (Spearman rank correlation coefficient [r(s)] 0.73, 95% confidence interval [CI] 0.42-0.89, p < 0.001). Similar correlations were observed with the number of indigenous BSE cases (r(s) 0.70, 95% CI 0.37-0.87, p = 0.001) and carcass meat imported from the UK from 1980 to 1996 (r(s) 0.75, 95% CI 0.45-0.89; p < 0.001) Bovine imports from the UK may have been an important source of human exposure to BSE and may have contributed to the global risk for disease.

Children in Burkina Faso who are protected by insecticide-treated materials are able to clear drug-resistant parasites better than unprotected children.

BACKGROUND: It has been suggested that reducing exposure to malaria by vector control might impair the development of naturally acquired immunity to malaria. It is also thought that an individual's ability to clear drug-resistant malarial parasites after treatment is enhanced by acquired immunity. METHODS: To investigate the hypothesis that insecticide-treated materials may affect the acquisition of immunity to malaria, we compared the ability of children living in villages in which insecticide-treated curtains (ITCs) had been used for 6-8 years to clear resistant parasites after treatment with chloroquine (CQ) with that of children living in unprotected villages. RESULTS: A total of 1035 children aged 6-59 months with falciparum malaria were treated with CQ; 409 were subsequently identified as carrying parasites with the pfcrt-76T allele. More children from ITC villages cleared parasites harboring this allele than did children from non-ITC villages (34.1% vs. 24.0%; adjusted odds ratio [OR], 1.80 [95% confidence interval {CI}, 1.15-2.80]; P=.01). The difference in the clearance of parasites with the pfcrt-76T allele was seen in children aged 6-35 months (32.3% vs. 19.3%; adjusted OR, 2.34 [95% CI, 1.18-4.66]; P=.02) but not in older children (37.3% vs. 37.0%; adjusted OR, 1.09 [95% CI, 0.56-2.10]; P=.97). Rates of adequate clinical response among children carrying parasites with the pfcrt-76T allele were similar in ITC and non-ITC villages (75.1% vs. 68.6%; adjusted OR, 1.21 [95% CI, 0.61-2.39]; P=.58). CONCLUSION: Our data suggest that the children who were protected from malaria by ITCs acquired functional immunity more rapidly than did the control children.

Sustained use of insecticide-treated curtains is not associated with greater circulation of drug-resistant malaria parasites, or with higher risk of treatment failure among children with uncomplicated malaria in Burkina Faso.

The impact of vector control measures on the evolution of antimalarial drug resistance is an important issue for malaria control programs. We investigated whether the in vivo efficacy of chloroquine (CQ) in children aged 6-59 months with uncomplicated malaria differed in 9 villages that had benefited from long-term use of insecticide-treated curtains (ITCs) and in 9 nearby non-ITC villages. We also compared the prevalence of genetic markers of resistance to CQ and sulfadoxine-pyrimethamine (SP) between the two groups of villages. The study enrolled 1,035 children with uncomplicated malaria and 231 infected but asymptomatic children. After taking account of re-infections, the proportions of children who experienced clinical failure after treatment with CQ were 14% and 19% in ITC and non-ITC villages, respectively (OR = 0.68; 95% CI: 0.39, 1.18). Parasitologic failure was observed in 49% of children in ITC villages and 58% of children in non-ITC villages (OR = 0.71 95%CI: 0.44, 1.13). The proportion of symptomatic children who harbored parasites carrying the pfcrt-76T allele was 43% in ITC villages and 40% in non-ITC villages (OR = 1.09; 95%CI: 0.80, 1.50). The pfmdr1-86Y allele was detected in 31% and 29% of children in the two groups of villages (OR = 1.14; 95%CI: 0.75, 1.72). Triple mutations in the dhfr gene were observed in 12% of children in both groups. No double mutations in the dhps gene were observed. Similar results were observed in asymptomatic children. In this setting, ITC use was not associated with increased circulation of parasites resistant to standard antimalarial drugs, or with a greater risk of treatment failure among children less than 5 years of age.

Estimating the causes of 4 million neonatal deaths in the year 2000.

BACKGROUND: Information on cause-of-death is lacking for 98% of the world's 4 million neonatal deaths that occur in countries with inadequate vital registration (VR). Our aim was to estimate, by country for the year 2000, the distribution of neonatal deaths across programme-relevant causes including: asphyxia, preterm birth, congenital abnormalities, sepsis/pneumonia, neonatal tetanus, diarrhoea, and 'other'. METHODS: Two sources of neonatal cause-of-death data were examined: VR datasets for countries with high coverage (>90%), and published and unpublished studies identified through systematic searches. Multinomial regression was used to model the distribution of neonatal deaths. A VR-based model was used to estimate the distribution of causes of death for 37 low-mortality countries without national data. A study-based model was applied to obtain estimates for 111 high-mortality countries. Uncertainty estimates were derived using the jackknife approach. RESULTS: Data from 44 countries with VR (96 797 neonatal deaths) and from 56 studies (29 countries, 13 685 neonatal deaths) met inclusion criteria. The distribution of reported causes of death varied substantially between countries and across studies. Based on 193 countries, the major causes of neonatal death globally were estimated to be infections (sepsis/pneumonia, tetanus, and diarrhoea, 35%), preterm birth (28%), and asphyxia (23%). Regional variation is important. Substantial uncertainty surrounds these estimates. CONCLUSIONS: This exercise highlights the lack of reliable cause-of-death data in the settings in which most neonatal deaths occur. Complex statistical models are not a panacea. Representative data with comparable case definitions and consistent hierarchical cause-of-death attribution are required.

Risk factors for variant Creutzfeldt-Jakob disease: a case-control study.

OBJECTIVE: To investigate the potential risk factors for variant Creutzfeldt-Jakob disease (VCJD) in the United Kingdom. METHODS: Definite and probable vCJD cases (n = 136) were residing in Great Britain at disease onset, and were referred between May 1995 and November 2003. Control subjects (n = 922) were recruited between 2002 and 2003, from 100 randomly selected geographical clusters sampled to represent the geographical distribution of vCJD. RESULTS: Reported frequent consumption of beef and beef products thought likely to contain mechanically recovered or head meat, or both, including burgers and meat pies, was associated with increased risk for vCJD, as was reported frequent chicken consumption. Surgical operations were generally similarly reported for cases and control subjects, with the exception of a small group of minor operations, possibly attributable to underreporting in control subjects. Cases and control subjects had similar reported occupational histories and exposure to animals. INTERPRETATION: These findings are consistent with dietary exposure to contaminated beef products being the main route of infection of vCJD, but recall bias cannot be excluded. There was no convincing evidence of increased risk through medical, surgical, or occupational exposure or exposure to animals.

A simple model to predict the sensitivity to change of visual acuity measurements.

BACKGROUND: Estimates of test-retest variability (TRV) in the form of a 95% range have been suggested as providing a cutoff value (or "change-criterion") against which measured acuity changes can be judged to decide whether they are indicative of a clinically important change. This approach is based on ensuring that the specificity of the procedure is 95% in individuals with no real change. In an earlier article we investigated empirically the ability of the procedure to detect varying degrees of change (its sensitivity). In this article, we develop a simple statistical model to examine further the sensitivity of the approach. METHODS: A statistical model was developed, and predictions from the model were compared with empirical visual acuity data. RESULTS: The model predicts that for changes equal in size to the magnitude of the change-criterion, sensitivity will be 50%. For changes 1.65 times the change-criterion, sensitivity is 90% and increasing to 95% for changes 1.84 times the size of the change-criterion. Predicted sensitivities agreed well with those measured empirically. CONCLUSIONS: The 95% range for TRV is often used to decide whether measured changes are indicative of clinically important changes. Evaluating the performance of visual acuity charts using a method analogous to that of estimating the sensitivity and specificity of a screening test highlights some limitations of this method. Use of the 95% range as a change-criterion ensures a high specificity, but a simple statistical model indicates that changes must approach twice the size of the change-criterion before they will be detected with sensitivity in excess of 95%. This has implications for the clinician attempting to assess the reliability of visual acuity charts, and in other similar tests, to detect change.

The effect of optical defocus on the test-retest variability of visual acuity measurements.

PURPOSE: To determine the effect of optical defocus on the test-retest variability (TRV) of visual acuity measurements in normal subjects. METHODS: Normal subjects underwent repeated visual acuity measurement with optical defocus of 0, 0.50, and 1.00 D. All measurements were taken using the Early Treatment Diabetic Retinopathy Study (ETDRS) version of the Bailey-Lovie logMAR chart. TRV was quantified in terms of its 95% range, both empirically and using the approach of Bland and Altman. RESULTS: According to the Bland and Altman approach, the estimated 95% TRV ranges were +/-0.11 logarithm of the minimum angle of resolution (logMAR) for 0-D defocus, +/-0.18 logMAR for 0.50-D defocus, and +/-0.25 logMAR for 1.00-D defocus. CONCLUSIONS: Optical defocus has a considerable effect on the TRV of visual acuity measurements. These findings have important implications for both clinical practice and clinical research. Uncorrected refractive errors as small as 0.50 D may compromise the detection of visual change in individuals, and contribute to unnecessarily large sample sizes in clinical trials in which visual acuity is used as a primary outcome measure.

How sensitive to clinical change are ETDRS logMAR visual acuity measurements?

PURPOSE: To determine the sensitivity to change and specificity achieved when published test-retest variability (TRV) data are used to determine whether measured changes in ETDRS logarithm of the minimum angle of resolution (logMAR) visual acuity reflect true clinical change or are attributable to measurement error alone. METHODS: Various degrees of change in visual acuity were simulated in a group of normal subjects by adjusting test difficulty through manipulation of viewing distance. Sensitivity to simulated change and specificity were determined with change criteria derived from published Bland-Altman 95% ranges for TRV. RESULTS: The relationship between viewing distance and measured acuity was as predicted theoretically. Simulated acuity change of 0.2 logMAR (two lines of letters) or greater can be reliably distinguished from no change (both sensitivity and specificity >95%) with the ETDRS chart, but a change of 0.1 logMAR or less cannot. CONCLUSIONS: The use of 95% ranges for TRV to establish the smallest measured visual acuity change that can be reliably detected ensures a high specificity but does not take account of sensitivity. Use of change criteria derived from published 95% ranges results in a sensitivity of approximately 50% (assuming identical levels of TRV). Sensitivity may be improved by using a change criterion that is smaller than the minimum change sought, providing the change criterion is still at least as large as the 95% range for TRV, so that specificity is maintained. Reducing TRV allows smaller changes in acuity to be reliably detected.