Performance metrics for models designed to predict treatment effect.

BACKGROUND: Measuring the performance of models that predict individualized treatment effect is challenging because the outcomes of two alternative treatments are inherently unobservable in one patient. The C-for-benefit was proposed to measure discriminative ability. However, measures of calibration and overall performance are still lacking. We aimed to propose metrics of calibration and overall performance for models predicting treatment effect in randomized clinical trials (RCTs). METHODS: Similar to the previously proposed C-for-benefit, we defined observed pairwise treatment effect as the difference between outcomes in pairs of matched patients with different treatment assignment. We match each untreated patient with the nearest treated patient based on the Mahalanobis distance between patient characteristics. Then, we define the Eavg-for-benefit, E50-for-benefit, and E90-for-benefit as the average, median, and 90th quantile of the absolute distance between the predicted pairwise treatment effects and local-regression-smoothed observed pairwise treatment effects. Furthermore, we define the cross-entropy-for-benefit and Brier-for-benefit as the logarithmic and average squared distance between predicted and observed pairwise treatment effects. In a simulation study, the metric values of deliberately "perturbed models" were compared to those of the data-generating model, i.e., "optimal model". To illustrate these performance metrics, different modeling approaches for predicting treatment effect are applied to the data of the Diabetes Prevention Program: 1) a risk modelling approach with restricted cubic splines; 2) an effect modelling approach including penalized treatment interactions; and 3) the causal forest. RESULTS: As desired, performance metric values of "perturbed models" were consistently worse than those of the "optimal model" (Eavg-for-benefit ≥ 0.043 versus 0.002, E50-for-benefit ≥ 0.032 versus 0.001, E90-for-benefit ≥ 0.084 versus 0.004, cross-entropy-for-benefit ≥ 0.765 versus 0.750, Brier-for-benefit ≥ 0.220 versus 0.218). Calibration, discriminative ability, and overall performance of three different models were similar in the case study. The proposed metrics were implemented in a publicly available R-package "HTEPredictionMetrics". CONCLUSION: The proposed metrics are useful to assess the calibration and overall performance of models predicting treatment effect in RCTs.

Diet quality is associated with primary melanoma thickness.

BACKGROUND: Patients' diets can influence the outcome of several common cancers, but the effect on melanoma prognosis is unknown. OBJECTIVE: To assess the association between quality of melanoma patients' prediagnosis diets and primary tumour thickness, the main prognostic indicator for melanoma. METHODS: We used baseline data from patients newly diagnosed with tumour stage Ib to IV cutaneous melanoma, with completed questionnaires about food intake in the past year and other factors. Diet quality was measured by the Healthy Eating Index (HEI) and melanoma thickness was extracted from histopathology reports. We estimated prevalence ratios (PRadj ) and 95% confidence intervals (CIs) adjusted for confounding factors using Poisson regression models to assess associations between HEI scores and melanoma thickness. RESULTS: Of 634 study patients, 238 (38%) had melanomas >2 mm thick at diagnosis. Patients with the highest HEI scores were significantly less likely to be diagnosed with thick melanoma than patients with lowest HEI scores (PRadj 0.93, 95% CI 0.86-0.99) (Ptrend = 0.03). There was no evidence of effect modification by age, sex, previous melanoma or comorbidities. CONCLUSIONS: Melanoma thickness at diagnosis is significantly associated with quality of patients' diets before diagnosis.

Polygenic risk score as a determinant of risk of keratinocyte cancer in an Australian population-based cohort.

BACKGROUND: Keratinocyte cancer (KC) risk is determined by genetic and environmental factors. Genetic risk can be quantified by polygenic risk scores (PRS), which sum the combined effects of single nucleotide polymorphisms (SNPs). OBJECTIVES: Our objective here was to evaluate the contribution of the summed genetic score to predict the KC risk in the phenotypically well-characterized Nambour population. METHODS: We used PLINK v1.90 to calculate PRS for 432 cases, 566 controls, using 78 genome-wide independent SNPs that are associated with KC risk. We assessed the association between PRS and KC using logistic regression, stratifying the cohort into three risk groups (high 20%, intermediate 60%, low 20%). RESULTS: The fully adjusted model including traditional risk factors (phenotypic and sun exposure-related), showed a significant 50% increase in odds of KC per standard deviation of PRS (odds ratio (OR) = 1.51; 95% confidence interval (CI) = 1.30-1.76, P = 5.75 × 10-8 ). Those in the top 20% PRS had over three times the risk of KC of those in the lowest 20% (OR = 3.45; 95% CI = 2.18-5.50, P = 1.5 × 10-7 ) and higher absolute risk of KC per 100 person-years of 2.96 compared with 1.34. Area under the ROC curve increased from 0.72 to 0.74 on adding PRS to the fully adjusted model. CONCLUSIONS: These results show that PRS can enhance the prediction of KC above traditional risk factors.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma.

BACKGROUND: Statins may restrict the cellular functions required for melanoma growth and metastasis. OBJECTIVES: To determine whether long-term statin use commenced before diagnosis of a primary melanoma is associated with reduced risk of melanoma recurrence. METHODS: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localized tumour-stage T1b to T4b melanoma in Queensland, Australia. We used Cox regression analyses to examine associations between long-term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration, due to evidence of effect modification. RESULTS: Among 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62 years, 59% male, 28% with ulcerated tumours), 94 patients (13%) developed melanoma recurrence within 2 years. Long-term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence than nonusers [adjusted hazard ratio (HRadj ) 0·55, 95% confidence Interval (CI) 0·32-0·97] regardless of statin subtype or potency. Compared with nonusers of statins, risk of recurrence was significantly decreased in male statin users (HRadj 0·39, 95% CI 0·19-0·79) but not in female statin users (HRadj 0·82, 95% CI 0·29-2·27) and in statin users with ulcerated (HRadj 0·17, 95% CI 0·05-0·52) but not nonulcerated (HRadj 0·91, 95% CI 0·46-1·81) primary melanoma. CONCLUSIONS: Statins commenced before melanoma diagnosis may reduce the risk of melanoma recurrence, especially in men and in those with ulcerated tumours. Clinical trial evaluation of the potential role of statins in improving the prognosis of high-risk melanoma is warranted.

Factors associated with premature skin aging (photoaging) before the age of 55: a population-based study.

BACKGROUND: Precise factors associated with premature skin aging, or photoaging, in the general population are unknown. OBJECTIVE: To examine the risk factors for photoaging in a Queensland community. METHODS: A cross-sectional study of 1,400 randomly selected residents aged 20-54 years, using casts of the back of the hand (surface microtopography) and dermatological assessment of photoaging. RESULTS: 83% of the participants had premature skin aging, worsening after the age of 30. Severe neck wrinkling was 3 times more likely in men and some 4 times more likely in fair-skinned people (odds ratio, OR=3.86, 95% confidence interval, CI=2.40-6.23). Red hair and mainly outdoor work or leisure raised the odds of microtopographic photoaging. Current smoking was strongly associated with facial comedones and telangiectasia, and among current smokers, the microtopography grade was significantly associated with moderate and heavy smoking measured by pack-years of exposure, with OR=3.18 (95% CI=1.38-7.35) in the heaviest (>20 pack-years) smoking category compared with 1-7 pack-years. CONCLUSIONS: Premature skin aging is common in the subtropics, more severe in men and the fair-skinned. It is associated with high sun exposure during leisure or work, and moderate to heavy smoking, and therefore is preventable.

Comparison of histological measures of skin photoaging.

BACKGROUND: Dermal elastosis is considered the histological 'gold standard' for evaluation of skin photoaging, but the relation of the level of dermal elastosis to other histological indicators of photoaging is not clear. OBJECTIVE: To investigate how various proposed histological measures of photoaging compare with the level of dermal elastosis. METHODS: Prospective, community-based study in Southeast Queensland, Australia, among 89 participants aged 40-82 years. Quantitative histology was used to evaluate 8 biomarkers of photoaged skin, and associations between grades of dermal elastosis and each of the other 7 biomarkers were analysed using ordinal logistic regression models with proportional odds assumption, using histological grades of elastosis as the outcome. RESULTS: Older age, male sex and high outdoor exposure levels were confirmed as predictors of high levels of dermal elastosis. After adjustment for age and sex, the only significant positive association with increasing elastosis grades was the proportion of p53-positive cells. Epidermal thickness, interdigitation index proportion of surface covered with melanin (% Fontana-Masson staining) and glycosaminoglycan content were not associated with elastosis in either crude or adjusted models. CONCLUSIONS: Among a range of suggested biomarkers of photoaged skin, only p53-positive cells appear to be strongly associated with the level of dermal elastosis.

Does blood flow limit acute hypoxia performance in larval zebrafish (Danio rerio)?

Oxygen uptake (MO2) in larval zebrafish prior to maturation of the gill relies on cutaneous O2 transfer. Under normoxic conditions, rates of cutaneous O2 transfer are unaffected by haemoglobin availability but are diminished in fish lacking a functional circulatory system, suggesting that internal convection is critically involved in setting the resting MO2 in zebrafish larvae, even when relying on cutaneous O2 transfer. The reliance of MO2 on blood circulation led to the first objective of the current study, to determine whether loss of internal convection would reduce acute hypoxia performance (as determined by measuring critical PO2; Pcrit) in larval zebrafish under conditions of moderate hypoxia (PO2 = 55 mmHg) at 28.5 and 34 °C. Internal convection was eliminated by preventing development of blood vessels using morpholino knockdown of vascular endothelial growth factor (VEGF); these fish are termed VEGF morphants. Breathing frequency (fV) and heart rate (fH) also were measured (at 28.5 °C) to determine whether any detriment in performance might be linked to cardiorespiratory dysfunction. Although MO2 was reduced in the VEGF morphants, there was no significant effect on Pcrit at 28.5 °C. Raising temperature to 34 °C resulted in the VEGF morphants exhibiting a higher Pcrit than the shams, suggesting an impairment of hypoxia tolerance in the morphants at the higher temperature. The usual robust increase in fV during hypoxia was absent or attenuated in VEGF morphants at 4 and 5 days post fertilization (dpf), respectively. Resting fH was reduced in the VEGF morphants and unlike the sham fish, the morphants did not exhibit hypoxic tachycardia at 4 or 5 dpf. The number of cutaneous neuroepithelial cells (presumptive O2 chemoreceptors) was significantly higher in the VEGF morphants and thus the cardiorespiratory impairment in the morphants during hypoxia was unlikely related to inadequate peripheral O2 sensing.

Alcohol intake and risk of skin cancer: a prospective study.

OBJECTIVE: To investigate the association between total alcohol intake and intake of different types of alcoholic beverages in relation to the risk of basal cell (BCC) and squamous cell (SCC) carcinoma of the skin. DESIGN: Prospective cohort study. SETTING: Follow-up data from a community-based skin cancer study in Australia. SUBJECTS: Randomly selected sample of 1360 adult residents of the township of Nambour who completed a food frequency questionnaire in 1992 and were monitored for BCC and SCC until 31 December 2002. RESULTS: No significant association was found between overall BCC or SCC risk and total alcohol intake, or intake of beer, white wine, red wine or sherry and port. However, among those with a prior skin cancer history, there was a significant doubling of risk of SCC for above-median consumption of sherry and port (multivariable adjusted relative risk 2.46, 95% confidence interval 1.06-5.72) compared with abstainers. CONCLUSIONS: There are no associations between first occurrence of skin cancers and alcoholic beverage consumption. People with a history of skin cancer who consume above-average quantities of sherry or port may be at a raised risk of SCC, although replication of these findings in different study populations is needed to confirm this possible role of specific alcoholic beverages in secondary keratinocytic skin cancer risk.

Forearm hair density and risk of keratinocyte cancers in Australian adults.

Evidence suggests that progenitor cells of keratinocyte cancers (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) may originate from epidermal stem cells including hair follicle stem cells. We hypothesised that, therefore, a relatively higher density of hair follicles on human skin may increase keratinocyte cancer risk. To evaluate this, we assessed density of mid-forearm hair in Australian adults who were randomly selected participants in a community-based cohort study of skin cancer. Hair density was assessed clinically against a set of four standard photographs showing grades of hair density, and incidence data on histologically confirmed BCC and SCC across a 20-year period were collected. Incidence rate ratios were calculated for categories of forearm hair density using multivariable regression analysis with adjustment for age, sex, phenotypic characteristics and markers of chronic sun exposure. Among the 715 participants (43 % male, average age 61 years), 237 developed at least one BCC and 115 persons developed at least one SCC. Participants with dense forearm hair (n = 169, all male) had a higher incidence of BCC (IRR = 2.24, 95 % CI 1.20, 4.18, P = 0.01) and SCC (IRR = 2.80, 95 % CI 1.20, 6.57, P = 0.02) compared to individuals with sparse forearm hair after multivariable adjustment. Stratified analyses showed that among men, those with dense versus sparse hair developed SCC more commonly (IRR = 3.01, 95 % CI 1.03, 8.78, P = 0.04). Women with moderate versus sparse hair density were more likely affected by BCC (IRR = 2.29, 95 % CI 1.05, 5.00, P = 0.038). Thus, our study suggests that in both men and women, a higher density of body hair may be associated with increased BCC and SCC risk.

Children with psychogenic abdominal pain and their families. Management during hospitalization.

Children hospitalized with psychogenic abdominal pain and the children's families are discussed from the perspective of a child psychiatrist working within the pediatric hospital. Psychosocial and emotional difficulties for the child and parents are noted as families use somatic symptoms to deal with psychic distress. Principles for management are emphasized, utilizing a comprehensive team approach by physicians, nurses, and other health professionals. Through constructive use of hospitalization and informed follow-up, these children and their parents can be helped toward symptomatic improvement and a more meaningful understanding and resolution of their underlying emotional difficulties.

Proteolytic specificity of cathepsin D on bovine F-actin.

Proteolysis of bovine F-actin by cathepsin D (E.C. 3.4.23.5) in 50 mM Na acetate buffer, pH 5.5, at 37°C was investigated using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and reverse-phase high performance liquid chromatography (RP-HPLC). Actin was hydrolyzed by cathepsin D during incubation to peptides detectable by RP-HPLC, although no degradation products were detected by SDS-PAGE. Peptides (2% trichloroacetic acid-soluble) from the hydrolyzate were isolated by RP-HPLC on a C(18) column using an acetonitrile/water gradient and identified from their N-terminal sequence and mass. Cathepsin D cleavage sites were identified at Cys(12)-Asp(13), Gly(22)-Phe(23), Arg(30)-Ala(31), Thr(79)-Asn(80), Ile(87)-Trp(88), Thr(91)-Phe(92), Phe(92)-Tyr(93), Arg(97)-Val(98), His(103)-Pro(104), Leu(107)-Thr(108), Thr(108)-Glu(109), Lys(120)-Met(121), Leu(144)-Tyr(145), Ile(153)-Val(154), Leu(155)-Asp(156), Ile(167)-Tyr(168), Leu(180)-Asp(181), Met(192)-Lys(193), Leu(195)-Thr(196), Arg(208)-Glu(209), Arg(212)-Asp(213), Leu(223)-Asp(224), Lys(240)-Ser(241), Thr(262)-Leu(263), Trp(342)-Ile(343), Arg(349)-Ser(350), Trp(358)-Ile(359), and Lys(375)-Cys(376). In general, cathepsin D preferentially cleaved bonds containing at least one hydrophobic amino acid residue. The results of this study showed that actin was degraded extensively by cathepsin D with peptides released from numerous locations in the protein molecule.

Characterization of peptides released from rabbit skeletal muscle troponin-T by µ-calpain under conditions of low temperature and high ionic strength.

Rabbit skeletal muscle troponin-T (200 µg ml(-1)) was incubated with µ-calpain (2 µl ml(-1)) under conditions of low temperature and high ionic strength for 180 min at 4°C and the peptides released analyzed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Troponin-T was hydrolyzed rapidly with the simultaneous appearance of eight peptides with masses of less than 14 up to 26 kDa. Two peptides produced by 10 min of incubation were electroblotted and analysis of these peptides by N-terminal sequencing and mass spectrometry showed that the principal cleavage sites of µ-calpain on troponin-T were at Thr(45)-Ala(46), Leu(69)-Met(70), Glu(220)-Lys(221) and Asn(231)-Val(232). The peptides present in insufficient quantity for electroblotting were isolated by reverse-phase high performance liquid chromatography (RP-HPLC). Cleavage sites were also identified at Met(151)-Gly(152), Asn(188)-Ile(189), Lys(223)-Arg(224), Arg(233)-Ala(234) and Ala(240)-Lys(241). In general, µ-calpain cleaved bonds containing one hydrophobic amino acid residue and mainly towards the C-terminus of troponin-T.

Characterization of proteolysis during the ripening of semi-dry fermented sausages.

The respective contribution of indigenous enzymes and enzymes from starter bacteria to proteolysis in fermented sausages were determined by comparing the proteolytic changes occurring in sausages resulting from the presence of a proteolytic strain of Staphylococcus carnosus, i.e. S. carnosus MC 1 to the proteolytic changes occurring in control sausages containing glucono-δ-lactone (GDL) and an antibiotic mixture. Proteolysis was quantified by assaying for non-protein nitrogen (NPN) and free amino acids. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and reversed phase high performance liquid chromatography (RP-HPLC) were used to qualitatively assess the proteolytic changes in the sarcoplasmic and myofibrillar proteins as ripening progressed. The concentration of NPN and free amino acids increased in both sausages initially, but subsequently decreased towards the end of ripening in sausages inoculated with the starter culture. SDS-PAGE showed a similar pattern of proteolysis of sarcoplasmic proteins in both sausages, while of the two sausage types; the S. carnosus MC 1 inoculated sausages exhibited the most intense degradation of myofibrillar proteins, especially myosin and actin. RP-HPLC profiles of 2% trichloroacetic acid (TCA)-soluble peptides for the two sausage types were similar, with the production of numerous hydrophilic peptides. N-Terminal amino acid sequence analysis and sequence homology with proteins of known primary structure showed that six of the TCA-soluble peptides were released from the sarcoplasmic (myoglobin and creatine kinase) and myofibrillar (troponin-I, troponin-T and myosin light chain-2) proteins. In addition, the initial degradation of sarcoplasmic proteins was due to the activity of indigenous proteinases, while both indigenous and bacterial enzymes contributed to the initial degradation of myofibrillar proteins. Furthermore, indigenous enzymes were responsible for the release of TCA-soluble peptides, which, were further hydrolysed by bacterial enzymes.

Deaf children's revision behaviors in conversations.

This study was designed to investigate school-age deaf children's responses to a listener's indication of communication breakdown and to determine if the deaf children's responses were related to their syntactic or semantic abilities and/or typical mode of communication. Subjects were 14 deaf children between the ages of 5 yr, 10 mo and 8 yr, 11 mo. Approximately once every 3 min during a 60-min conversation, the experimenter said, and simultaneously signed, "What?" The child's responses to the "What?" probe were classified as Revision, Repetition, and No Response. Revisions were categorized into eight subcategories involving changes in sentence constituents and supraconstituents. Revisions were the most frequent responses when communication broke down. Most of the children's revisions involved changes in sentence constituents. The frequency of revisions, repetitions, and no responses was related to the children's level of syntactic production.

Oral diadochokinesis in hearing-impaired adolescents.

Oscillographic tracings for time-by-count measures of diadochokinetic syllable rate (Fletcher, 1972) were collected from a group of 30 hearing-impaired and five normal-hearing high-school students. Results indicated that hearing-impaired subjects performed significantly slower on all speech-timing tasks than their normal-hearing peers. Within-group differences were identified for the hearing-impaired subjects with respect to speech intelligibility, degree of hearing loss, and gender. The differences, in general, indicate that for varying degrees of hearing loss severity there are speech-timing coordination deficits commensurate to that level.

Critical care nursing for the patient with a spinal cord injury.

Knowledge of the dynamics of spinal cord injury to anticipate the myriad of physiologic and psychological complications is essential for effective interventions to achieve optimal patient outcomes. Continuous expert nursing care must be provided to ensure that the patient survives life-threatening events and to facilitate optimal adaptation of the patient and family during this enormous emotional upheaval of their lives. Given the devastating effects of a spinal cord injury, the critical care nurse faces one of the most complex and potentially rewarding challenges of his or her career.

A prospective study of cigarette smoking and basal cell carcinoma.

To investigate the relationship between smoking and primary basal cell carcinoma (BCC), we analyzed data from a 16 year prospective study among randomly selected adults in Nambour, Queensland, Australia. Participants underwent a skin examination in 1992 and took part in an intervention study and follow-up. Information about complexion type and smoking habits including duration and number of cigarettes smoked per day and sun exposure behavior were collected at baseline in 1992, with updates to end of follow-up in 2007. Newly-diagnosed BCCs were ascertained from regional pathology laboratories. Relative risks (RR) of BCC among former and current smokers were estimated using generalized linear models specifying a Poisson distribution with robust error variance and (log) person-years at-risk as offset, adjusting for BCC risk factors. From 1992 to 2007, 281 BCCs were diagnosed in 1,277 participants with available smoking history and no past BCC. Relative to non-smokers, a non-significant inverse association between current smoking and BCC was seen (RR 0.69; 95 % CI 0.45-1.05) but not for former smokers (RR 1.05; 95 % CI 0.84-1.31). Amongst current smokers, inverse associations with BCC were found in those who smoked for up to 18 years (RR 0.44) but not more and those who smoked up to 15 cigarettes per day but not more. The associations with both current and former smoking varied by degree of sunburn propensity. The modest inverse association between current smoking and BCC is considered unlikely to be causal given lack of clear relation with duration or intensity of smoking.

Food intake and risk of basal cell carcinoma in an 11-year prospective study of Australian adults.

BACKGROUND/OBJECTIVE: Experimental studies suggest that dietary factors may influence skin cancer risk, but there have been few human studies of diet and basal cell carcinoma (BCC), the most common type of skin cancer. The objective was to prospectively investigate the association between food intake and incidence of BCC skin cancers. SUBJECTS/METHODS: At baseline in 1992, 1056 adults in a subtropical Australian community completed a validated food-frequency questionnaire from which we estimated the intake of 15 food groups, selected based on hypothesized associations in the literature. Between 1992 and 2002, incident, histologically confirmed BCCs were recorded in terms of number of persons newly affected by BCC, as well as BCC tumor counts. RESULTS: Intakes of the food groups were not associated with the incidence of persons affected by BCC. However, there was a borderline positive association between intake of eggs and incidence of BCC tumors (highest vs lowest tertile adjusted relative risk (RR) 1.5; 95% confidence interval (CI): 1.0-2.2; P for trend = 0.06). A borderline inverse association with potato intake (highest vs lowest tertile RR 0.7; 95% CI: 0.4-1.0, P for trend = 0.06) disappeared after exclusion of three subjects with more than 10 BCCs. CONCLUSION: Despite some suggestive evidence that egg and potato consumption may be associated with BCC tumor incidence, there are no plausible grounds for considering these as truly causal rather than chance associations. This study provides little evidence for a role of food intake in BCC prevention.