tbuckley/cabot-search huggingface dataset:
Verification problems in diagnostic accuracy studies: consequences and solutions
Authors: J. A. H. de Groot, P. M. M. Bossuyt, J. B. Reitsma, A. W. S. Rutjes, N. Dendukuri, K. J. M. Janssen, K. G. M. Moons
Journal: BMJ (2011)

The accuracy of a diagnostic test or combination of tests (such as in a diagnostic model) is the ability to correctly identify patients with or without the target disease. In studies of diagnostic accuracy, the results of the test or model under study are verified by comparing them with results of a reference standard, applied to the same patients, to verify disease status (see first panel in figure⇓).1 Measures such as predictive values, post-test probabilities, ROC (receiver operating characteristics) curves, sensitivity, specificity, likelihood ratios, and odds ratios express how well the results of an index test agree with the outcome of the reference standard.2 Biased and exaggerated estimates of diagnostic accuracy can lead to inefficiencies in diagnostic testing in practice, unnecessary costs, and physicians making incorrect treatment decisions.



Diagnostic accuracy studies with ( a ) complete verification by the same reference standard, ( b ) partial verification, or ( c )differential verification



The reference standard ideally provides error-free classification of the disease outcome presence or absence. In some cases, it is not possible to verify the definitive presence or absence of disease in all patients with the (single) reference standard, which may result in bias. In this paper, we describe the most important types of disease verification problems using examples from published diagnostic accuracy studies. We also propose solutions to alleviate the associated biases. 

Often not all study subjects who undergo the index test receive the reference standard, leading to missing data on disease outcome (see middle panel in figure⇑). The bias associated with such situations of partial verification is known as partial verification bias, work-up bias, or referral bias.3 4 5 

### Clinical examples of partial verification

Various mechanisms can lead to partial verification (see examples in table 1⇓). 

View this table:

Table 1 
 Examples of diagnostic accuracy studies with problems in disease verification



When the condition of interest …
Drug Treatment of Depressed Patients Referred for Hospitalization
Authors: JOEL KOTIN, ROBERT M. POST, FREDERICK K. GOODWIN
Journal: American Journal of Psychiatry (1973)

The authors' clinical impression that many depressed patients are admitted to hospitals without having received adequate drug treatment as outpatients was confirmed with a sample of 51 depressed patients. Of these, only 20 percent had received proper drug treatment before referral. The authors propose a larger study of the actual patterns of drug prescription to seek the causes of inadequate treatment.
The effects of deoxygenation of adult and fetal hemoglobin on the synthesis of red cell 2,3-diphosphoglycerate and its in vivo consequences
Authors: Frank A. Oski, Arlan J. Gottlieb, William W. Miller, Maria Delivoria-Papadopoulos
Journal: Journal of Clinical Investigation (1970)

Patients over 1 month of age with arterial oxygen pressures of less than 60 mm Hg were found to have elevated red cell 2,3-diphosphoglycerate (2,3-DPG) levels and blood with a decreased affinity for oxygen. The increase in 2,3-DPG was proportional to the degree of hypoxemia. In patients under 1 month of age this relationship was not observed. Red cells from adults, but not newborns, showed rapid increases in 2,3-DPG when incubated under nitrogen. Adult, but not fetal, deoxyhemoglobin was shown to facilitate in vitro synthesis of 2,3-DPG by binding this organic phosphate and relieving the product inhibition of 2,3-DPG mutase. Throughout a wide range change in oxygen affinity as measured by the P(50) is linear with respect to the 2,3-DPG concentration; a change of 430 mmumoles of 2,3-DPG/ml of red blood corpuscles (RBC) resulting in a change of the P(50) of 1 mm Hg. It appears that the 2,3-DPG of the adult's red cells responds rapidly to metabolic and environmental influences and in turn effects metabolism and the cellular environment. Many of these effects are not shared by the red cells of the newborn.
Gene transfer: Bax to the future for cancer therapy
Authors: N R Lemoine
Journal: Gut (2004)

The Bax gene as a competitor in the marathon towards licensed cancer gene therapy

Intraperitoneal spread of gastrointestinal malignancies is a significant clinical problem and contributes to an incidence of distant relapse as high as 30% in gastric cancer. Local dissemination of tumour cells into the peritoneal cavity determines the outcome in advanced gastric cancer and diffuse-type carcinoma, and patients with negative peritoneal washings have a more favourable prognosis. Extensive lymph node dissection has been shown (by quantitative reverse transcription-polymerase chain reaction for carcinoembryonic antigen and cytokeratin 20 combined with extensive intraoperative peritoneal lavage1) to open lymphatic channels and spread viable cancer cells into the peritoneal cavity. Hence patient subpopulations that might benefit from intraperitoneal therapy regimens may be identified.

Malignant disease localised within the abdominal cavity has been a target for the staged development of clinical gene therapy approaches because of the smaller doses of experimental agent and increased safety margins over systemic administration. There has been extensive—and safe—experience of p53 gene therapy which culminated in a randomised phase III trial in which women with p53 null or p53 mutant ovarian cancer were randomised to chemotherapy alone or chemotherapy plus intraperitoneal Ad p53 following optimum debulking primary surgery. However, the first interim analysis indicated that not only did Ad p53 fail to improve effectiveness but it was also associated with increased toxicity. As a result, the study has been abandoned (reported in Zeimet and Marth2). Two broad possibilities exist to explain why the trials were relatively unsuccessful. Firstly, there is the perennial problem of suboptimal gene transfer. Secondly, there is the possibility that p53 is the “wrong” transgene. Although p53 mutations are found in many malignancies3 and defective p53 function may be causally linked to chemotherapy resistance,4 many …
Diagnostic value of serum primary bile acids in detecting bile acid malabsorption.
Authors: R Aldini, A Roda, D Festi, G Mazzella, A M Morselli, C Sama, E Roda, N Scopinaro, L Barbara
Journal: Gut (1982)

Serum cholic and chenodeoxycholic acid conjugates were measured in fasting conditions and after meals in 14 patients with bile acid malabsorption due to ileal resection. Mean serum fasting levels of both primary bile acids did not differ from the controls. After meals, serum cholic acid peaks were lower in patients with ileal resection than in control subjects (p less than 0.001), while chenodeoxycholic acid peaks were reduced in colectomised patients (p less than 0.01). In the sera from patients with ileal resection, the glycine/glycine + taurine ratio for cholic and chenodeoxycholic acid increased (p less than 0.001) from morning to evening, and glycine/glycine + taurine ratio for chenodeoxycholic acid was significantly (p less than 0.01) different from the controls in the sera collected in the evening. The results are consistent with the concept of a better intestinal conservation of chenyl, mainly of the glycine conjugated from, than of cholylconjugates, in patients with ileal resection; this is probably because of passive absorption in the intestine. The postprandial peaks of serum cholic acid conjugates may therefore be regarded as a test of ileal dysfunction, while peaks of chenodeoxycholic acid conjugates suggest colonic impairment.
Renin Content of Systemic Blood of Rats with Desoxycorticosterone and Metacorticoid Hypertension
Authors: J. L. PRADO, ZULEIKA P. PICARELLI, REGINA KUPPER, ELINE S. PRADO, J. R. VALLE
Journal: Circulation Research (1954)

No increased renin concentration was detected in the systemic blood of rats with desoxycorti-costerone and metacorticoid hypertension, using the guinea-pig; ileum method of renin estimation. Re-establishment of the circulation through totally ischemic rat kidney is followed by the liberation of large amounts of renin.
Regional Differences in Dialysis Care and Mortality among American Indians and Alaska Natives
Authors: Yoshio N. Hall, Stacey E. Jolly, Ping Xu, Christine K. Abrass, Dedra Buchwald, Jonathan Himmelfarb
Journal: Journal of the American Society of Nephrology (2011)

American Indians/Alaska Natives (AIANs) compose a heterogeneous population that includes geographically distinct tribal communities, many with high rates of ESRD. Regional features of dialysis care and mortality are unknown in this population. Here, we describe the structure of dialysis care and mortality of adult AIANs who initiated maintenance dialysis during 1995-2008 in different regions of the US. Overall, 13,716 AIANs received dialysis at 2054 facilities. Approximately 10% (n = 197) of these facilities provided care to two-thirds (n = 9011) of AIANs. AIANs from the Southwest and Alaska were concentrated in relatively few dialysis facilities whereas those in the Eastern US and Pacific Coast were distributed more diffusely. Despite comparably high rates of poverty, diabetes, and cardiovascular disease, annual mortality rates were lower in the Southwest (13.9%) compared with the Southern Plains (23.2%), Alaska (21.2%), Eastern US (20.0%), Northern Plains (20.8%), and Pacific Coast (22.0%). These regional differences were consistent over time and persisted after adjusting for sociodemographic and clinical variables and area-based poverty. In conclusion, regional differences in the structure of dialysis care and patient mortality exist among AIANs. Southwestern AIANs experience the highest concentration of dialysis care and the lowest mortality. Our findings suggest that an area-based approach examining the care structure of relatively few dialysis facilities may delineate determinants of these differences and improve the quality of care to many AIAN communities.
Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients
Authors: M Feletar
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate the effectiveness and toxicity of infliximab in patients with recalcitrant psoriatic arthritis (PsA).Patients with treatment resistant PsA and at least six actively inflamed joints, who had failed to respond to at least two disease modifying agents, were included. Infliximab (5 mg/kg) was given at weeks 0, 2, 6, and every 6-8 weeks pending response. Clinical and laboratory measures included actively inflamed joint count (AJC), swollen joint count (SJC), psoriasis severity (PASI), HAQ, and SF-36. Response was defined as at least a 30% reduction in AJC and PASI. Differences from baseline were analysed using the signed rank test.Sixteen patients (12 male, 4 female), mean age 48 and disease duration 14 years, were included. At baseline the mean AJC was 22.5 and mean PASI 4.5. Eleven patients continued receiving methotrexate. The AJC did not show a statistically significant response. SJC improved significantly at week 54 (p = 0.01). The PASI improved significantly at weeks 14 (p = 0.001) and 30 (p = 0.002) and CRP was reduced significantly at week 30 (p = 0.02). The HAQ score improved at week 30 (p = 0.02). Six patients became positive for dsDNA without clinical features of a connective tissue disease. Six patients discontinued treatment owing to lack of efficacy (1) and toxicity (5). Other serious adverse events included: urticaria (3); thrombocytopenia (1); lower gastrointestinal bleeding (2); severe diarrhoea (2); serious infections (6). Raised transaminases, at least 1.5x normal, occurred in four patients.In refractory PsA, infliximab led to a marked improvement in psoriasis but modest response in joint disease. Toxicity and rate of treatment termination was high.
Polyene Potentiation of Antitumor Agents2
Authors: G. Medoff, D. Schlessinger, G. S. Kobayashi
Journal: JNCI Journal of the National Cancer Institute (1973)

Amphotericin B combined with 1,3-bis(2-chloroethyl)-1-nitrosourea inhibited RNA synthesis in mouse L cells and killed 90% of the cells in culture. Each agent alone at the same concentrations had no effect. AKR leukemic mice treated with the combination survived 4 weeks, whereas mice treated with each drug alone died within 1 week. In vivo quantitation of surviving tumor cells by a spleen colony assay also showed synergy of the combination.
Treatment of Locally Recurrent Mucosal Melanoma With Topical Imiquimod
Authors: Elizabeth C. Smyth, Marisa Flavin, Melissa P. Pulitzer, Ginger J. Gardner, Peter D. Costantino, Dennis S. Chi, Kita Bogatch, Paul B. Chapman, Jedd D. Wolchok, Gary K. Schwartz, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2011)
Amygdalar Volume and Emotional Memory in Alzheimer’s Disease
Authors: E Mori, M Ikeda, N Hirono, H Kitagaki, T Imamura, T Shimomura
Journal: American Journal of Psychiatry (1999)

Everyday experience suggests that highly emotional events are often the most memorable. Experimental work in animals and humans has demonstrated that the amygdaloid complex plays a crucial role in emotional memory, i.e., memory of events arousing strong emotions. The aim of this study was to elucidate the relationship between medial temporal damage and impaired memory of real-life emotional events in patients with Alzheimer's disease.In 36 patients with probable Alzheimer's disease who experienced the 1995 earthquake in Kobe, Japan, memories of events surrounding the earthquake were examined as an index of emotional memory with the use of a semistructured interview, and amygdalar and hippocampal volumes were quantified by magnetic resonance imaging. The effects of the atrophy of these structures on recall performance were determined by multiple regression analysis.Irrespective of generalized brain atrophy and cognitive impairments, emotional memory was correlated more with normalized amygdalar volume (right and left averaged) than with normalized hippocampal volume. General knowledge of the earthquake was correlated with neither amygdalar nor hippocampal volume.The results indicate that impairment of emotional event memory in patients with Alzheimer's disease is related to intensity of amygdalar damage and provide evidence of the amygdala's involvement in emotional memory in humans.
Independent prognostic value of C-reactive protein and troponin I in patients with unstable angina or non-Q-wave myocardial infarction
Authors: R de Winter
Journal: Cardiovascular Research (1999)

Elevated concentrations of C-reactive protein (CRP), a non-specific acute phase reactant, and troponin I (TnI), a cardiac-specific marker of myocardial damage, have been found to be associated with a higher risk for cardiac events in patients with an acute coronary syndrome. We evaluated CRP alone and in combination with TnI for predicting the incidence of major cardiac complications within 6 months in patients with unstable angina or non-Q-wave infarction (NQMI).CRP and TnI was measured on admission in patients with unstable angina or NQMI, but results were kept blinded. Patients were treated according to a conservative management strategy, and the incidence of major cardiac events within 6 months was assessed.An abnormal CRP (> 5 mg/l) and an abnormal TnI (> 0.4 microgram/l) were more frequent in patients that suffered a major cardiac event (CRP: 93 vs. 35%, P < 0.0001; TnI: 73 vs. 26%, P < 0.001). The incidence of major cardiac events was higher in patients with an abnormal CRP than in patients with a normal CRP, both when TnI was abnormal (42 vs. 4.5%, P = 0.003) and when TnI was normal (11 vs. 0%, P = 0.014). Mean event-free survival was excellent in patients with both a normal CRP and TnI, whereas survival was poorest in patients with both an abnormal CRP and TnI (121 +/- 16 vs. 180 days, P < 0.0001).An abnormal CRP on admission in patients with unstable angina or NQMI is associated with increased incidence of major cardiac events within 6 months, both in patients with normal and abnormal TnI. CRP and TnI have independent and additive prognostic value in this patient group, and the combination may be useful for early risk stratification.
Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model
Authors: Christof Renner, Nadine Zemitzsch, Beate Fuchs, Kathrin D Geiger, Matthias Hermes, Jan Hengstler, Rolf Gebhardt, Jürgen Meixensberger, Frank Gaunitz
Journal: Molecular Cancer (2010)

Abstract Background It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. In the present work we investigated whether carnosine also affects tumor growth in vivo and may therefore be considered for human cancer therapy. Results A mouse model was used to investigate whether tumor growth in vivo can be inhibited by carnosine. Therefore, NIH3T3 fibroblasts, conditionally expressing the human epidermal growth factor receptor 2 (HER2/neu), were implanted into the dorsal skin of nude mice, and tumor growth in treated animals was compared to control mice. In two independent experiments nude mice that received tumor cells received a daily intra peritoneal injection of 500 μl of 1 M carnosine solution. Measurable tumors were detected 12 days after injection. Aggressive tumor growth in control animals, that received a daily intra peritoneal injection of NaCl solution started at day 16 whereas aggressive growth in mice treated with carnosine was delayed, starting around day 19. A significant effect of carnosine on tumor growth was observed up to day 24. Although carnosine was not able to completely prevent tumor growth, a microscopic examination of tumors revealed that those from carnosine treated animals had a significant lower number of mitosis (p &lt; 0.0003) than untreated animals, confirming that carnosine affects proliferation in vivo. Conclusion As a naturally occurring substance with a high potential to inhibit growth of malignant cells in vivo, carnosine should be considered as a potential anti-cancer drug. Further experiments should be performed in order to understand how carnosine acts at the molecular level.
Kenneth Fowler Wood
Authors: K. A. Stewart
Journal: BMJ (2011)

Born in Manchester, Kenneth Fowler Wood (“Ken”) was a true general surgeon. He recalled how, when he was a senior registrar in Sheffield, he repaired aortic aneurysms with a synthetic mesh, woven by nurses in a theatre annexe. Ambidexterity complimented his surgical skills. He once filled his own troublesome tooth.

He was a member of the prestigious Moynihan Surgeon’s Travelling Club. As …
Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group.
Authors: L Fabbri, P S Burge, L Croonenborgh, F Warlies, B Weeke, A Ciaccia, C Parker
Journal: Thorax (1993)

BACKGROUND--High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma. Although effective, they may cause systemic side effects. Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses. METHODS--Fluticasone propionate, 1.5 mg per day, was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate. The study was multicentre, double blind and of a parallel design. For the first three months patients attended the clinic every four weeks and completed daily diary cards. For the next nine months they were only seen at three monthly intervals in the clinic. RESULTS--During the first three months diary card peak expiratory flow (PEF) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate (difference in morning PEF 15 l/min (95% CI 6 to 25)), and these differences were apparent at the end of the first week. The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8% compared with those receiving beclomethasone dipropionate. No significant differences between the two groups were observed in morning plasma cortisol levels, urinary free cortisol levels, or response to synthetic ACTH stimulation. In addition, both the rates of withdrawal and of adverse events were low, and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate. CONCLUSIONS--This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate, with no increase in systemic or other side effects.
Reduction of Lung Distensibility in Acromegaly after Suppression of Growth Hormone Hypersecretion
Authors: FRANCISCO GARCÍA-RÍO, JOSÉ M. PINO, JUAN J. DÍEZ, ANTONIO RUÍZ, CARLOS VILLASANTE, JOSÉ VILLAMOR
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Whether the growth of the lungs in acromegaly is due to alveolar hypertrophy or alveolar hyperplasia is a subject of debate. To discriminate these hypotheses, we compared pulmonary distensibility and diffusing capacity among 11 patients with active acromegaly and 11 matched control subjects, evaluating the response of pulmonary distensibility and diffusing capacity to suppression of growth hormone (GH) hypersecretion. We performed lineal and exponential analyses of quasistatic pressure–volume curves. Patients with active acromegaly had a greater TLC, lung compliance, and shape constant, K, than did normal subjects. We found no significant differences between the study groups in carbon monoxide diffusing capacity or diffusing capacity per unit of alveolar volume. After treatment, patients with inactive acromegaly showed a reduced TLC (6.95 ± 1.40 [mean ± SD] L versus 6.35 ± 1.23 L), reduced lung compliance (3.61 ± 0.90 L/kPa versus 2.36 ± 0.79 L/ kPa), reduced K coefficient (2.62 ± 0.65 kPa− 1 versus 1.35 ± 0.40 kPa− 1), and increased maximal recoil pressure (1.74 ± 0.38 kPa versus 2.28 ± 0.25 kPa). We conclude that the increased lung distensibility with normal diffusion capacity demonstrated in patients with active acromegaly, which was partly reversible after suppression of GH hypersecretion, suggests that lung growth in acromegaly may result from an increase in alveolar size.Keywords: lung volume measurements; lung compliance; pulmonary gas exchange; somatotropin; acromegaly