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Background The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease. Methods A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. Results A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. Conclusions Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

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Pp. xi, 338. $34.95 (US). Reviewed by John L. Kessell HEINZ DUCHHARDT. Altes Reich und Europàische Staatenwelt 1648-1806. Munich: R. Oldenbourg Vedag, 1990. Pp. viii, 128. DM28. Reviewed by H. Liebel-Weckowicz JAMES J. SHEEHAN. German History 1770-1866. New York: Oxford University Press, 1990. Pp. xvii, 969. $110.00 (CDN). Reviewed by Daniel Moran KINLEY BRAUER and WILLIAM E. WRIGHT, eds. Austria in the Age of the French Revolution 1789-1815. Minneapolis: University of Minnesota, Center for Austrian Studies, 1990. Pp. xxv, 192. $12.00 (US). Reviewed by Christine L. Mueller FRANK GRIFFITH DAWSON. The First Latin American Debt Crisis: The City of London and the 1822-25 Loan Bubble. New Haven and London: Yale University Press, 1990. Pp. xii, 281. $30.00 (US). Reviewed by Neville Thompson JAMES P. RONDA. Astoria and Empire. Lincoln and London: University of Nebraska Press, 1990. Pp. xiv, 400. $25.00 (US). Reviewed by Reginald C. Stuart PATRICIA GRIMSHAW. Paths of Duty: American Missionary Wives in Nineteenth-Century Hawaii. Honolulu: University of Hawaii Press, 1989. Pp. xxiii, 246. $25.00 (US). Reviewed by Chester Raymond Young ALEX ROBERTO HYBEL. How Leaders Reason: US Intervention in the Caribbean Basin and Latin America. Oxford and Cambridge, Mass.: Basil Blackwell, 1900. Pp. x, 326. $44-95 (US) Reviewed by Thomas Schoonover MICHAEL L. KRENN. US Policy toward Economic Nationalism in Latin America, 1917-1929. Wilmington, Del.: Scholarly Resources, 1990. Pp. xxi, 169. $35.00 (US) Reviewed by Thomas Schoonover J. VALERIE FIFER. United States Perceptions of Latin America 1850-1930: A 'New West' South of Capricorn? Manchester Manchester University Press; dist. New York: St. Martin's Press, 1991. Pp. vii, 203. $49.95 (US). Reviewed by Thomas Schoonover DONALD HARMAN AKENSON. Half the World from Home: Perspectives on the Irish in New Zealand 1860-1950. Wellington: Victoria University Press, 1990. Pp. 250. $45.00 (CDN). Reviewed by Hugh Laracy EMMET LARKIN. The Roman Catholic Church and the Home Rule Movement in Ireland, 1870-1874. Dublin: Gill and Macmillan, 1990. Pp. xxi, 416. £35.00. Reviewed by Paul Bew CAROLINE CAHM. Kropotkin and the Rise of Revolutionary Anarchism 1872-1886. New York: Cambridge University Press, 1989. Pp. xii, 372. (49.50 (US). Reviewed by T.R. Ravindranathan MICHAEL L. HADLEY and ROGER SARTY. Tin-Pots and Pirate Ships: Canadian Naval Forces and German Sea Raiders 1880-1918. Montreal and Kingston: McGill-Queen's University Press, 1991. Pp. xvi, 391. $34.95 (CDN). Reviewed by James A. Boutilier DON C. OHADIKE. The Ekumeku Movement: Western Igbo Resistance to the British Conquest of Nigeria, 1883-1914. Athens: Ohio University Press, 1991. Pp. xi, 203. $29.95 (US), cloth; $16.95 (US), paper. Reviewed by John Flint AGATHA RAMM, ed. Beloved Darling Child: Last Letters between Queen Victoria and Her Eldest Daughter 1886-1901. Gloucestershire, UK: Alan Sutton, 1990. 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Diplomatie uni Reichsinteresse: Das Geheimdienstkatkül in der deutschen Amerikapolitik 1914 bis 1917. New York: Peter Lang, 1990. Pp. 435- $73.80 (US). Reviewed by Ulrich Trumpener P.J. FLOOD. France 1914-18: Public Opinion and the War Effort. London: Macmillan, 1990. Pp. xii, 209. £35.00. Reviewed by J.F.V. Keiger RICHARD CONNAUGHTON. 'The Republic of the Ushakovka': Admiral Kolchak and the Allied Intervention in Siberia, 1918-20. London and New York: Roudedge, 1990. Pp. ix, 193. $62.50 (US). Reviewed by David W. McFadden J. CALVITT CLARKE, III. Russia and Italy against Hitler: The Bobhevik-Fascist Rapprochement of the 1930s. Westport, Conn.: Greenwood Press, 1991. Pp. xvii, 218. $45.00 (US). Reviewed by Alan Cassels WILLIAM R. TROTTER. A Frozen Hell: The Russo-Finnish Winter War of 1939-1940. Chapel Hill: Algonquin Books of Chapel Hill, 1991. Pp. xv, 283. $22.95 (US). Reviewed by Marvin Rintala JAMES J. SADKOVICH, ed. Reevaluating Major Naval Combatants of World War II. 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Toronto: University of Toronto Press, 1989. Pp. x, 82. $25.00 (CDN), cloth; $12.95 (CDN), paper. Reviewed by Hector Mackenzie JACQUES DALLOZ. The War in Indo-China 1945-54. Dublin: Gill and Macmillan, 1990. Pp. xi, 280. £27.50. Reviewed by Anthony Short GALIA GOLAN. Soviet Policies in the Middle East from World War Two to Gorbachev. New York: Cambridge University Press, 1990. Pp. viii, 319. $44.50 (US), cloth; $14.95 (US), paper. Reviewed by Michael Fry JENNIFER E. SIMS. Icarus Restrained: An Intellectual History of Nuclear Arms Control, 1945-1960. Boulder, Col.: Westview Press, 1990. Pp. x, 264. $29.95 (US). Reviewed by Robert Malcolmson FRANK M. BUSCHER. The US War Crimes Trial Program in Germany, 1946-1955. Westport, Conn.: Greenwood Press, 1989. Pp. x, 197. $39.95 (US). Reviewed by Priscilla Dale Jones MICHAEL J. COHEN. Truman and Israel. Berkeley: University of California Press, 1990. Pp. xiii, 342. $24.95 (US). Reviewed by Don Peretz SELWYN ILAN TROEN and MOSHE SHEMESH, eds. The Suez-Sinai Crisis 1956: Retrospective and Reappraisal. London: Frank Cass, 1990. Pp. xiv, 395. £30.00. Reviewed by Diane B. Kunz JOHN DARWIN. The End of the British Empire: The Historical Debate. Oxford: Bas